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  • 51. Demirkan, Ayse
    et al.
    van Duijn, Cornelia M.
    Ugocsai, Peter
    Isaacs, Aaron
    Pramstaller, Peter P.
    Liebisch, Gerhard
    Wilson, James F.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Rudan, Igor
    Aulchenko, Yurii S.
    Kirichenko, Anatoly V.
    Janssens, A. Cecile J. W.
    Jansen, Ritsert C.
    Gnewuch, Carsten
    Domingues, Francisco S.
    Pattaro, Cristian
    Wild, Sarah H.
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Polasek, Ozren
    Zorkoltseva, Irina V.
    Hofman, Albert
    Karssen, Lennart C.
    Struchalin, Maksim
    Floyd, James
    Igl, Wilmar
    Biloglav, Zrinka
    Broer, Linda
    Pfeufer, Arne
    Pichler, Irene
    Campbell, Susan
    Zaboli, Ghazal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kolcic, Ivana
    Rivadeneira, Fernando
    Huffman, Jennifer
    Hastie, Nicholas D.
    Uitterlinden, Andre
    Franke, Lude
    Franklin, Christopher S.
    Vitart, Veronique
    Nelson, Christopher P.
    Preuss, Michael
    Bis, Joshua C.
    O'Donnell, Christopher J.
    Franceschini, Nora
    Witteman, Jacqueline C. M.
    Axenovich, Tatiana
    Oostra, Ben A.
    Meitinger, Thomas
    Hicks, Andrew A.
    Hayward, Caroline
    Wright, Alan F.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Campbell, Harry
    Schmitz, Gerd
    Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations2012Inngår i: PLoS Genetics, ISSN 1553-7390, Vol. 8, nr 2, s. e1002490-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.

  • 52.
    den Hoed, Marcel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eijgelsheim, Mark
    Esko, Tonu
    Brundel, Bianca J. J. M.
    Peal, David S.
    Evans, David M.
    Nolte, Ilja M.
    Segre, Ayellet V.
    Holm, Hilma
    Handsaker, Robert E.
    Westra, Harm-Jan
    Johnson, Toby
    Isaacs, Aaron
    Yang, Jian
    Lundby, Alicia
    Zhao, Jing Hua
    Kim, Young Jin
    Go, Min Jin
    Almgren, Peter
    Bochud, Murielle
    Boucher, Gabrielle
    Cornelis, Marilyn C.
    Gudbjartsson, Daniel
    Hadley, David
    van der Harst, Pim
    Hayward, Caroline
    den Heijer, Martin
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Jackson, Anne U.
    Kutalik, Zoltan
    Luan, Jian'an
    Kemp, John P.
    Kristiansson, Kati
    Ladenvall, Claes
    Lorentzon, Mattias
    Montasser, May E.
    Njajou, Omer T.
    O'Reilly, Paul F.
    Padmanabhan, Sandosh
    Pourcain, Beate St.
    Rankinen, Tuomo
    Salo, Perttu
    Tanaka, Toshiko
    Timpson, Nicholas J.
    Vitart, Veronique
    Waite, Lindsay
    Wheeler, William
    Zhang, Weihua
    Draisma, Harmen H. M.
    Feitosa, Mary F.
    Kerr, Kathleen F.
    Lind, Penelope A.
    Mihailov, Evelin
    Onland-Moret, N. Charlotte
    Song, Ci
    Weedon, Michael N.
    Xie, Weijia
    Yengo, Loic
    Absher, Devin
    Albert, Christine M.
    Alonso, Alvaro
    Arking, Dan E.
    de Bakker, Paul I. W.
    Balkau, Beverley
    Barlassina, Cristina
    Benaglio, Paola
    Bis, Joshua C.
    Bouatia-Naji, Nabila
    Brage, Soren
    Chanock, Stephen J.
    Chines, Peter S.
    Chung, Mina
    Darbar, Dawood
    Dina, Christian
    Doerr, Marcus
    Elliott, Paul
    Felix, Stephan B.
    Fischer, Krista
    Fuchsberger, Christian
    de Geus, Eco J. C.
    Goyette, Philippe
    Gudnason, Vilmundur
    Harris, Tamara B.
    Hartikainen, Anna-Liisa
    Havulinna, Aki S.
    Heckbert, Susan R.
    Hicks, Andrew A.
    Hofman, Albert
    Holewijn, Suzanne
    Hoogstra-Berends, Femke
    Hottenga, Jouke-Jan
    Jensen, Majken K.
    Johansson, Asa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Junttila, Juhani
    Kaeaeb, Stefan
    Kanon, Bart
    Ketkar, Shamika
    Khaw, Kay-Tee
    Knowles, Joshua W.
    Kooner, Angrad S.
    Kors, Jan A.
    Kumari, Meena
    Milani, Lili
    Laiho, Paeivi
    Lakatta, Edward G.
    Langenberg, Claudia
    Leusink, Maarten
    Liu, Yongmei
    Luben, Robert N.
    Lunetta, Kathryn L.
    Lynch, Stacey N.
    Markus, Marcello R. P.
    Marques-Vidal, Pedro
    Leach, Irene Mateo
    McArdle, Wendy L.
    McCarroll, Steven A.
    Medland, Sarah E.
    Miller, Kathryn A.
    Montgomery, Grant W.
    Morrison, Alanna C.
    Mueller-Nurasyid, Martina
    Navarro, Pau
    Nelis, Mari
    O'Connell, Jeffrey R.
    O'Donnell, Christopher J.
    Ong, Ken K.
    Newman, Anne B.
    Peters, Annette
    Polasek, Ozren
    Pouta, Anneli
    Pramstaller, Peter P.
    Psaty, Bruce M.
    Rao, Dabeeru C.
    Ring, Susan M.
    Rossin, Elizabeth J.
    Rudan, Diana
    Sanna, Serena
    Scott, Robert A.
    Sehmi, Jaban S.
    Sharp, Stephen
    Shin, Jordan T.
    Singleton, Andrew B.
    Smith, Albert V.
    Soranzo, Nicole
    Spector, Tim D.
    Stewart, Chip
    Stringham, Heather M.
    Tarasov, Kirill V.
    Uitterlinden, Andre G.
    Vandenput, Liesbeth
    Hwang, Shih-Jen
    Whitfield, John B.
    Wijmenga, Cisca
    Wild, Sarah H.
    Willemsen, Gonneke
    Wilson, James F.
    Witteman, Jacqueline C. M.
    Wong, Andrew
    Wong, Quenna
    Jamshidi, Yalda
    Zitting, Paavo
    Boer, Jolanda M. A.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    van Duijn, Cornelia M.
    Ekelund, Ulf
    Forouhi, Nita G.
    Froguel, Philippe
    Hingorani, Aroon
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kivimaki, Mika
    Kronmal, Richard A.
    Kuh, Diana
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Martin, Nicholas G.
    Oostra, Ben A.
    Pedersen, Nancy L.
    Quertermous, Thomas
    Rotter, Jerome I.
    van der Schouw, Yvonne T.
    Verschuren, W. M. Monique
    Walker, Mark
    Albanes, Demetrius
    Arnar, David O.
    Assimes, Themistocles L.
    Bandinelli, Stefania
    Boehnke, Michael
    de Boer, Rudolf A.
    Bouchard, Claude
    Caulfield, W. L. Mark
    Chambers, John C.
    Curhan, Gary
    Cusi, Daniele
    Eriksson, Johan
    Ferrucci, Luigi
    van Gilst, Wiek H.
    Glorioso, Nicola
    de Graaf, Jacqueline
    Groop, Leif
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Hsueh, Wen-Chi
    Hu, Frank B.
    Huikuri, Heikki V.
    Hunter, David J.
    Iribarren, Carlos
    Isomaa, Bo
    Jarvelin, Marjo-Riitta
    Jula, Antti
    Kahonen, Mika
    Kiemeney, Lambertus A.
    van der Klauw, Melanie M.
    Kooner, Jaspal S.
    Kraft, Peter
    Iacoviello, Licia
    Lehtimaki, Terho
    Lokki, Marja-Liisa L.
    Mitchell, Braxton D.
    Navis, Gerjan
    Nieminen, Markku S.
    Ohlsson, Claes
    Poulter, Neil R.
    Qi, Lu
    Raitakari, Olli T.
    Rimm, Eric B.
    Rioux, John D.
    Rizzi, Federica
    Rudan, Igor
    Salomaa, Veikko
    Sever, Peter S.
    Shields, Denis C.
    Shuldiner, Alan R.
    Sinisalo, Juha
    Stanton, Alice V.
    Stolk, Ronald P.
    Strachan, David P.
    Tardif, Jean-Claude
    Thorsteinsdottir, Unnur
    Tuomilehto, Jaako
    van Veldhuisen, Dirk J.
    Virtamo, Jarmo
    Viikari, Jorma
    Vollenweider, Peter
    Waeber, Gerard
    Widen, Elisabeth
    Cho, Yoon Shin
    Olsen, Jesper V.
    Visscher, Peter M.
    Willer, Cristen
    Franke, Lude
    Erdmann, Jeanette
    Thompson, John R.
    Pfeufer, Arne
    Sotoodehnia, Nona
    Newton-Cheh, Christopher
    Ellinor, Patrick T.
    Stricker, Bruno H. Ch
    Metspalu, Andres
    Perola, Markus
    Beckmann, Jacques S.
    Smith, George Davey
    Stefansson, Kari
    Wareham, Nicholas J.
    Munroe, Patricia B.
    Sibon, Ody C. M.
    Milan, David J.
    Snieder, Harold
    Samani, Nilesh J.
    Loos, Ruth J. F.
    Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders2013Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 6, s. 621-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

