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  • 201. Murray, Christopher J L
    et al.
    Ortblad, Katrina F
    Guinovart, Caterina
    Lim, Stephen S
    Wolock, Timothy M
    Roberts, D Allen
    Dansereau, Emily A
    Graetz, Nicholas
    Barber, Ryan M
    Brown, Jonathan C
    Wang, Haidong
    Duber, Herbert C
    Naghavi, Mohsen
    Dicker, Daniel
    Dandona, Lalit
    Salomon, Joshua A
    Heuton, Kyle R
    Foreman, Kyle
    Phillips, David E
    Fleming, Thomas D
    Flaxman, Abraham D
    Phillips, Bryan K
    Johnson, Elizabeth K
    Coggeshall, Megan S
    Abd-Allah, Foad
    Abera, Semaw Ferede
    Abraham, Jerry P
    Abubakar, Ibrahim
    Abu-Raddad, Laith J
    Abu-Rmeileh, Niveen Me
    Achoki, Tom
    Adeyemo, Austine Olufemi
    Adou, Arsène Kouablan
    Adsuar, José C
    Agardh, Emilie Elisabet
    Akena, Dickens
    Al Kahbouri, Mazin J
    Alasfoor, Deena
    Albittar, Mohammed I
    Alcalá-Cerra, Gabriel
    Alegretti, Miguel Angel
    Alemu, Zewdie Aderaw
    Alfonso-Cristancho, Rafael
    Alhabib, Samia
    Ali, Raghib
    Alla, Francois
    Allen, Peter J
    Alsharif, Ubai
    Alvarez, Elena
    Alvis-Guzman, Nelson
    Amankwaa, Adansi A
    Amare, Azmeraw T
    Amini, Hassan
    Ammar, Walid
    Anderson, Benjamin O
    Antonio, Carl Abelardo T
    Anwari, Palwasha
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Arsenijevic, Valentina S Arsic
    Artaman, Ali
    Asghar, Rana J
    Assadi, Reza
    Atkins, Lydia S
    Badawi, Alaa
    Balakrishnan, Kalpana
    Banerjee, Amitava
    Basu, Sanjay
    Beardsley, Justin
    Bekele, Tolesa
    Bell, Michelle L
    Bernabe, Eduardo
    Beyene, Tariku Jibat
    Bhala, Neeraj
    Bhalla, Ashish
    Bhutta, Zulfiqar A
    Abdulhak, Aref Bin
    Binagwaho, Agnes
    Blore, Jed D
    Bose, Dipan
    Brainin, Michael
    Breitborde, Nicholas
    Castañeda-Orjuela, Carlos A
    Catalá-López, Ferrán
    Chadha, Vineet K
    Chang, Jung-Chen
    Chiang, Peggy Pei-Chia
    Chuang, Ting-Wu
    Colomar, Mercedes
    Cooper, Leslie Trumbull
    Cooper, Cyrus
    Courville, Karen J
    Cowie, Benjamin C
    Criqui, Michael H
    Dandona, Rakhi
    Dayama, Anand
    De Leo, Diego
    Degenhardt, Louisa
    Del Pozo-Cruz, Borja
    Deribe, Kebede
    Des Jarlais, Don C
    Dessalegn, Muluken
    Dharmaratne, Samath D
    Dilmen, Uğur
    Ding, Eric L
    Driscoll, Tim R
    Durrani, Adnan M
    Ellenbogen, Richard G
    Ermakov, Sergey Petrovich
    Esteghamati, Alireza
    Faraon, Emerito Jose A
    Farzadfar, Farshad
    Fereshtehnejad, Seyed-Mohammad
    Fijabi, Daniel Obadare
    Forouzanfar, Mohammad H
    Fra Paleo, Urbano
    Gaffikin, Lynne
    Gamkrelidze, Amiran
    Gankpé, Fortuné Gbètoho
    Geleijnse, Johanna M
    Gessner, Bradford D
    Gibney, Katherine B
    Ginawi, Ibrahim Abdelmageem Mohamed
    Glaser, Elizabeth L
    Gona, Philimon
    Goto, Atsushi
    Gouda, Hebe N
    Gugnani, Harish Chander
    Gupta, Rajeev
    Gupta, Rahul
    Hafezi-Nejad, Nima
    Hamadeh, Randah Ribhi
    Hammami, Mouhanad
    Hankey, Graeme J
    Harb, Hilda L
    Haro, Josep Maria
    Havmoeller, Rasmus
    Hay, Simon I
    Hedayati, Mohammad T
    Pi, Ileana B Heredia
    Hoek, Hans W
    Hornberger, John C
    Hosgood, H Dean
    Hotez, Peter J
    Hoy, Damian G
    Huang, John J
    Iburg, Kim M
    Idrisov, Bulat T
    Innos, Kaire
    Jacobsen, Kathryn H
    Jeemon, Panniyammakal
    Jensen, Paul N
    Jha, Vivekanand
    Jiang, Guohong
    Jonas, Jost B
    Juel, Knud
    Kan, Haidong
    Kankindi, Ida
    Karam, Nadim E
    Karch, André
    Karema, Corine Kakizi
    Kaul, Anil
    Kawakami, Norito
    Kazi, Dhruv S
    Kemp, Andrew H
    Kengne, Andre Pascal
    Keren, Andre
    Kereselidze, Maia
    Khader, Yousef Saleh
    Khalifa, Shams Eldin Ali Hassan
    Khan, Ejaz Ahmed
    Khang, Young-Ho
    Khonelidze, Irma
    Kinfu, Yohannes
    Kinge, Jonas M
    Knibbs, Luke
    Kokubo, Yoshihiro
    Kosen, S
    Defo, Barthelemy Kuate
    Kulkarni, Veena S
    Kulkarni, Chanda
    Kumar, Kaushalendra
    Kumar, Ravi B
    Kumar, G Anil
    Kwan, Gene F