  • 53. Devoto, M.
    et al.
    Castagnola, S.
    Saha, N.
    Chetsanga, C.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Romeo, G.
    Screening for the major cystic fibrosis mutation in non-Caucasian populations1991Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 49, nr 4, s. 903-4Artikkel i tidsskrift (Fagfellevurdert)
  • 54.
    Divne, AM
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rasten-Almqvist, P
    Rajs, J
    Gyllensten, U
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Allen, M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Analysis of the mitochondrial genome in sudden infant death syndrome.2003Inngår i: Acta Paediatr, Vol. 92, s. 386-Artikkel i tidsskrift (Fagfellevurdert)
  • 55. Do, Ron
    et al.
    Willer, Cristen J.
    Schmidt, Ellen M.
    Sengupta, Sebanti
    Gao, Chi
    Peloso, Gina M.
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kanoni, Stavroula
    Ganna, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chen, Jin
    Buchkovich, Martin L.
    Mora, Samia
    Beckmann, Jacques S.
    Bragg-Gresham, Jennifer L.
    Chang, Hsing-Yi
    Demirkan, Ayse
    Den Hertog, Heleen M.
    Donnelly, Louise A.
    Ehret, Georg B.
    Esko, Tonu
    Feitosa, Mary F.
    Ferreira, Teresa
    Fischer, Krista
    Fontanillas, Pierre
    Fraser, Ross M.
    Freitag, Daniel F.
    Gurdasani, Deepti
    Heikkila, Kauko
    Hyppoenen, Elina
    Isaacs, Aaron
    Jackson, Anne U.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Johnson, Toby
    Kaakinen, Marika
    Kettunen, Johannes
    Kleber, Marcus E.
    Li, Xiaohui
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Magnusson, Patrik K. E.
    Mangino, Massimo
    Mihailov, Evelin
    Montasser, May E.
    Mueller-Nurasyid, Martina
    Nolte, Ilja M.
    O'Connell, Jeffrey R.
    Palmer, Cameron D.
    Perola, Markus
    Petersen, Ann-Kristin
    Sanna, Serena
    Saxena, Richa
    Service, Susan K.
    Shah, Sonia
    Shungin, Dmitry
    Sidore, Carlo
    Song, Ci
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strawbridge, Rona J.
    Surakka, Ida
    Tanaka, Toshiko
    Teslovich, Tanya M.
    Thorleifsson, Gudmar
    Van den Herik, Evita G.
    Voight, Benjamin F.
    Volcik, Kelly A.
    Waite, Lindsay L.
    Wong, Andrew
    Wu, Ying
    Zhang, Weihua
    Absher, Devin
    Asiki, Gershim
    Barroso, Ines
    Been, Latonya F.
    Bolton, Jennifer L.
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Burnett, Mary S.
    Cesana, Giancarlo
    Dimitriou, Maria
    Doney, Alex S. F.
    Doering, Angela
    Elliott, Paul
    Epstein, Stephen E.
    Eyjolfsson, Gudmundur Ingi
    Gigante, Bruna
    Goodarzi, Mark O.
    Grallert, Harald
    Gravito, Martha L.
    Groves, Christopher J.
    Hallmans, Goran
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Hernandez, Dena
    Hicks, Andrew A.
    Holm, Hilma
    Hung, Yi-Jen
    Illig, Thomas
    Jones, Michelle R.
    Kaleebu, Pontiano
    Kastelein, John J. P.
    Khaw, Kay-Tee
    Kim, Eric
    Klopp, Norman
    Komulainen, Pirjo
    Kumari, Meena
    Langenberg, Claudia
    Lehtimaki, Terho
    Lin, Shih-Yi
    Lindstrom, Jaana
    Loos, Ruth J. F.
    Mach, Francois
    McArdle, Wendy L.
    Meisinger, Christa
    Mitchell, Braxton D.
    Mueller, Gabrielle
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nieminen, Tuomo V. M.
    Nsubuga, Rebecca N.
    Olafsson, Isleifur
    Ong, Ken K.
    Palotie, Aarno
    Papamarkou, Theodore
    Pomilla, Cristina
    Pouta, Anneli
    Rader, Daniel J.
    Reilly, Muredach P.
    Ridker, Paul M.
    Rivadeneira, Fernando
    Rudan, Igor
    Ruokonen, Aimo
    Samani, Nilesh
    Scharnagl, Hubert
    Seeley, Janet
    Silander, Kaisa
    Stancakova, Alena
    Stirrups, Kathleen
    Swift, Amy J.
    Tiret, Laurence
    Uitterlinden, Andre G.
    van Pelt, L. Joost
    Vedantam, Sailaja
    Wainwright, Nicholas
    Wijmenga, Cisca
    Wild, Sarah H.
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wilson, James F.
    Young, Elizabeth H.
    Zhao, Jing Hua
    Adair, Linda S.
    Arveiler, Dominique
    Assimes, Themistocles L.
    Bandinelli, Stefania
    Bennett, Franklyn
    Bochud, Murielle
    Boehm, Bernhard O.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Bornstein, Stefan R.
    Bovet, Pascal
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chambers, John C.
    Chen, Yii-Der Ida
    Collins, Francis S.
    Cooper, Richard S.
    Danesh, John
    Dedoussis, George
    de Faire, Ulf
    Feranil, Alan B.
    Ferrieres, Jean
    Ferrucci, Luigi
    Freimer, Nelson B.
    Gieger, Christian
    Groop, Leif C.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Hamsten, Anders
    Harris, Tamara B.
    Hingorani, Aroon
    Hirschhorn, Joel N.
    Hofman, Albert
    Hovingh, G. Kees
    Hsiung, Chao Agnes
    Humphries, Steve E.
    Hunt, Steven C.
    Hveem, Kristian
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Jula, Antti
    Kahonen, Mika
    Kaprio, Jaakko
    Kesaniemi, Antero
    Kivimaki, Mika
    Kooner, Jaspal S.
    Koudstaal, Peter J.
    Krauss, Ronald M.
    Kuh, Diana
    Kuusisto, Johanna
    Kyvik, Kirsten O.
    Laakso, Markku
    Lakka, Timo A.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M.
    Martin, Nicholas G.
    Maerz, Winfried
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Metspalu, Andres
    Moilanen, Leena
    Morris, Andrew D.
    Munroe, Patricia B.
    Njolstad, Inger
    Pedersen, Nancy L.
    Power, Chris
    Pramstaller, Peter P.
    Price, Jackie F.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rauramaa, Rainer
    Saleheen, Danish
    Salomaa, Veikko
    Sanghera, Dharambir K.
    Saramies, Jouko
    Schwarz, Peter E. H.
    Sheu, Wayne H-H
    Shuldiner, Alan R.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Spector, Tim D.
    Stefansson, Kari
    Strachan, David P.
    Tayo, Bamidele O.
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van Duijn, Cornelia M.
    Vollenweider, Peter
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Wareham, Nicholas J.
    Whitfield, John B.
    Wolffenbuttel, Bruce H. R.
    Altshuler, David
    Ordovas, Jose M.
    Boerwinkle, Eric
    Palmer, Colin N. A.
    Thorsteinsdottir, Unnur
    Chasman, Daniel I.
    Rotter, Jerome I.
    Franks, Paul W.
    Ripatti, Samuli
    Cupples, L. Adrienne
    Sandhu, Manjinder S.
    Rich, Stephen S.
    Boehnke, Michael
    Deloukas, Panos
    Mohlke, Karen L.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abecasis, Goncalo R.
    Daly, Mark J.
    Neale, Benjamin M.
    Kathiresan, Sekar
    Common variants associated with plasma triglycerides and risk for coronary artery disease2013Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 11, s. 1345-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

  • 56.
    Edlund, Karolina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Larsson, Ola
    Ameur, Adam
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bunikis, Ignas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Leroy, Bernard
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Soussi, Thierry
    Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors2012Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 24, s. 9551-9556Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer mutation databases are expected to play central roles in personalized medicine by providing targets for drug development and biomarkers to tailor treatments to each patient. The accuracy of reported mutations is a critical issue that is commonly overlooked, which leads to mutation databases that include a sizable number of spurious mutations, either sequencing errors or passenger mutations. Here we report an analysis of the latest version of the TP53 mutation database, including 34,453 mutations. By using several data-driven methods on multiple independent quality criteria, we obtained a quality score for each report contributing to the database. This score can now be used to filter for high-confidence mutations and reports within the database. Sequencing the entire TP53 gene from various types of cancer using next-generation sequencing with ultradeep coverage validated our approach for curation. In summary, 9.7% of all collected studies, mostly comprising numerous tumors with multiple infrequent TP53 mutations, should be excluded when analyzing TP53 mutations. Thus, by combining statistical and experimental analyses, we provide a curated mutation database for TP53 mutations and a framework for mutation database analysis.