    Lai, Taavi
    Balaji, Arjun Lakshmana
    Lam, Hilton
    Lan, Qing
    Lansingh, Van C
    Larson, Heidi J
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lee, Jong-Tae
    Leigh, James
    Leinsalu, Mall
    Leung, Ricky
    Li, Yichong
    Li, Yongmei
    De Lima, Graça Maria Ferreira
    Lin, Hsien-Ho
    Lipshultz, Steven E
    Liu, Shiwei
    Liu, Yang
    Lloyd, Belinda K
    Lotufo, Paulo A
    Machado, Vasco Manuel Pedro
    Maclachlan, Jennifer H
    Magis-Rodriguez, Carlos
    Majdan, Marek
    Mapoma, Christopher Chabila
    Marcenes, Wagner
    Marzan, Melvin Barrientos
    Masci, Joseph R
    Mashal, Mohammad Taufiq
    Mason-Jones, Amanda J
    Mayosi, Bongani M
    Mazorodze, Tasara T
    Mckay, Abigail Cecilia
    Meaney, Peter A
    Mehndiratta, Man Mohan
    Mejia-Rodriguez, Fabiola
    Melaku, Yohannes Adama
    Memish, Ziad A
    Mendoza, Walter
    Miller, Ted R
    Mills, Edward J
    Mohammad, Karzan Abdulmuhsin
    Mokdad, Ali H
    Mola, Glen Liddell
    Monasta, Lorenzo
    Montico, Marcella
    Moore, Ami R
    Mori, Rintaro
    Moturi, Wilkister Nyaora
    Mukaigawara, Mitsuru
    Murthy, Kinnari S
    Naheed, Aliya
    Naidoo, Kovin S
    Naldi, Luigi
    Nangia, Vinay
    Narayan, K M Venkat
    Nash, Denis
    Nejjari, Chakib
    Nelson, Robert G
    Neupane, Sudan Prasad
    Newton, Charles R
    Ng, Marie
    Nisar, Muhammad Imran
    Nolte, Sandra
    Norheim, Ole F
    Nowaseb, Vincent
    Nyakarahuka, Luke
    Oh, In-Hwan
    Ohkubo, Takayoshi
    Olusanya, Bolajoko O
    Omer, Saad B
    Opio, John Nelson
    Orisakwe, Orish Ebere
    Pandian, Jeyaraj D
    Papachristou, Christina
    Caicedo, Angel J Paternina
    Patten, Scott B
    Paul, Vinod K
    Pavlin, Boris Igor
    Pearce, Neil
    Pereira, David M
    Pervaiz, Aslam
    Pesudovs, Konrad
    Petzold, Max
    Pourmalek, Farshad
    Qato, Dima
    Quezada, Amado D
    Quistberg, D Alex
    Rafay, Anwar
    Rahimi, Kazem
    Rahimi-Movaghar, Vafa
    Rahman, Sajjad Ur
    Raju, Murugesan
    Rana, Saleem M
    Razavi, Homie
    Reilly, Robert Quentin
    Remuzzi, Giuseppe
    Richardus, Jan Hendrik
    Ronfani, Luca
    Roy, Nobhojit
    Sabin, Nsanzimana
    Saeedi, Mohammad Yahya
    Sahraian, Mohammad Ali
    Samonte, Genesis May J
    Sawhney, Monika
    Schneider, Ione J C
    Schwebel, David C
    Seedat, Soraya
    Sepanlou, Sadaf G
    Servan-Mori, Edson E
    Sheikhbahaei, Sara
    Shibuya, Kenji
    Shin, Hwashin Hyun
    Shiue, Ivy
    Shivakoti, Rupak
    Sigfusdottir, Inga Dora
    Silberberg, Donald H
    Silva, Andrea P
    Simard, Edgar P
    Singh, Jasvinder A
    Skirbekk, Vegard
    Sliwa, Karen
    Soneji, Samir
    Soshnikov, Sergey S
    Sreeramareddy, Chandrashekhar T
    Stathopoulou, Vasiliki Kalliopi
    Stroumpoulis, Konstantinos
    Swaminathan, Soumya
    Sykes, Bryan L
    Tabb, Karen M
    Talongwa, Roberto Tchio
    Tenkorang, Eric Yeboah
    Terkawi, Abdullah Sulieman
    Thomson, Alan J
    Thorne-Lyman, Andrew L
    Towbin, Jeffrey A
    Traebert, Jefferson
    Tran, Bach X
    Dimbuene, Zacharie Tsala
    Tsilimbaris, Miltiadis
    Uchendu, Uche S
    Ukwaja, Kingsley N
    Vallely, Andrew J
    Vasankari, Tommi J
    Venketasubramanian, N
    Violante, Francesco S
    Vlassov, Vasiliy Victorovich
    Waller, Stephen
    Wallin, Mitchell T
    Wang, Linhong
    Wang, Sharon Xiaorong
    Wang, Yanping
    Weichenthal, Scott
    Weiderpass, Elisabete
    Weintraub, Robert G
    Westerman, Ronny
    White, Richard A
    Wilkinson, James D
    Williams, Thomas Neil
    Woldeyohannes, Solomon Meseret
    Wong, John Q
    Xu, Gelin
    Yang, Yang C
    Yano, Yuichiro
    Yip, Paul
    Yonemoto, Naohiro
    Yoon, Seok-Jun
    Younis, Mustafa
    Yu, Chuanhua
    Jin, Kim Yun
    El Sayed Zaki, Maysaa
    Zhao, Yong
    Zheng, Yingfeng
    Zhou, Maigeng
    Zhu, Jun
    Zou, Xiao Nong
    Lopez, Alan D
    Vos, Theo
    Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 20132014In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, no 9947, p. 1005-1070Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

    METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

    FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

    INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

  • 202. Nead, Kevin T.
    et al.
    Li, Aihua
    Wehner, Mackenzie R.
    Neupane, Binod
    Gustafsson, Stefan
    Butterworth, Adam
    Engert, James C.
    Davis, A. Darlene
    Hegele, Robert A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Miller, Ruby
    den Hoed, Marcel
    Khaw, Kay-Tee
    Kilpelaeinen, Tuomas O.
    Wareham, Nick
    Edwards, Todd L.
    Hallmans, Goeran
    Varga, Tibor V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kardia, Sharon L. R.
    Smith, Jennifer A.
    Zhao, Wei
    Faul, Jessica D.
    Weir, David
    Mi, Jie
    Xi, Bo
    Quinteros, Samuel Canizales
    Cooper, Cyrus
    Sayer, Avan Aihie
    Jameson, Karen
    Grontved, Anders
    Fornage, Myriam
    Sidney, Stephen
    Hanis, Craig L.
    Highland, Heather M.
    Haering, Hans-Ulrich
    Heni, Martin
    Lasky-Su, Jessica
    Weiss, Scott T.
    Gerhard, Glenn S.
    Still, Christopher
    Melka, Melkaey M.
    Pausova, Zdenka
    Paus, Tomas
    Grant, Struan F. A.
    Hakonarson, Hakon
    Price, R. Arlen
    Wang, Kai
    Scherag, Andre
    Hebebrand, Johannes
    Hinney, Anke
    Franks, Paul W.
    Frayling, Timothy M.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Loos, Ruth J.
    Ingelsson, Erik
    Gerstein, Hertzel C.
    Yusuf, Salim
    Beyene, Joseph
    Anand, Sonia S.
    Meyre, David
    Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3582-3594Article in journal (Refereed)
    Abstract [en]

    Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) a parts per thousand yen 40 kg/m(2)], but their contribution to common obesity (BMI a parts per thousand yen 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 x 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 x 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 x 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

  • 203. Nelson, C. P.
    et al.
    Hamby, S. E.
    Saleheen, D.
    Hopewell, J. C.
    Zeng, L.
    Assimes, T. L.
    Kanoni, S.
    Willenborg, C.
    Burgess, S.
    Amouyel, P.
    Anand, S.
    Blankenberg, S.
    Boehm, B. O.
    Clarke, R. J.
    Collins, R.
    Dedoussis, G.
    Farrall, M.
    Franks, P. W.
    Groop, L.
    Hall, A. S.
    Hamsten, A.
    Hengstenberg, C.
    Hovingh, G. Kees
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kathiresan, S.
    Kee, F.
    Koenig, I. R.
    Kooner, J.
    Lehtimaeki, T.
    Maerz, W.
    McPherson, R.
    Metspalu, A.
    Nieminen, M. S.
    O'Donnell, C. J.
    Palmer, C. N. A.
    Peters, A.
    Perola, M.
    Reilly, M. P.
    Ripatti, S.
    Roberts, R.
    Salomaa, V.
    Shah, S. H.
    Schreiber, S.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Thorsteinsdottir, U.
    Veronesi, G.
    Wareham, N.
    Willer, C. J.
    Zalloua, P. A.
    Erdmann, J.
    Deloukas, P.
    Watkins, H.
    Schunkert, H.
    Danesh, J.
    Thompson, J. R.
    Samani, N. J.
    Genetically Determined Height and Coronary Artery Disease2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 372, no 17, p. 1608-1618Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.

  • 204.
    Nerpin, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Högskolan Dalarna-Medicinsk vetenskap.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Andrén, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Jobs, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Högskolan Dalarna Medicinsk vetenskap.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Högskolan Dalarna Medicinsk vetenskap.
    The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, no 11, p. 2069-2074Article in journal (Refereed)
    Abstract [en]

    The cardiorenal syndrome, the detrimental bi-directional interplay between symptomatic heart failure and chronic kidney disease, is a major clinical challenge. Nonetheless, it is unknown if this interplay begins already at an asymptomatic stage. Therefore we investigated whether the glomerular filtration rate (GFR) is associated with left ventricular function in participants free from clinical heart failure and with a left ventricular ejection fraction (LVEF) > 40% and with pre-specified sub-group analyses in individuals with a GFR > 60 mL/min/m(2). Two independent community-based cohorts were used; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 911; 50% women; mean age: 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 538; mean age: 71 years). We investigated cross-sectional association between cystatin C-based GFR (estimated glomerular function [eGFR]) and systolic (LVEF), diastolic- (isovolumic relaxation time [IVRT]) and global left ventricular function (myocardial performance index [MPI]) determined by echocardiography. In both PIVUS and ULSAM, higher eGFR was significantly associated with higher LVEF (P = 0.004 [PIVUS] and P = 0.005 [ULSAM]). In PIVUS, higher eGFR was significantly associated with lower IVRT (P = 0.001) and MPI (P = 0.006), in age- and sex-adjusted models. After further adjustment for cardiovascular risk factors, the association between higher eGFR and higher LVEF was still statistically significant (P = 0.008 [PIVUS] and P = 0.02 [ULSAM]). In PIVUS, the age- and sex-adjusted association between eGFR and left ventricular function was similar in participants with eGFR > 60 mL/min/m(2). Our data suggest that the interplay between kidney and heart function begins prior to the development of symptomatic heart failure and kidney disease.