  • 57. Ehret, Georg B.
    et al.
    Munroe, Patricia B.
    Rice, Kenneth M.
    Bochud, Murielle
    Johnson, Andrew D.
    Chasman, Daniel I.
    Smith, Albert V.
    Tobin, Martin D.
    Verwoert, Germaine C.
    Hwang, Shih-Jen
    Pihur, Vasyl
    Vollenweider, Peter
    O'Reilly, Paul F.
    Amin, Najaf
    Bragg-Gresham, Jennifer L.
    Teumer, Alexander
    Glazer, Nicole L.
    Launer, Lenore
    Zhao, Jing Hua
    Aulchenko, Yurii
    Heath, Simon
    Sober, Siim
    Parsa, Afshin
    Luan, Jian'an
    Arora, Pankaj
    Dehghan, Abbas
    Zhang, Feng
    Lucas, Gavin
    Hicks, Andrew A.
    Jackson, Anne U.
    Peden, John F.
    Tanaka, Toshiko
    Wild, Sarah H.
    Rudan, Igor
    Igl, Wilmar
    Milaneschi, Yuri
    Parker, Alex N.
    Fava, Cristiano
    Chambers, John C.
    Fox, Ervin R.
    Kumari, Meena
    Go, Min Jin
    van der Harst, Pim
    Kao, Wen Hong Linda
    Sjogren, Marketa
    Vinay, D. G.
    Alexander, Myriam
    Tabara, Yasuharu
    Shaw-Hawkins, Sue
    Whincup, Peter H.
    Liu, Yongmei
    Shi, Gang
    Kuusisto, Johanna
    Tayo, Bamidele
    Seielstad, Mark
    Sim, Xueling
    Nguyen, Khanh-Dung Hoang
    Lehtimaki, Terho
    Matullo, Giuseppe
    Wu, Ying
    Gaunt, Tom R.
    Onland-Moret, N. Charlotte
    Cooper, Matthew N.
    Platou, Carl G. P.
    Org, Elin
    Hardy, Rebecca
    Dahgam, Santosh
    Palmen, Jutta
    Vitart, Veronique
    Braund, Peter S.
    Kuznetsova, Tatiana
    Uiterwaal, Cuno S. P. M.
    Adeyemo, Adebowale
    Palmas, Walter
    Campbell, Harry
    Ludwig, Barbara
    Tomaszewski, Maciej
    Tzoulaki, Ioanna
    Palmer, Nicholette D.
    Aspelund, Thor
    Garcia, Melissa
    Chang, Yen-Pei C.
    O'Connell, Jeffrey R.
    Steinle, Nanette I.
    Grobbee, Diederick E.
    Arking, Dan E.
    Kardia, Sharon L.
    Morrison, Alanna C.
    Hernandez, Dena
    Najjar, Samer
    McArdle, Wendy L.
    Hadley, David
    Brown, Morris J.
    Connell, John M.
    Hingorani, Aroon D.
    Day, Ian N. M.
    Lawlor, Debbie A.
    Beilby, John P.
    Lawrence, Robert W.
    Clarke, Robert
    Hopewell, Jemma C.
    Ongen, Halit
    Dreisbach, Albert W.
    Li, Yali
    Young, J. Hunter
    Bis, Joshua C.
    Kahonen, Mika
    Viikari, Jorma
    Adair, Linda S.
    Lee, Nanette R.
    Chen, Ming-Huei
    Olden, Matthias
    Pattaro, Cristian
    Bolton, Judith A. Hoffman
    Koettgen, Anna
    Bergmann, Sven
    Mooser, Vincent
    Chaturvedi, Nish
    Frayling, Timothy M.
    Islam, Muhammad
    Jafar, Tazeen H.
    Erdmann, Jeanette
    Kulkarni, Smita R.
    Bornstein, Stefan R.
    Graessler, Juergen
    Groop, Leif
    Voight, Benjamin F.
    Kettunen, Johannes
    Howard, Philip
    Taylor, Andrew
    Guarrera, Simonetta
    Ricceri, Fulvio
    Emilsson, Valur
    Plump, Andrew
    Barroso, Ine S.
    Khaw, Kay-Tee
    Weder, Alan B.
    Hunt, Steven C.
    Sun, Yan V.
    Bergman, Richard N.
    Collins, Francis S.
    Bonnycastle, Lori L.
    Scott, Laura J.
    Stringham, Heather M.
    Peltonen, Leena
    Perola, Markus
    Vartiainen, Erkki
    Brand, Stefan-Martin
    Staessen, Jan A.
    Wang, Thomas J.
    Burton, Paul R.
    Artigas, Maria Soler
    Dong, Yanbin
    Snieder, Harold
    Wang, Xiaoling
    Zhu, Haidong
    Lohman, Kurt K.
    Rudock, Megan E.
    Heckbert, Susan R.
    Smith, Nicholas L.
    Wiggins, Kerri L.
    Doumatey, Ayo
    Shriner, Daniel
    Veldre, Gudrun
    Viigimaa, Margus
    Kinra, Sanjay
    Prabhakaran, Dorairaj
    Tripathy, Vikal
    Langefeld, Carl D.
    Rosengren, Annika
    Thelle, Dag S.
    Corsi, Anna Maria
    Singleton, Andrew
    Forrester, Terrence
    Hilton, Gina
    McKenzie, Colin A.
    Salako, Tunde
    Iwai, Naoharu
    Kita, Yoshikuni
    Ogihara, Toshio
    Ohkubo, Takayoshi
    Okamura, Tomonori
    Ueshima, Hirotsugu
    Umemura, Satoshi
    Eyheramendy, Susana
    Meitinger, Thomas
    Wichmann, H. -Erich
    Cho, Yoon Shin
    Kim, Hyung-Lae
    Lee, Jong-Young
    Scott, James
    Sehmi, Joban S.
    Zhang, Weihua
    Hedblad, Bo
    Nilsson, Peter
    Smith, George Davey
    Wong, Andrew
    Narisu, Narisu
    Stancakova, Alena
    Raffel, Leslie J.
    Yao, Jie
    Kathiresan, Sekar
    O'Donnell, Christopher J.
    Schwartz, Stephen M.
    Ikram, M. Arfan
    Longstreth, W. T., Jr.
    Mosley, Thomas H.
    Seshadri, Sudha
    Shrine, Nick R. G.
    Wain, Louise V.
    Morken, Mario A.
    Swift, Amy J.
    Laitinen, Jaana
    Prokopenko, Inga
    Zitting, Paavo
    Cooper, Jackie A.
    Humphries, Steve E.
    Danesh, John
    Rasheed, Asif
    Goel, Anuj
    Hamsten, Anders
    Watkins, Hugh
    Bakker, Stephan J. L.
    van Gilst, Wiek H.
    Janipalli, Charles S.
    Mani, K. Radha
    Yajnik, Chittaranjan S.
    Hofman, Albert
    Mattace-Raso, Francesco U. S.
    Oostra, Ben A.
    Demirkan, Ayse
    Isaacs, Aaron
    Rivadeneira, Fernando
    Lakatta, Edward G.
    Orru, Marco
    Scuteri, Angelo
    Ala-Korpela, Mika
    Kangas, Antti J.
    Lyytikainen, Leo-Pekka
    Soininen, Pasi
    Tukiainen, Taru
    Wurtz, Peter
    Ong, Rick Twee-Hee
    Doerr, Marcus
    Kroemer, Heyo K.
    Voelker, Uwe
    Voelzke, Henry
    Galan, Pilar
    Hercberg, Serge
    Lathrop, Mark
    Zelenika, Diana
    Deloukas, Panos
    Mangino, Massimo
    Spector, Tim D.
    Zhai, Guangju
    Meschia, James F.
    Nalls, Michael A.
    Sharma, Pankaj
    Terzic, Janos
    Kumar, M. V. Kranthi
    Denniff, Matthew
    Zukowska-Szczechowska, Ewa
    Wagenknecht, Lynne E.
    Fowkes, F. Gerald R.
    Charchar, Fadi J.
    Schwarz, Peter E. H.
    Hayward, Caroline
    Guo, Xiuqing
    Rotimi, Charles
    Bots, Michiel L.
    Brand, Eva
    Samani, Nilesh J.
    Polasek, Ozren
    Talmud, Philippa J.
    Nyberg, Fredrik
    Kuh, Diana
    Laan, Maris
    Hveem, Kristian
    Palmer, Lyle J.
    van der Schouw, Yvonne T.
    Casas, Juan P.
    Mohlke, Karen L.
    Vineis, Paolo
    Raitakari, Olli
    Ganesh, Santhi K.
    Wong, Tien Y.
    Tai, E. Shyong
    Cooper, Richard S.
    Laakso, Markku
    Rao, Dabeeru C.
    Harris, Tamara B.
    Morris, Richard W.
    Dominiczak, Anna F.
    Kivimaki, Mika
    Marmot, Michael G.
    Miki, Tetsuro
    Saleheen, Danish
    Chandak, Giriraj R.
    Coresh, Josef
    Navis, Gerjan
    Salomaa, Veikko
    Han, Bok-Ghee
    Zhu, Xiaofeng
    Kooner, Jaspal S.
    Melander, Olle
    Ridker, Paul M.
    Bandinelli, Stefania
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wright, Alan F.
    Wilson, James F.
    Ferrucci, Luigi
    Farrall, Martin
    Tuomilehto, Jaakko
    Pramstaller, Peter P.
    Elosua, Roberto
    Soranzo, Nicole
    Sijbrands, Eric J. G.
    Altshuler, David
    Loos, Ruth J. F.
    Shuldiner, Alan R.
    Gieger, Christian
    Meneton, Pierre
    Uitterlinden, Andre G.
    Wareham, Nicholas J.
    Gudnason, Vilmundur
    Rotter, Jerome I.
    Rettig, Rainer
    Uda, Manuela
    Strachan, David P.
    Witteman, Jacqueline C. M.
    Hartikainen, Anna-Liisa
    Beckmann, Jacques S.
    Boerwinkle, Eric
    Vasan, Ramachandran S.
    Boehnke, Michael
    Larson, Martin G.
    Jarvelin, Marjo-Riitta
    Psaty, Bruce M.
    Abecasis, Goncalo R.
    Chakravarti, Aravinda
    Elliott, Paul
    van Duijn, Cornelia M.
    Newton-Cheh, Christopher
    Levy, Daniel
    Caulfield, Mark J.
    Johnson, Toby
    Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk2011Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 478, nr 7367, s. 103-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

  • 58.
    Ek, Weronica E.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ahsan, Muhammad
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02115 USA..
    Moffatt, Miriam F.
    Imperial Coll London, Natl Heart & Lung Inst, London SW3 6LY, England..
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies2017Inngår i: Epigenomics, ISSN 1750-1911, Vol. 9, nr 4, s. 407-418Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: Epigenetic mechanisms are critical for normal immune development and epigenetic alterations might therefore be possible contributors to immune diseases. To investigate if DNA methylation in whole blood is associated with total and allergen-specific IgE levels.

    METHODS: We performed an epigenome-wide association study to investigate the association between DNA methylation and IgE level, allergen-specific IgE and self-reported immune diseases and allergies in 728 individuals.

    RESULTS: We identified and replicated 15 CpG sites associated with IgE, mapping to biologically relevant genes, including ACOT7, ILR5A, KCNH2, PRG2 and EPX. A total of 331 loci were associated with allergen-specific IgE, but none of these CpG sites were associated with self-reported allergies and immune diseases.

    CONCLUSION: This study shows that IgE levels are associated with DNA methylation levels at numerous CpG sites, which might provide new leads for investigating the links between IgE and allergic inflammation.

  • 59.
    Ek, Weronica E
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia M
    Mahajan, Anubha
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-152016Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, nr 4, s. 817-827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.

  • 60.
    Ek, Weronica E
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karlsson, Torgny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genetic variants influencing phenotypic variance heterogeneity2018Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, nr 5, s. 799-810Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene x gene or gene x environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P < 9.4 x 10(-11)). This is a relatively low number compared to 52 335 CpG sites for which SNPs were associated with mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

  • 61.
    Engelmark, Malin
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Medicinsk Genetik.
    Beskow, Anna
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Jessica
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer.2004Inngår i: Hum Mol Genet, ISSN 0964-6906, Vol. 13, nr 17, s. 1951-8Artikkel i tidsskrift (Annet vitenskapelig)
  • 62.
    Engelmark, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ivansson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wyöni, Per-Ivan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ingman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis2008Inngår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 123, nr 5, s. 437-443Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cervical cancer is a multifactorial disease influenced by both environmental and genetic factors. We have previously found linkage to 9q32 in a genomewide scan of affected sib-pairs (ASPs) with cervical cancer and to the thymic stromal co-transporter (TSCOT), a candidate gene in this region. Here we examined the contribution of 9q32 and TSCOT to cervical cancer susceptibility using at larger material of 641 ASPs, 278 of which were included in the earlier genome-scan. Since heritable forms of cancer frequently show stronger genetic effects in families with early onset of disease, we stratified the ASPs into two groups based on mean age at diagnosis (MAAD) within sib-pairs. Surprisingly, ASPs with high MAAD (30.5-47.5 years) showed increased sharing at all microsatellite markers at 9q31.1-33.1 and linkage signals of up to MLS = 2.74 for TSCOT SNPs, while ASPs with low MAAD (19-30 years) showed no deviation from random genetic sharing (MLS = 0.00). The difference in allelic sharing between the two MAAD strata was significant (P < 0.005) and is not likely to be explained by the HLA haplotype, a previously known genetic susceptibility factor for cervical cancer. Our results indicate locus heterogeneity in the susceptibility to cervical cancer between the two strata, with polymorphisms in the 9q32 region mainly showing an effect in women with high MAAD.

  • 63.
    Engelmark, Malin T.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ivansson, Emma L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Jessica J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Inger M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Beskow, Anna H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Patrik K. E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Identification of susceptibility loci for cervical carcinoma by genome scan of affected sib-pairs2006Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 15, nr 22, s. 3351-3360Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cervical cancer is caused by a combination of environmental and genetic risk factors. Infection by oncogenic types of human papillomavirus is recognized as the major environmental risk factor and epidemiological studies indicate that host genetic factors predispose to disease development. A number of genetic susceptibility factors have been proposed, but with exception of the human leukocyte antigen CHLA, class II, have not shown consistent results among studies. We have performed the first genomewide linkage scan using 278 affected sib-pairs to identify loci involved in susceptibility to cervical cancer. A two-step qualitative non-parametric linkage analysis using 387 microsatellites with an average spacing of 10.5 cM revealed excess allelic sharing at nine regions on eight chromosomes. These regions were further analysed with 125 markers to increase the map density to 1.28 cM. Nominal significant linkage was found for three of the nine loci [9q32 (maximum lod-score, MLS) =1.95, P < 0.002), 12q24 (MLS=1.25, P < 0.015) and 16q24 (MLS=1.35, P < 0.012)]. These three regions have previously been connected to human cancers that share characteristics with cervical carcinoma, such as esophageal cancer and Hodgkin's lymphoma. A number of candidate genes involved in defence against viral infections, immune response and tumour suppression are found in these regions. One such gene is the thymic stromal co-transporter (TSCOT). Analyses of TSCOT single nucleotide polymorphisms further strengthen the linkage to this region (MLS=2.40, P < 0.001). We propose that the 9q32 region contains susceptibility locus for cervical cancer and that TSCOT is a candidate gene potentially involved in the genetic predisposition to this disease.

  • 64.
    Engelmark, Malin T
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Medicinsk Genetik.
    Renkema, Kirsten Y
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf B
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    No evidence of the involvement of the Fas -670 promoter polymorphism in cervical cancer in situ.2004Inngår i: Int J Cancer, ISSN 0020-7136, Vol. 112, nr 6, s. 1084-5Artikkel i tidsskrift (Annet vitenskapelig)
  • 65.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Omega-3 and omega-6 fatty acids are more efficiently synthesized in populations having a high frequency of the derived FADS-haplotype2013Inngår i: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 72, nr Suppl. 1, s. 511-512Artikkel i tidsskrift (Fagfellevurdert)
  • 66.
    Enroth, Stefan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Berggrund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lycke, Maria
    Broberg, John
    Lundberg, Martin
    Assarsson, Erika
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Sundfeldt, Karin
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer2019Inngår i: Communications biology, ISSN 2399-3642, Vol. 2, artikkel-id 221Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.

  • 67.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berggrund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lycke, Maria
    Gothenburg Univ, Inst Clin Sci, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden.
    Lundberg, Martin
    OLINK Prote, Uppsala Sci Pk, S-75183 Uppsala, Sweden.
    Assarsson, Erika
    OLINK Prote, Uppsala Sci Pk, S-75183 Uppsala, Sweden.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Sundfeldt, Karin
    Gothenburg Univ, Inst Clin Sci, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer2018Inngår i: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 15, artikkel-id 38Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening.

    Methods: In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n=106), endometrial cancer (n=74), benign ovarian tumors (n=150) and healthy population controls (n=399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n=280), endometrial cancer (n=228), women with benign ovarian tumors (n=76) and healthy controls (n=57).

    Results: In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC=0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p=9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC=0.89).

    Conclusion: The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination.

  • 68.
    Enroth, Stefan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Dahlbom, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Hansson, Tony
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Prevalence and sensitization of atopic allergy and coeliac disease in the Northern Sweden Population Health Study2013Inngår i: International Journal of Circumpolar Health, ISSN 2242-3982, E-ISSN 2242-3982, Vol. 72, s. 21403-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Atopic allergy is effected by a number of environmental exposures, such as dry air and time spent outdoors, but there are few estimates of the prevalence in populations from sub-arctic areas.

    OBJECTIVE:

    To determine the prevalence and severity of symptoms of food, inhalation and skin-related allergens and coeliac disease (CD) in the sub-arctic region of Sweden. To study the correlation between self-reported allergy and allergy test results. To estimate the heritability of these estimates.

    STUDY DESIGN:

    The study was conducted in Karesuando and Soppero in Northern Sweden as part of the Northern Sweden Population Health Study (n=1,068). We used a questionnaire for self-reported allergy and CD status and measured inhalation-related allergens using Phadiatop, food-related allergens using the F×5 assay and IgA and IgG antibodies against tissue transglutaminase (anti-tTG) to indicate prevalence of CD.

    RESULTS:

    The prevalence of self-reported allergy was very high, with 42.3% reporting mild to severe allergy. Inhalation-related allergy was reported in 26.7%, food-related allergy in 24.9% and skin-related allergy in 2.4% of the participants. Of inhalation-related allergy, 11.0% reported reactions against fur and 14.6% against pollen/grass. Among food-related reactions, 14.9% reported milk (protein and lactose) as the cause. The IgE measurements showed that 18.4% had elevated values for inhalation allergens and 11.7% for food allergens. Self-reported allergies and symptoms were positively correlated (p<0.01) with age- and sex-corrected inhalation allergens. Allergy prevalence was inversely correlated with age and number of hours spent outdoors. High levels of IgA and IgG anti-tTG antibodies, CD-related allergens, were found in 1.4 and 0.6% of participants, respectively. All allergens were found to be significantly (p<3 e-10) heritable, with estimated heritabilities ranging from 0.34 (F×5) to 0.65 (IgA).

    CONCLUSIONS:

    Self-reported allergy correlated well with the antibody measurements. The prevalence of allergy was highest in the young and those working inside. Heritability of atopy and sensitization was high. The prevalence of CD-related autoantibodies was high and did not coincide with the self-reported allergy.

  • 69.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Enroth, Sofia Bosdotter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Effect of genetic and environmental factors on protein biomarkers for common non-communicable disease and use of personally normalized plasma protein profiles (PNPPP)2015Inngår i: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 20, nr 6-7, s. 355-364Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance.Materials and methods: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases.Results: Genetic and lifestyle factors explained 20-88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%.Conclusion: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.

  • 70.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Sofia Bosdotter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Protein profiling reveals consequences of lifestyle choices on predicted biological aging2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 17282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount. This method can be applied to dried blood spots and may thus be useful in forensic medicine to provide basic anthropometrical measures for an individual based on a biological evidence sample.

  • 71.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Enroth, Sofia Bosdotter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Protein profiling reveals consequences of lifestyle choices on predicted biological aging2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 17282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount. This method can be applied to dried blood spots and may thus be useful in forensic medicine to provide basic anthropometrical measures for an individual based on a biological evidence sample.

  • 72.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hallmans, Göran
    Umea Univ, Dept Biobank Res, SE-90187 Umea, Sweden..
    Grankvist, Kjell
    Umea Univ, Dept Med Biosci, Clin Chem, SE-90185 Umea, Sweden..
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations2016Inngår i: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, s. 309-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8-34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1-33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

  • 73.
    Enroth, Stefan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs2014Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. 4684-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ideal biomarkers used for disease diagnosis should display deviating levels in affected individuals only and be robust to factors unrelated to the disease. Here we show the impact of genetic, clinical and lifestyle factors on circulating levels of 92 protein biomarkers for cancer and inflammation, using a population-based cohort of 1,005 individuals. For 75% of the biomarkers, the levels are significantly heritable and genome-wide association studies identifies 16 novel loci and replicate 2 previously known loci with strong effects on one or several of the biomarkers with P-values down to 4.4 × 10−58. Integrative analysis attributes as much as 56.3% of the observed variance to non-disease factors. We propose that information on the biomarker-specific profile of major genetic, clinical and lifestyle factors should be used to establish personalized clinical cutoffs, and that this would increase the sensitivity of using biomarkers for prediction of clinical end points.

  • 74.
    Enroth, Stefan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Maturi, Varun
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Berggrund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Med Prod Agcy, POB 26, SE-75103 Uppsala, Sweden..
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 5531Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two-stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management.