  • 205.
    Nettleton, Jennifer A.
    et al.
    Univ Texas Houston, Hlth Sci Ctr, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA..
    Follis, Jack L.
    Univ St Thomas, Dept Math, Houston, TX 77006 USA..
    Ngwa, Julius S.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Smith, Caren E.
    Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA USA.;Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA..
    Ahmad, Shafqat
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Tanaka, Toshiko
    NIA, Clin Res Branch, Baltimore, MD 21224 USA..
    Wojczynski, Mary K.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Voortman, Trudy
    Erasmus MC, Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands..
    Lemaitre, Rozenn N.
    Univ Washington, Dept Med, Seattle, WA 98195 USA..
    Kristiansson, Kati
    Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki 00290, Finland..
    Nuotio, Marja-Liisa
    Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki 00290, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland..
    Houston, Denise K.
    Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA..
    Perala, Mia-Maria
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00290, Finland..
    Qi, Qibin
    Harvard Univ, Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Albert Einstein Coll Med, Dept Epidemiol & Publ Hlth, Bronx, NY 10467 USA..
    Sonestedt, Emily
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Manichaikul, Ani
    Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA.;Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Ganna, Andrea
    Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Mikkila, Vera
    Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA..
    Siscovick, David S.
    New York Acad Med, New York, NY USA..
    Harald, Kennet
    THL Natl Inst Hlth & Welf, Helsinki 00300, Finland..
    Mckeown, Nicola M.
    Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA USA.;Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA..
    Johansson, Ingegerd
    Umea Univ, Dept Odontol, Umea, Sweden..
    Rissanen, Harri
    THL Natl Inst Hlth & Welf, Helsinki 00300, Finland..
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA..
    Lahti, Jari
    Univ Helsinki, Inst Behav Sci, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Hu, Frank B.
    Harvard Univ, Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Bandinelli, Stefania
    ASF, Geriatr Unit, Florence, Italy..
    Rukh, Gull
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Rich, Stephen
    Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA..
    Booij, Lisanne
    NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Dmitriou, Maria
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Ax, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Raitakari, Olli
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.;Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland..
    Mukamal, Kenneth
    Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00290, Finland..
    Hallmans, Goran
    Umea Univ, Dept Publ Hlth & Clin Med Nutr Res, Umea, Sweden..
    Jula, Antti
    THL Natl Inst Hlth & Welf, Helsinki 00300, Finland..
    Ericson, Ulrika
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Jacobs, David R., Jr.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Van Rooij, Frank J. A.
    Erasmus MC, Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Hinxton, Cambs, England..
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kahonen, Mika
    Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland.;Tampere Univ Hosp, Tampere, Finland..
    Djousse, Luc
    Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Boston VA Healthcare Syst, Boston, MA USA..
    Perola, Markus
    Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki 00290, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Metab Dis Grp, Hinxton, Cambs, England.;Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England..
    Hofman, Albert
    Erasmus MC, Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands..
    Stirrups, Kathleen
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Viikari, Jorma
    Univ Turku, Dept Med, Turku, Finland.;Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland..
    Uitterlinden, Andre G.
    NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Kalafati, Ioanna P.
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Franco, Oscar H.
    Erasmus MC, Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands..
    Mozaffarian, Dariush
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA..
    Salomaa, Veikko
    THL Natl Inst Hlth & Welf, Helsinki 00300, Finland..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Knekt, Paul
    THL Natl Inst Hlth & Welf, Helsinki 00300, Finland..
    Kritchevsky, Stephen B.
    Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA..
    Eriksson, Johan G.
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00290, Finland.;Univ Helsinki, Inst Clin Med, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland..
    Dedoussis, George V.
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Qi, Lu
    Harvard Univ, Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Ferrucci, Luigi
    NIA, Clin Res Branch, Baltimore, MD 21224 USA..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Zillikens, M. Carola
    NCHA, Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lehtimaki, Terho
    Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland.;Univ Tampere, Sch Med, FIN-33101 Tampere, Finland..
    Renstrom, Frida
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Biobank Res, Umea, Sweden..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard Univ, Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 16, p. 4728-4738Article in journal (Refereed)
    Abstract [en]

    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

  • 206.
    Ng, Esther
    et al.
    Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Uppsala Univ, Dept Med Sci Occupat & Environm Med, S-75185 Uppsala, Sweden..
    Lindgren, Cecilia
    Harvard Univ, Inst Technol, Broad Inst Massachusetts, Cambridge, MA 02142 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mahajan, Anubha
    Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Morris, Andrew
    Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Genome-wide association study of toxic metals and trace elements reveals novel associations2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 16, p. 4739-4745Article in journal (Refereed)
    Abstract [en]

    The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism(SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 x 10(-11), beta = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 x 10(-14), beta = -0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4x10(-10), beta = -1.2 and P = 1.8x10(-9), beta = -1.8, respectively). Whole blood measurements of toxicmetals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity.