  • 75. Erlich, Henry
    et al.
    Bergström, Tomas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Stoneking, Mark
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    HLA sequence polymorphism and the origin of humans.1996Inngår i: Science, ISSN 0036-8075, Vol. 274, nr 5292, s. 1552-4Artikkel i tidsskrift (Fagfellevurdert)
  • 76. Evangelou, Evangelos
    et al.
    Warren, Helen R
    Mosen-Ansorena, David
    Mifsud, Borbala
    Pazoki, Raha
    Gao, He
    Ntritsos, Georgios
    Dimou, Niki
    Cabrera, Claudia P
    Karaman, Ibrahim
    Ng, Fu Liang
    Evangelou, Marina
    Witkowska, Katarzyna
    Tzanis, Evan
    Hellwege, Jacklyn N
    Giri, Ayush
    Velez Edwards, Digna R
    Sun, Yan V
    Cho, Kelly
    Gaziano, J Michael
    Wilson, Peter W F
    Tsao, Philip S
    Kovesdy, Csaba P
    Esko, Tonu
    Mägi, Reedik
    Milani, Lili
    Almgren, Peter
    Boutin, Thibaud
    Debette, Stéphanie
    Ding, Jun
    Giulianini, Franco
    Holliday, Elizabeth G
    Jackson, Anne U
    Li-Gao, Ruifang
    Lin, Wei-Yu
    Luan, Jian'an
    Mangino, Massimo
    Oldmeadow, Christopher
    Prins, Bram Peter
    Qian, Yong
    Sargurupremraj, Muralidharan
    Shah, Nabi
    Surendran, Praveen
    Thériault, Sébastien
    Verweij, Niek
    Willems, Sara M
    Zhao, Jing-Hua
    Amouyel, Philippe
    Connell, John
    de Mutsert, Renée
    Doney, Alex S F
    Farrall, Martin
    Menni, Cristina
    Morris, Andrew D
    Noordam, Raymond
    Paré, Guillaume
    Poulter, Neil R
    Shields, Denis C
    Stanton, Alice
    Thom, Simon
    Abecasis, Gonçalo
    Amin, Najaf
    Arking, Dan E
    Ayers, Kristin L
    Barbieri, Caterina M
    Batini, Chiara
    Bis, Joshua C
    Blake, Tineka
    Bochud, Murielle
    Boehnke, Michael
    Boerwinkle, Eric
    Boomsma, Dorret I
    Bottinger, Erwin P
    Braund, Peter S
    Brumat, Marco
    Campbell, Archie
    Campbell, Harry
    Chakravarti, Aravinda
    Chambers, John C
    Chauhan, Ganesh
    Ciullo, Marina
    Cocca, Massimiliano
    Collins, Francis
    Cordell, Heather J
    Davies, Gail
    de Borst, Martin H
    de Geus, Eco J
    Deary, Ian J
    Deelen, Joris
    Del Greco M, Fabiola
    Demirkale, Cumhur Yusuf
    Dörr, Marcus
    Ehret, Georg B
    Elosua, Roberto
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Erzurumluoglu, A Mesut
    Ferreira, Teresa
    Frånberg, Mattias
    Franco, Oscar H
    Gandin, Ilaria
    Gasparini, Paolo
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gieger, Christian
    Girotto, Giorgia
    Goel, Anuj
    Gow, Alan J
    Gudnason, Vilmundur
    Guo, Xiuqing
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hamsten, Anders
    Harris, Tamara B
    Harris, Sarah E
    Hartman, Catharina A
    Havulinna, Aki S
    Hicks, Andrew A
    Hofer, Edith
    Hofman, Albert
    Hottenga, Jouke-Jan
    Huffman, Jennifer E
    Hwang, Shih-Jen
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    James, Alan
    Jansen, Rick
    Jarvelin, Marjo-Riitta
    Joehanes, Roby
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johnson, Andrew D
    Joshi, Peter K
    Jousilahti, Pekka
    Jukema, J Wouter
    Jula, Antti
    Kähönen, Mika
    Kathiresan, Sekar
    Keavney, Bernard D
    Khaw, Kay-Tee
    Knekt, Paul
    Knight, Joanne
    Kolcic, Ivana
    Kooner, Jaspal S
    Koskinen, Seppo
    Kristiansson, Kati
    Kutalik, Zoltan
    Laan, Maris
    Larson, Marty
    Launer, Lenore J
    Lehne, Benjamin
    Lehtimäki, Terho
    Liewald, David C M
    Lin, Li
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M
    Liu, YongMei
    Loos, Ruth J F
    Lopez, Lorna M
    Lu, Yingchang
    Lyytikäinen, Leo-Pekka
    Mahajan, Anubha
    Mamasoula, Chrysovalanto
    Marrugat, Jaume
    Marten, Jonathan
    Milaneschi, Yuri
    Morgan, Anna
    Morris, Andrew P
    Morrison, Alanna C
    Munson, Peter J
    Nalls, Mike A
    Nandakumar, Priyanka
    Nelson, Christopher P
    Niiranen, Teemu
    Nolte, Ilja M
    Nutile, Teresa
    Oldehinkel, Albertine J
    Oostra, Ben A
    O'Reilly, Paul F
    Org, Elin
    Padmanabhan, Sandosh
    Palmas, Walter
    Palotie, Aarno
    Pattie, Alison
    Penninx, Brenda W J H
    Perola, Markus
    Peters, Annette
    Polasek, Ozren
    Pramstaller, Peter P
    Nguyen, Quang Tri
    Raitakari, Olli T
    Ren, Meixia
    Rettig, Rainer
    Rice, Kenneth
    Ridker, Paul M
    Ried, Janina S
    Riese, Harriëtte
    Ripatti, Samuli
    Robino, Antonietta
    Rose, Lynda M
    Rotter, Jerome I
    Rudan, Igor
    Ruggiero, Daniela
    Saba, Yasaman
    Sala, Cinzia F
    Salomaa, Veikko
    Samani, Nilesh J
    Sarin, Antti-Pekka
    Schmidt, Reinhold
    Schmidt, Helena
    Shrine, Nick
    Siscovick, David
    Smith, Albert V
    Snieder, Harold
    Sõber, Siim
    Sorice, Rossella
    Starr, John M
    Stott, David J
    Strachan, David P
    Strawbridge, Rona J
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Swertz, Morris A
    Taylor, Kent D
    Teumer, Alexander
    Tobin, Martin D
    Tomaszewski, Maciej
    Toniolo, Daniela
    Traglia, Michela
    Trompet, Stella
    Tuomilehto, Jaakko
    Tzourio, Christophe
    Uitterlinden, André G
    Vaez, Ahmad
    van der Most, Peter J
    van Duijn, Cornelia M
    Vergnaud, Anne-Claire
    Verwoert, Germaine C
    Vitart, Veronique
    Völker, Uwe
    Vollenweider, Peter
    Vuckovic, Dragana
    Watkins, Hugh
    Wild, Sarah H
    Willemsen, Gonneke
    Wilson, James F
    Wright, Alan F
    Yao, Jie
    Zemunik, Tatijana
    Zhang, Weihua
    Attia, John R
    Butterworth, Adam S
    Chasman, Daniel I
    Conen, David
    Cucca, Francesco
    Danesh, John
    Hayward, Caroline
    Howson, Joanna M M
    Laakso, Markku
    Lakatta, Edward G
    Langenberg, Claudia
    Melander, Olle
    Mook-Kanamori, Dennis O
    Palmer, Colin N A
    Risch, Lorenz
    Scott, Robert A
    Scott, Rodney J
    Sever, Peter
    Spector, Tim D
    van der Harst, Pim
    Wareham, Nicholas J
    Zeggini, Eleftheria
    Levy, Daniel
    Munroe, Patricia B
    Newton-Cheh, Christopher
    Brown, Morris J
    Metspalu, Andres
    Hung, Adriana M
    O'Donnell, Christopher J
    Edwards, Todd L
    Psaty, Bruce M
    Tzoulaki, Ioanna
    Barnes, Michael R
    Wain, Louise V
    Elliott, Paul
    Caulfield, Mark J
    Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.2018Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, nr 10, s. 1412-1425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

  • 77. Folkersen, Lasse
    et al.
    Fauman, Eric
    Sabater-Lleal, Maria
    Strawbridge, Rona J
    Frånberg, Mattias
    Sennblad, Bengt
    Baldassarre, Damiano
    Veglia, Fabrizio
    Humphries, Steve E
    Rauramaa, Rainer
    de Faire, Ulf
    Smit, Andries J
    Giral, Philippe
    Kurl, Sudhir
    Mannarino, Elmo
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lindgren, Cecilia
    Morris, Andrew P
    Giedraitis, Vilmantas
    Silveira, Angela
    Franco-Cereceda, Anders
    Tremoli, Elena
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brunak, Søren
    Eriksson, Per
    Ziemek, Daniel
    Hamsten, Anders
    Mälarstig, Anders
    Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease2017Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 4, artikkel-id e1006706Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

  • 78. Graff, Mariaelisa
    et al.
    Scott, Robert A
    Justice, Anne E
    Young, Kristin L
    Feitosa, Mary F
    Barata, Llilda
    Winkler, Thomas W
    Chu, Audrey Y
    Mahajan, Anubha
    Hadley, David
    Xue, Luting
    Workalemahu, Tsegaselassie
    Heard-Costa, Nancy L
    den Hoed, Marcel
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
    Ahluwalia, Tarunveer S
    Qi, Qibin
    Ngwa, Julius S
    Renström, Frida
    Quaye, Lydia
    Eicher, John D
    Hayes, James E
    Cornelis, Marilyn
    Kutalik, Zoltan
    Lim, Elise
    Luan, Jian'an
    Huffman, Jennifer E
    Zhang, Weihua
    Zhao, Wei
    Griffin, Paula J
    Haller, Toomas
    Ahmad, Shafqat
    Marques-Vidal, Pedro M
    Bien, Stephanie
    Yengo, Loic
    Teumer, Alexander
    Smith, Albert Vernon
    Kumari, Meena
    Harder, Marie Neergaard
    Justesen, Johanne Marie
    Kleber, Marcus E
    Hollensted, Mette
    Lohman, Kurt
    Rivera, Natalia V
    Whitfield, John B
    Zhao, Jing Hua
    Stringham, Heather M
    Lyytikäinen, Leo-Pekka
    Huppertz, Charlotte
    Willemsen, Gonneke
    Peyrot, Wouter J
    Wu, Ying
    Kristiansson, Kati
    Demirkan, Ayse
    Fornage, Myriam
    Hassinen, Maija
    Bielak, Lawrence F
    Cadby, Gemma
    Tanaka, Toshiko
    Mägi, Reedik
    van der Most, Peter J
    Jackson, Anne U
    Bragg-Gresham, Jennifer L
    Vitart, Veronique
    Marten, Jonathan
    Navarro, Pau
    Bellis, Claire
    Pasko, Dorota
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Snitker, Søren
    Cheng, Yu-Ching
    Eriksson, Joel
    Lim, Unhee
    Aadahl, Mette
    Adair, Linda S
    Amin, Najaf
    Balkau, Beverley
    Auvinen, Juha
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Bertoni, Alain G
    Blangero, John
    Bonnefond, Amélie
    Bonnycastle, Lori L
    Borja, Judith B
    Brage, Søren
    Busonero, Fabio
    Buyske, Steve
    Campbell, Harry
    Chines, Peter S
    Collins, Francis S
    Corre, Tanguy
    Smith, George Davey
    Delgado, Graciela E
    Dueker, Nicole
    Dörr, Marcus
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tõnu
    Faul, Jessica D
    Fu, Mao
    Færch, Kristine
    Gieger, Christian
    Gläser, Sven
    Gong, Jian
    Gordon-Larsen, Penny
    Grallert, Harald
    Grammer, Tanja B
    Grarup, Niels
    van Grootheest, Gerard
    Harald, Kennet
    Hastie, Nicholas D
    Havulinna, Aki S
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J
    Holmens, Oddgeir L
    Holzapfel, Christina
    Hottenga, Jouke Jan
    Huang, Jie
    Huang, Tao
    Hui, Jennie
    Huth, Cornelia
    Hutri-Kähönen, Nina
    James, Alan L
    Jansson, John-Olov
    Jhun, Min A
    Juonala, Markus
    Kinnunen, Leena
    Koistinen, Heikki A
    Kolcic, Ivana
    Komulainen, Pirjo
    Kuusisto, Johanna
    Kvaløy, Kirsti
    Kähönen, Mika
    Lakka, Timo A
    Launer, Lenore J
    Lehne, Benjamin
    Lindgren, Cecilia M
    Lorentzon, Mattias
    Luben, Robert
    Marre, Michel
    Milaneschi, Yuri
    Monda, Keri L
    Montgomery, Grant W
    De Moor, Marleen H M
    Mulas, Antonella
    Müller-Nurasyid, Martina
    Musk, A W
    Männikkö, Reija
    Männistö, Satu
    Narisu, Narisu
    Nauck, Matthias
    Nettleton, Jennifer A
    Nolte, Ilja M
    Oldehinkel, Albertine J
    Olden, Matthias
    Ong, Ken K
    Padmanabhan, Sandosh
    Paternoster, Lavinia
    Perez, Jeremiah
    Perola, Markus
    Peters, Annette
    Peters, Ulrike
    Peyser, Patricia A
    Prokopenko, Inga
    Puolijoki, Hannu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J
    Rawal, Rajesh
    Ridker, Paul M
    Rose, Lynda M
    Rudan, Igor
    Sarti, Cinzia
    Sarzynski, Mark A
    Savonen, Kai
    Scott, William R
    Sanna, Serena
    Shuldiner, Alan R
    Sidney, Steve
    Silbernagel, Günther
    Smith, Blair H
    Smith, Jennifer A
    Snieder, Harold
    Stančáková, Alena
    Sternfeld, Barbara
    Swift, Amy J
    Tammelin, Tuija
    Tan, Sian-Tsung
    Thorand, Barbara
    Thuillier, Dorothée
    Vandenput, Liesbeth
    Vestergaard, Henrik
    van Vliet-Ostaptchouk, Jana V
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Walker, Mark
    Wild, Sarah
    Wong, Andrew
    Wright, Alan F
    Zillikens, M Carola
    Zubair, Niha
    Haiman, Christopher A
    Lemarchand, Loic
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ohlsson, Claes
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Pérusse, Louis
    Wilson, James F
    Hayward, Caroline
    Polasek, Ozren
    Cucca, Francesco
    Hveem, Kristian
    Hartman, Catharina A
    Tönjes, Anke
    Bandinelli, Stefania
    Palmer, Lyle J
    Kardia, Sharon L R
    Rauramaa, Rainer
    Sørensen, Thorkild I A
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Penninx, Brenda W J H
    de Geus, Eco J C
    Boomsma, Dorret I
    Lehtimäki, Terho
    Mangino, Massimo
    Laakso, Markku
    Bouchard, Claude
    Martin, Nicholas G
    Kuh, Diana
    Liu, Yongmei
    Linneberg, Allan
    März, Winfried
    Strauch, Konstantin
    Kivimäki, Mika
    Harris, Tamara B
    Gudnason, Vilmundur
    Völzke, Henry
    Qi, Lu
    Järvelin, Marjo-Riitta
    Chambers, John C
    Kooner, Jaspal S
    Froguel, Philippe
    Kooperberg, Charles
    Vollenweider, Peter
    Hallmans, Göran
    Hansen, Torben
    Pedersen, Oluf
    Metspalu, Andres
    Wareham, Nicholas J
    Langenberg, Claudia
    Weir, David R
    Porteous, David J
    Boerwinkle, Eric
    Chasman, Daniel I
    Abecasis, Gonçalo R
    Barroso, Inês
    McCarthy, Mark I
    Frayling, Timothy M
    O'Connell, Jeffrey R
    van Duijn, Cornelia M
    Boehnke, Michael
    Heid, Iris M
    Mohlke, Karen L
    Strachan, David P
    Fox, Caroline S
    Liu, Ching-Ti
    Hirschhorn, Joel N
    Klein, Robert J
    Johnson, Andrew D
    Borecki, Ingrid B
    Franks, Paul W
    North, Kari E
    Cupples, L Adrienne
    Loos, Ruth J F
    Kilpeläinen, Tuomas O
    Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.2017Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 4, artikkel-id e1006528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

  • 79.
    Gustavsson, Inger
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lindell, Monica
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ska HPV-test ersätta gynekologisk cellprovtagning hos kvinnor i menopaus?2010Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, nr 8, s. 528-529Artikkel i tidsskrift (Fagfellevurdert)
  • 80.
    Gustavsson, Inger
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Juko-Pecirep, Ivana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Backlund, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Comparison between the Hybrid Capture 2 and the hpVIR real-time PCR for detection of human papillomavirus in women with ASCUS or low grade dysplasia2009Inngår i: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 45, nr 2, s. 85-89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Human papillomavirus (HPV) testing is an important part of cervical carcinoma screening, and the most widely used assay for detection of HPV is Hybrid Capture 2 (HC2). OBJECTIVES: We compare the HC2 with the real-time PCR hpVIR assay for detection of HPV in follow-up smears of 398 women diagnosed with atypical squamous cells of unknown significance (ASCUS) or low grade cervical intraepithelial neoplasia (CIN 1) in their initial smear. STUDY DESIGN: The two assays target the same set of high-risk (HR) HPVs with exception of HPV68. hpVIR identify individual or groups of HPV types as well as their viral load, while HC2 identify HR HPVs without specification of type. RESULTS: 34% (131/391) of the women were positive with HC2 and 45% (175/391) with hpVIR. 16% (63/391) were positive only with hpVIR and among those with cytology available 6% (3/52) had a CIN 2. The 3% (13/391) of women positive only with HC2 either contained low-risk HPVs or copy numbers below the cut-off for the hpVIR assay. CONCLUSION: The hpVIR assay has a similar sensitivity and specificity as HC2, but hpVIR detect a higher frequency of high-risk HPV infections.

  • 81.
    Gustavsson, Inger
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lindell, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Strand, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Use of FTA card for dry collection, transportation and storage of cervical cell specimen to detect high-risk HPV2009Inngår i: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 46, nr 2, s. 112-116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The FTA elute micro card, which enable the collection, transport, and archiving of DNA could be an attractive alternative to a liquid based collection system for detection of human papillomavirus (HPV). OBJECTIVES: To develop a method based on the FTA elute micro card for dry collection of cervical epithelial cell samples, suitable for subsequent PCR-based HPV testing. STUDY DESIGN: The method was evaluated by a comparison of the DNA collected by cytobrush and the regular FTA elute micro card from 50 cervical cell samples. The method was then used to estimate the DNA amount in 1040 samples applied to the indicating FTA elute micro card. RESULT: The agreement in HPV positivity between the cytobrush and FTA samples (94%) was excellent (kappa=0.88, 95% CI 0.748-1). All the 1040 samples on the indicating FTA card had sufficient amounts of genomic DNA (>10 copies of a single copy gene) to be suitable for HPV typing. In 53 of the 1040 women the day in the menstrual cycle was noted, and the copy number during follicular phase day 9-13 was found to be statistically significantly lower than for the other three stages in the menstrual cycle (day 4-8, 14, >14) and during menopause. CONCLUSION: The indicating FTA elute micro card represents a suitable medium for collection of cervical cell samples, although follow-up studies are needed to verify the detection of low frequency HPV types.

  • 82.
    Gustavsson, Inger M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Aarnio, Riina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Berggrund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Julia Hedlund
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Randomised study of HPV prevalence and detection of CIN2+ in vaginal self-sampling compared to cervical specimens collected by medical personnel.2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, nr 1, s. 89-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We conducted a randomised study to compare vaginal self-sampling with assisted sampling by medical personnel on the cervix for HPV testing in primary screening. The first aim was to determine if the HPV prevalence is independent of sampling location (vagina versus cervix) and the person performing the sampling. The second aim was to evaluate if the two sampling strategies differed in the detection rate of CIN2+. In total, 19,523 women were randomised into two groups, with 9926 invited to perform self-sampling (SS arm) using the Rover VIBA-brush and 9597 offered assisted sampling using the cytobrush (AS arm). All samples were applied to the indicating FTA elute card and analysed for high-risk HPV using the hpVIR real-time PCR assay. The outcome for the first aim was HPV prevalence and for the second aim the number of CIN2+ based on histology. In the SS arm, 52.7% of invited women participated in the study, as compared to 34.2% in the AS arm. All samples contained sufficient amount of nuclear DNA for a valid HPV result, with vaginal samples having a higher DNA amount than cervical samples (p < 4.62 × 10-11 ). HPV prevalence was 4.6% in the SS arm and 4.1% in the AS arm (p = 5.5 × 10-2 ), and the distribution of HPV types similar between arms. There was no difference in the prevalence of CIN2+ per 1000 women screened between arms (p = 0.86). The results show that vaginal self-sampling is an equivalent alternative to sampling by medical personnel for HPV typing and identification of CIN2+.

  • 83.
    Gustavsson, Inger M.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Aarnio, Riina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Berggrund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Julia Hedlund
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Strand, Ann-Sofi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology2018Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, nr 6, s. 896-904Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    This randomised study compared the detection rate of cervical intraepithelial neoplasia-positive (CIN2+) based on histology in women performing repeated self-sampling of vaginal fluid (VF) for human papillomavirus (HPV) test with a control group following the ordinary screening by Pap smear cytology.

    Methods:

    36390 women aged 30–49 years scheduled for invitation to organised screening were randomised in two groups, one to perform self-sampling of VF for HPV test (n=17 997, HPV arm) and the other group to perform screening by PAP smear cytology (n=18 393, control arm). HPV positive women in the HPV arm repeated the self-sampling and the HPV test on average 4.4 months later and those with two consecutive positive HPV tests were referred to colposcopy. Outcome was CIN2+ based on histology during 18-month follow-up.

    Results:

    Participation rate was 47% in the HPV arm and 39% in the control arm. The HPV prevalence in the first self-sampling was 6.9%, and 71% of these women were HPV positive in their second test. For the per-protocol approach, cumulative prevalence of histological CIN2+ in the HPV arm was 20.2 per 1000 women screened as compared to 10.8 in the control arm. The cumulative prevalence of CIN2+ diagnosed per 1000 years screened was 160.8 in the HPV arm as compared with 25.4 in the control arm.

    Conclusions:

    Repeated self-sampling of VF and HPV test had more than a two-fold higher discovery rate of CIN2+ per 1000 women screened as compared with PAP smear cytology.

  • 84.
    Gustavsson, Inger
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Lindell, Monica
    Strand, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Type-specific detection of high-risk human papillomavirus (HPV) in self-sampled cervicovaginal cells applied to FTA elute cartridge2011Inngår i: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 51, nr 4, s. 255-258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Most procedures for self-sampling of cervical cells are based on liquid-based media for transportation and storage. An alternative is to use a solid support, such as dry filter paper media.

    Objectives

    To evaluate if self-sampling of cervicovaginal fluid using a cytobrush (Viba-brush; Rovers Medical Devices B.V., Oss, The Netherlands) and a solid support such as the Whatman Indicating FTA® Elute cartridge (GE Healthcare, United Kingdom) can be used for reliable typing of human papillomavirus (HPV), as compared to cervical samples obtained by a physician using a cytobrush and the indicating FTA® Elute Micro card and biopsy analysis.

    Study design

    A total of 50 women with a previous high-risk (HR) HPV positive test were invited to perform self-sampling using the Viba-brush and the FTA cartridge and thereafter a physician obtained a cervical sample using the cytobrush and a FTA card, together with a cervical biopsy for histology and HPV typing. Detection of HR-HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 was performed using three multiplex real-time polymerase chain reaction (PCR) assays.

    Result

    All samples contained sufficient amounts of genomic DNA and the self-samples yielded on average 3.5 times more DNA than those obtained by the physician. All women that were positive for HR-HPV in the biopsy sample also typed positive both by self-sampling and physician-obtained sampling. For women with a histological diagnosis of cervical intraepithelial neoplasia grades 2–3 (CIN 2–3) all three HPV samples showed 100% concordance. A higher number of women were HPV positive by self-sampling than by physician-obtained sampling or by biopsy analysis.