  • 207. Ng, Esther
    et al.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Mahajan, Anubha
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindgren, Cecilia M
    van Bavel, Bert
    Morris, Andrew P
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample2015In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 140, p. 95-101Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.

    OBJECTIVES: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.

    METHODS: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.

    RESULTS: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7×10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8×10(-12)) for PCB-118, rs4802104 (p=1.4×10(-9)) for PCB-74 and rs4803413 (p=2.5×10(-9)) for PCB-105, all of which map to CYP2B6.

    CONCLUSIONS: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity.

  • 208.
    Nielsen, Jonas B.
    et al.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Fritsche, Lars G.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Zhou, Wei
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Teslovich, Tanya M.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Holmen, Oddgeir L.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway..
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Gabrielsen, Maiken E.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Schmidt, Ellen M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Beaumont, Robin
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Wolford, Brooke N.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Lin, Maoxuan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Brummett, Chad M.
    Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA..
    Preuss, Michael H.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Refsgaard, Lena
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA..
    Graham, Sarah E.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Surakka, Ida
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Chu, Yunhan
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Skogholt, Anne Heidi
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Dalen, Havard
    St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, N-7491 Trondheim, Norway..
    Boyle, Alan P.
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Oral, Hakan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Herron, Todd J.
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Kitzman, Jacob
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Jalife, Jose
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA.;Fdn Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain..
    Svendsen, Jesper H.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark..
    Olesen, Morten S.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed, DK-2200 Copenhagen, Denmark..
    Njolstad, Inger
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Lochen, Maja-Lisa
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Baras, Aris
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Gottesman, Omri
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Marcketta, Anthony
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    O'Dushlaine, Colm
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Danville, PA 17822 USA..
    Wilsgaard, Tom
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Frayling, Timothy M.
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Boehnke, Michael
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Depart- ment of Medicine, Stanford University School of Medicine, Stanford, USA.
    Carey, David J.
    Dewey, Frederick E.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Kang, Hyun M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway..
    Willer, Cristen J.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 1, p. 103-115Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