    Conclusion

    The Viba-brush and the FTA cartridge are suitable for self-sampling of vaginal cells and subsequent HR-HPV typing.

  • 85.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    PCR-based HLA class II typing1991Inngår i: PCR methods and applications, ISSN 1054-9803, Vol. 1, nr 2, s. 91-8Artikkel i tidsskrift (Fagfellevurdert)
  • 86.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sequencing of in vitro amplified DNA1993Inngår i: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 218, s. 3s. 3-16Artikkel i tidsskrift (Annet vitenskapelig)
  • 87.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    SSO: genetic typing with sequence-specific oligonucleotides1996Inngår i: Laboratory protocols for mutation detection, 1996, Vol. 00, s. 78-Konferansepaper (Fagfellevurdert)
  • 88.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindell, Monica
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Primary high-risk HPV screening for cervical cancer in post-menopausal women2012Inngår i: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 125, nr 2, s. 343-345Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. The present study was conducted to examine the value of screening for high-risk HPV in post-menopausal women.

    Methods. A cohort of post-menopausal women (n =2113), age range 55-76 years, from Uppsala County, Sweden, were offered testing for both high-risk HPV and a Pap smear in the gynaecological screening during 2008-2010. For the HPV test the cervical smear sample was applied to a filter paper matrix, an indicating FTA elute card and HPV typing performed using a real-time PCR assay. Histological verified CIN2+ lesion was used as an end-point measurement.

    Results. High-risk HPV were found in 6.2% (95% CI 5.2-7.3%) of the women (n = 130) and 22% (95% CI 14-32%) (n = 17) of these had CIN2 + lesions based on histology. The Pap smear taken in conjunction with the HPV test was abnormal in 9.7% (95% CI 5.7-16.3%) (n = 12) of HPV positive women. Among HPV positive women with an abnormal Pap smear, the frequency of histology verified CIN2+ lesions was 67% (95% Cl 38-86%) (n = 8), as compared to 14% (95% CI 7-24%) (n = 9) in HPV positive women with a normal smear. The prevalence of HPV16 in CIN2+ lesions (29%, 95% CI 22-37%) in post-menopausal women was less than half of previous estimates in pre-menopausal women from this population.

    Conclusions. Most histological CIN2+ lesions in post-menopausal women are not recognized by a single Pap smear. A large fraction of pre-invasive cervical cancer cases in post-menopausal women result from infections by HPV types not included in the present vaccine formulas.

  • 89.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Assessing The Effects Of Climate Change On Health And Lifestyle In Sub-Arctic Areas In Sweden - The Northern Sweden Population Health Study2013Inngår i: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 72, nr Suppl. 1, s. 516-517Artikkel i tidsskrift (Annet vitenskapelig)
  • 90.
    Gyllensten, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindell, Monica
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Short-time repeat high-risk HPV testing by self-sampling for screening of cervical cancer2011Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, nr 5, s. 694-697Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30-65 years, with the primary sample for HPV analysis taken by self-sampling. METHODS: A total of 8000 women in Uppsala County, aged 30-65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test. RESULTS: In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18-30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31-51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30-39 years to 24% in women at age 50-65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%). CONCLUSION: The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high-risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30-65 years.

  • 91. Heard-Costa, Nancy L
    et al.
    Zillikens, M Carola
    Monda, Keri L
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Harris, Tamara B
    Fu, Mao
    Haritunians, Talin
    Feitosa, Mary F
    Aspelund, Thor
    Eiriksdottir, Gudny
    Garcia, Melissa
    Launer, Lenore J
    Smith, Albert V
    Mitchell, Braxton D
    McArdle, Patrick F
    Shuldiner, Alan R
    Bielinski, Suzette J
    Boerwinkle, Eric
    Brancati, Fred
    Demerath, Ellen W
    Pankow, James S
    Arnold, Alice M
    Chen, Yii-Der Ida
    Glazer, Nicole L
    McKnight, Barbara
    Psaty, Bruce M
    Rotter, Jerome I
    Amin, Najaf
    Campbell, Harry
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pattaro, Cristian
    Pramstaller, Peter P
    Rudan, Igor
    Struchalin, Maksim
    Vitart, Veronique
    Gao, Xiaoyi
    Kraja, Aldi
    Province, Michael A
    Zhang, Qunyuan
    Atwood, Larry D
    Dupuis, Josée
    Hirschhorn, Joel N
    Jaquish, Cashell E
    O'Donnell, Christopher J
    Vasan, Ramachandran S
    White, Charles C
    Aulchenko, Yurii S
    Estrada, Karol
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Witteman, Jacqueline C M
    Oostra, Ben A
    Kaplan, Robert C
    Gudnason, Vilmundur
    O'Connell, Jeffrey R
    Borecki, Ingrid B
    van Duijn, Cornelia M
    Cupples, L Adrienne
    Fox, Caroline S
    North, Kari E
    NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium2009Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 5, nr 6, s. e1000539-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

  • 92. Hicks, Andrew A.
    et al.
    Pramstaller, Peter P.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Vitart, Veronique
    Rudan, Igor
    Ugocsai, Peter
    Aulchenko, Yurii
    Franklin, Christopher S.
    Liebisch, Gerhard
    Erdmann, Jeanette
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Zorkoltseva, Irina V
    Pattaro, Cristian
    Hayward, Caroline
    Isaacs, Aaron
    Hengstenberg, Christian
    Campbell, Susan
    Gnewuch, Carsten
    Janssens, A. Cecilej W.
    Kirichenko, Anatoly V.
    König, Inke R.
    Marroni, Fabio
    Polasek, Ozren
    Demirkan, Ayse
    Kolcic, Ivana
    Schwienbacher, Christine
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Biloglav, Zrinka
    Witteman, Jacqueline C. M.
    Pichler, Irene
    Zaboli, Ghazal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Axenovich, Tatiana I
    Peters, Annette
    Schreiber, Stefan
    Wichmann, H.-Erich
    Schunkert, Heribert
    Hastie, Nick
    Oostra, Ben A.
    Wild, Sarah H.
    Meitinger, Thomas
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    van Duijn, Cornelia M.
    Wilson, James F.
    Wright, Alan
    Schmitz, Gerd
    Campbell, Harry
    Genetic determinants of circulating sphingolipid concentrations in European populations2009Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 5, nr 10, s. e1000672-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.

  • 93. Huffman, Jennifer E.
    et al.
    Albrecht, Eva
    Teumer, Alexander
    Mangino, Massimo
    Kapur, Karen
    Johnson, Toby
    Kutalik, Zoltn
    Pirastu, Nicola
    Pistis, Giorgio
    Lopez, Lorna M.
    Haller, Toomas
    Salo, Perttu
    Goel, Anuj
    Li, Man
    Tanaka, Toshiko
    Dehghan, Abbas
    Ruggiero, Daniela
    Malerba, Giovanni
    Smith, Albert V.
    Nolte, Ilja M.
    Portas, Laura
    Phipps-Green, Amanda
    Boteva, Lora
    Navarro, Pau
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Hicks, Andrew A.
    Polasek, Ozren
    Esko, Tonu
    Peden, John F.
    Harris, Sarah E.
    Murgia, Federico
    Wild, Sarah H.
    Tenesa, Albert
    Tin, Adrienne
    Mihailov, Evelin
    Grotevendt, Anne
    Gislason, Gauti K.
    Coresh, Josef
    D'Adamo, Pio
    Ulivi, Sheila
    Vollenweider, Peter
    Waeber, Gerard
    Campbell, Susan
    Kolcic, Ivana
    Fisher, Krista
    Viigimaa, Margus
    Metter, Jeffrey E.
    Masciullo, Corrado
    Trabetti, Elisabetta
    Bombieri, Cristina
    Sorice, Rossella
    Doering, Angela
    Reischl, Eva
    Strauch, Konstantin
    Hofman, Albert
    Uitterlinden, Andre G.
    Waldenberger, Melanie
    Wichmann, H-Erich
    Davies, Gail
    Gow, Alan J.
    Dalbeth, Nicola
    Stamp, Lisa
    Smit, Johannes H.
    Kirin, Mirna
    Nagaraja, Ramaiah
    Nauck, Matthias
    Schurmann, Claudia
    Budde, Kathrin
    Farrington, Susan M.
    Theodoratou, Evropi
    Jula, Antti
    Salomaa, Veikko
    Sala, Cinzia
    Hengstenberg, Christian
    Burnier, Michel
    Maegi, Reedik
    Klopp, Norman
    Kloiber, Stefan
    Schipf, Sabine
    Ripatti, Samuli
    Cabras, Stefano
    Soranzo, Nicole
    Homuth, Georg
    Nutile, Teresa
    Munroe, Patricia B.
    Hastie, Nicholas
    Campbell, Harry
    Rudan, Igor
    Cabrera, Claudia
    Haley, Chris
    Franco, Oscar H.
    Merriman, Tony R.
    Gudnason, Vilmundur
    Pirastu, Mario
    Penninx, Brenda W.
    Snieder, Harold
    Metspalu, Andres
    Ciullo, Marina
    Pramstaller, Peter P.
    van Duijn, Cornelia M.
    Ferrucci, Luigi
    Gambaro, Giovanni
    Deary, Ian J.
    Dunlop, Malcolm G.
    Wilson, James F.
    Gasparini, Paolo
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Spector, Tim D.
    Wright, Alan F.
    Hayward, Caroline
    Watkins, Hugh
    Perola, Markus
    Bochud, Murielle
    Kao, W. H. Linda
    Caulfield, Mark
    Toniolo, Daniela
    Voelzke, Henry
    Gieger, Christian
    Koettgen, Anna
    Vitart, Veronique
    Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikkel-id e0119752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

  • 94. Huffman, Jennifer E.
    et al.
    Knezevic, Ana
    Vitart, Veronique
    Kattla, Jayesh
    Adamczyk, Barbara
    Novokmet, Mislav
    Igl, Wilmar
    Pucic, Maja
    Zgaga, Lina
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Redzic, Irma
    Gornik, Olga
    Zemunik, Tatijana
    Polasek, Ozren
    Kolcic, Ivana
    Pehlic, Marina
    Koeleman, Carolien A. M.
    Campbell, Susan
    Wild, Sarah H.
    Hastie, Nicholas D.
    Campbell, Harry
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wuhrer, Manfred
    Wilson, James F.
    Hayward, Caroline
    Rudan, Igor
    Rudd, Pauline M.
    Wright, Alan F.
    Lauc, Gordan
    Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults2011Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, nr 24, s. 5000-5011Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The majority of human proteins are post-translationally modified by covalent addition of one or more complex oligosaccharides (glycans). Alterations in glycosylation processing are associated with numerous diseases and glycans are attracting increasing attention both as disease biomarkers and as targets for novel therapeutic approaches. Using a recently developed high-throughput high-performance liquid chromatography (HPLC) analysis method, we have reported, in a pilot genome-wide association study of 13 glycan features in 2705 individuals from three European populations, that polymorphisms at three loci (FUT8, FUT6/FUT3 and HNF1A) affect plasma levels of N-glycans. Here, we extended the analysis to 33 directly measured and 13 derived glycosylation traits in 3533 individuals and identified three novel gene association (MGAT5, B3GAT1 and SLC9A9) as well as replicated the previous findings using an additional European cohort. MGAT5 (meta-analysis association P-value = 1.80 x 10(-10) for rs1257220) encodes a glycosyltransferase which is known to synthesize the associated glycans. In contrast, neither B3GAT1 (rs7928758, P = 1.66 x 10(-08)) nor SLC9A9 (rs4839604, P = 3.50 x 10(-13)) had previously been associated functionally with glycosylation of plasma proteins. Given the glucuronyl transferase activity of B3GAT1, we were able to show that glucuronic acid is present on antennae of plasma glycoproteins underlying the corresponding HPLC peak. SLC9A9 encodes a proton pump which affects pH in the endosomal compartment and it was recently reported that changes in Golgi pH can impair protein sialylation, giving a possible mechanism for the observed association.

  • 95.
    Höijer, Ida
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Tsai, Yu-Chih
    Pacific Biosci, Menlo Pk, CA USA.
    Clark, Tyson A.
    Pacific Biosci, Menlo Pk, CA USA.
    Kotturi, Paul
    Pacific Biosci, Menlo Pk, CA USA.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Stattin, Evalena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Bondeson, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic, Australia.
    Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing2018Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, nr 9, s. 1262-1272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amplification of DNA is required as a mandatory step during library preparation in most targeted sequencing protocols. This can be a critical limitation when targeting regions that are highly repetitive or with extreme guanine-cytosine (GC) content, including repeat expansions associated with human disease. Here, we used an amplification-free protocol for targeted enrichment utilizing the CRISPR/Cas9 system (No-Amp Targeted sequencing) in combination with single molecule, real-time (SMRT) sequencing for studying repeat elements in the huntingtin (HTT) gene, where an expanded CAG repeat is causative for Huntington disease. We also developed a robust data analysis pipeline for repeat element analysis that is independent of alignment of reads to a reference genome. The method was applied to 11 diagnostic blood samples, and for all 22 alleles the resulting CAG repeat count agreed with previous results based on fragment analysis. The amplification-free protocol also allowed for studying somatic variability of repeat elements in our samples, without the interference of PCR stutter. In summary, with No-Amp Targeted sequencing in combination with our analysis pipeline, we could accurately study repeat elements that are difficult to investigate using PCR-based methods.

  • 96.
    Igl, Wilmar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    The Northern Swedish Population Health Study (NSPHS): a paradigmatic study in a rural population combining community health and basic research2010Inngår i: Rural and remote health, ISSN 1445-6354, Rural and remote health, ISSN 1445-6354, Vol. 10, nr 2, s. 1363-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION:

    Health care and research in rural populations are often limited due to poor infrastructure and small sample sizes. However, such populations have a need for medical care and can be of great value when studying the health effects of lifestyle and genetic factors. The Northern Sweden Population Health Study (NSPHS) is a paradigmatic study that combines a survey of the health status and specific needs of the community with basic research into the environmental and genetic determinants of non-communicable diseases. This article presents the NSPHS results on lifestyle, subclinical, and clinical measures and gives a review of the past contributions of this study to our understanding of the genetic determinants of disease in international collaborations.

    METHODS:

    A population-representative, cross-sectional sample (n=656) was examined from the Karesuando parish in Northern Sweden north of the Arctic Circle. The population consists of individuals living a traditional, subsistence-based lifestyle (TLS, n=96), mainly based on reindeer herding, hunting and fishing, and others following a modern, more industrialized lifestyle (MLS, n=560), similar to other western European countries. Subgroups with a modern versus traditional lifestyle were compared separately in men and women, highlighting differences in lifestyle (eg diet, physical activity), subclinical (eg blood circulation, blood lipids, lung function) and clinical measures (eg disorders of the cardiovascular, metabolic, and musculoskeletal system).

    RESULTS:

    TLS men and women consumed much more game meat (Men: 71 vs 194 g/day, p=0.0011; Women: 56 vs 140 g/day, p=0.0020) and less non-game meat (Men: 88 vs 42 g/day, p=1.4x10(-7); Women: 81 vs 42 g/day, p=0.026) compared with the respective MLS group. TLS men consumed less milk (p=4.2x10(-4)), and TLS women less vegetables (p=0.042). TLS men reported more physical activity at work (p=0.042) and TLS women less physical activity at leisure (p=0.0023). Total cholesterol (Men: 220 vs 244 mg/dl, p=0.0031; Women: 225 vs 246 mg/dl, (p=0.049) and LDL cholesterol levels (Men: 134 vs 153 mg/dl, p=0.012; Women: 133 vs 146 mg/dl, p>0.05) were higher in the blood serum of TLS men and women than in the MLS comparison group. While TLS women showed a higher rate of myocardial infarction (5% vs 16%, p=0.024), TLS men reported a dramatically higher frequency of body pain consistently, for example in the lower back (0% vs 25%; p>0.05).

    CONCLUSIONS:

    A consistent pattern was found of differences between individuals living a traditional versus modern lifestyle and between the sexes, identifying specific health risks for each group. Women with a traditional lifestyle were exposed to a greater risk for cardiovascular disease (especially myocardial infarction) and men with a traditional lifestyle reported higher rates of orthopedic symptoms (eg body pain). We also show that studies of rural populations can make a substantial contribution to basic research into understanding the environmental and genetic determinants of disease. The European Special Populations Research Network (EUROSPAN) provided an excellent example of a platform combining studies of rural populations from different parts of Europe that can leverage these for collaboration with large international consortia.

  • 97.
    Igl, Wilmar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kamal-Eldin, Afaf
    Johansson, Asa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Liebisch, Gerhard
    Gnewuch, Carsten
    Schmitz, Gerd
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Animal source food intake and association with blood cholesterol, glycerophospholipids and sphingolipids in a northern Swedish population2013Inngår i: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 72, s. 421-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The high intake of game meat in populations with a subsistence-based diet may affect their blood lipids and health status. Objective. To examine the association between diet and circulating levels of blood lipid levels in a northern Swedish population. Study design. We compared a group with traditional lifestyle (TLS) based on reindeer herding (TLS group) with those from the same area with a non-traditional lifestyle (NTLS) typical of more industrialized regions of Sweden (NTLS group). The analysis was based on self-reported intake of animal source food (i.e. non-game meat, game meat, fish, dairy products and eggs) and the serum blood level of a number of lipids [total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides (TG), glycerophospholipids and sphingolipids]. Results. The TLS group had higher cholesterol, LDL and HDL levels than the reference group. Of the TLS group, 65% had cholesterol levels above the threshold for increased risk of coronary heart disease (>= 240 mg/dl), as compared to 38% of the NTLS group. Self-reported consumption of game meat was positively associated with TC and LDL. Conclusions. The high game meat consumption of the TLS group is associated with increased cholesterol levels. High intake of animal protein and fat and low fibre is known to increase the risk of cardiovascular disease, but other studies of the TLS in northern Sweden have shown comparable incidences of cardiovascular disease to the reference (NTLS) group from the same geographical area. This indicates that factors other than TC influence disease risk. One such possible factor is dietary phospholipids, which are also found in high amounts specifically in game meat and have been shown to inhibit cholesterol absorption.

  • 98.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A recent genetic link between Sami and the Volga-Ural region of Russia2007Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, nr 1, s. 115-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic origin of the Sami is enigmatic and contributions from Continental Europe, Eastern Europe and Asia have been proposed. To address the evolutionary history of northern and southern Swedish Sami, we have studied their mtDNA haplogroup frequencies and complete mtDNA genome sequences. While the majority of mtDNA diversity in the northern Swedish, Norwegian and Finnish Sami is accounted for by haplogroups V and U5b1b1, the southern Swedish Sami have other haplogroups and a frequency distribution similar to that of the Continental European population. Stratification of the southern Sami on the basis of occupation indicates that this is the result of recent admixture with the Swedish population. The divergence time for the Sami haplogroup V sequences is 7600 YBP (years before present), and for U5b1b1, 5500 YBP amongst Sami and 6600 YBP amongst Sami and Finns. This suggests an arrival in the region soon after the retreat of the glacial ice, either by way of Continental Europe and/or the Volga-Ural region. Haplogroup Z is found at low frequency in the Sami and Northern Asian populations but is virtually absent in Europe. Several conserved substitutions group the Sami Z lineages strongly with those from Finland and the Volga-Ural region of Russia, but distinguish them from Northeast Asian representatives. This suggests that some Sami lineages shared a common ancestor with lineages from the Volga-Ural region as recently as 2700 years ago, indicative of a more recent contribution of people from the Volga-Ural region to the Sami population.

  • 99.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Analysis of the complete human mtDNA genome: methodology and inferences for human evolution2001Inngår i: Journal of Heredity, ISSN 0022-1503, E-ISSN 1465-7333, Vol. 92, nr 6, s. 454-61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The analysis of mitochondrial DNA (mtDNA) sequences has been a potent tool in our understanding of human evolution. However, almost all studies of human evolution based on mtDNA sequencing have focused on the control region, which constitutes less than 7% of the mitochondrial genome. The rapid development of technology for automated DNA sequencing has made it possible to study the complete mtDNA genomes in large numbers of individuals, opening the field of mitochondrial population genomics. Here we describe a suitable methodology for determining the complete human mitochondrial sequence and the global mtDNA diversity in humans. Also, we discuss the implications of the results with respect to the different hypotheses for the evolution of modern humans.

  • 100.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mitochondrial genome variation and evolutionary history of Australian and New Guinean aborigines2003Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 13, nr 7, s. 1600-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To study the evolutionary history of the Australian and New Guinean indigenous peoples, we analyzed 101 complete mitochondrial genomes including populations from Australia and New Guinea as well as from Africa, India, Europe, Asia, Melanesia, and Polynesia. The genetic diversity of the Australian mitochondrial sequences is remarkably high and is similar to that found across Asia. This is in contrast to the pattern seen in previously described Y-chromosome data where an Australia-specific haplotype was found at high frequency. The mitochondrial genome data indicate that Australia was colonized between 40 and 70 thousand years ago, either by a single migration from a heterogeneous source population or by multiple movements of smaller groups occurring over a period of time. Some Australian and New Guinea sequences form clades, suggesting the possibility of a joint colonization and/or admixture between the two regions.

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