  • 209.
    Nikpay, Majid
    et al.
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Goel, Anuj
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Won, Hong-Hee
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA USA..
    Hall, Leanne M.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Saleheen, Danish
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Kyriakou, Theodosios
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Webb, Thomas R.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Zeng, Lingyao
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Dehghan, Abbas
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Alver, Maris
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Armasu, Sebastian M.
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA..
    Auro, Kirsi
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Bjonnes, Andrew
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Chen, Shufeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Franceschini, Nora
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA..
    Gieger, Christian
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Grace, Christopher
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Jie
    Wellcome Trust Sanger Inst, Hinxton, England..
    Hwang, Shih-Jen
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Kim, Yun Kyoung
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany..
    Lau, King Wai
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Lu, Xiangfeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Qu, Liming
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Salfati, Elias
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Saxena, Richa
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA..
    Scholz, Markus
    Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany.;LIFE Res Ctr Civilizat Dis, Leipzig, Germany..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Tikkanen, Emmi
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Uitterlinden, Andre
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Yang, Xueli
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England..
    Zhao, Wei
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA..
    de Andrade, Mariza
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA..
    de Vries, Paul S.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    van Zuydam, Natalie R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Dundee, Med Res Inst, Dundee, Scotland..
    Anand, Sonia S.
    McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada..
    Bertram, Lars
    Univ Lubeck, Inst Neurogenet & Integrat, Platform Genome Analyt, Lubeck, Germany.;Univ Lubeck, Inst Expt Gen, Platform Genome Analyt, Lubeck, Germany.;Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, England..
    Beutner, Frank
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Leipzig, Heart Ctr Leipzig, Cardiol, D-04109 Leipzig, Germany..
    Dedoussis, George
    Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Frossard, Philippe
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Gauguier, Dominique
    INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France..
    Goodall, Alison H.
    Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.;Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Haber, Marc
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon..
    Han, Bok-Ghee
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Huang, Jianfeng
    Peking Union Med Coll, Beijing 100021, Peoples R China.;Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Hypertens Div, Beijing 100730, Peoples R China..
    Jalilzadeh, Shapour
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Kessler, Thorsten
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;Klinikum Rechts Der Isar, Munich, Germany..
    Koenig, Inke R.
    DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lieb, Wolfgang
    Univ Kiel, Inst Epidemiol, Kiel, Germany..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst MIT & Harvard Univ, Cambridge, MA USA..
    Lokki, Marja-Liisa
    Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Mallick, Nadeem H.
    Punjab Inst Cardiol, Lahore, Pakistan..
    Mehra, Narinder
    All India Inst Med Sci, New Delhi, India..
    Meitinger, Thomas
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Humangenet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany..
    Memon, Fazal-ur-Rehman
    Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Nieminen, Markku S.
    Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Peters, Annette
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Rallidis, Loukianos S.
    Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, GR-11527 Athens, Greece..
    Rasheed, Asif
    Ctr Noncommunicable Dis, Karachi, Pakistan.;Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan..
    Samuel, Maria
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Shah, Svati H.
    Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA..
    Sinisalo, Juha
    Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Wang, Laiyuan
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China.;Natl Human Genome Ctr Beijing, Beijing, Peoples R China..
    Zaman, Khan S.
    Natl Inst Cardiovasc Dis, Karachi, Pakistan..
    Ardissino, Diego
    Univ Parma, Azienda Osped, Div Cardiol, I-43100 Parma, Italy.;Assoc Studio Trombosi Cardiol, Pavia, Italy..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Buring, Julie E.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Collins, Rory
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Cupples, L. Adrienne
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Danesh, John
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Demuth, Ilja
    Berlin Aging Study 2, Berlin, Germany.;Charite, Res Grp Geriatr, D-13353 Berlin, Germany.;Charite, Inst Med & Human Genet, D-13353 Berlin, Germany..
    Elosua, Roberto
    Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain..
    Epstein, Stephen E.
    MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC USA..
    Esko, Tonu
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol & Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Franco, Oscar H.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Franzosi, Maria Grazia
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy..
    Granger, Christopher B.
    Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA..
    Gu, Dongfeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Hall, Alistair S.
    Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Hazen, Stanley L.
    Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA..
    Hengstenberg, Christian
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Iribarren, Carlos
    Kaiser Permanente Div Res, Oakland, CA USA..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.;Interunivers Cardiol Inst Netherlands, Utrecht, Netherlands..
    Karhunen, Pekka J.
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Forens Med, FIN-33101 Tampere, Finland..
    Kim, Bong-Jo
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Kooner, Jaspal S.
    Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Kullo, Iftikhar J.
    Mayo Clin, Dept Med, Cardiovasc Dis, Rochester, MN USA..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Melander, Olle
    Lund Univ, Univ Hosp Malmo, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany.;Synlab Acad, Synlab Serv, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Palmer, Colin N.
    Univ Dundee, Med Res Inst, Dundee, Scotland..
    Perola, Markus
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Quertermous, Thomas
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA..
    Rader, Daniel J.
    Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Roberts, Robert
    Univ Ottawa, Inst Heart, Ottawa, ON, Canada..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Sanghera, Dharambir K.
    Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Coll Med, Oklahoma City, OK 73190 USA.;Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA.;Oklahoma Ctr Neurosci, Oklahoma City, OK USA..
    Schwartz, Stephen M.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA..
    Seedorf, Udo
    Univ Med Ctr Hamburg Eppendorf, Ctr Dent & Oral Med, Dept Prosthet Dent, Hamburg, Germany..
    Stewart, Alexandre F.
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Stott, David J.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Thiery, Joachim
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany..
    Zalloua, Pierre A.
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA..
    O'Donnell, Christopher J.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;NHLBI, Div Intramural Res, Bethesda, MD 20892 USA.;Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02114 USA..
    Reilly, Muredach P.
    Assimes, Themistocles L.
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA..
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany..
    Clarke, Robert
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Watkins, Hugh
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Kathiresan, Sekar
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA USA..
    McPherson, Ruth
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia..
    Schunkert, Heribert
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Farrall, Martin
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 10, p. 1121-1130Article in journal (Refereed)
    Abstract [en]

    Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

  • 210.
    Nolte, Ilja M.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Munoz, M. Loretto
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Tragante, Vinicius
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Amare, Azmeraw T.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Univ Adelaide, Sch Med, Dept Epidemiol, Adelaide, SA 5005, Australia.;Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar 6000, Ethiopia..
    Jansen, Rick
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Vaez, Ahmad
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Isfahan Univ Med Sci, Sch Med, Esfahan 8174673461, Iran..
    von der Heyde, Benedikt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Avery, Christy L.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA..
    Dierckx, Bram
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Generat Study Grp R, POB 2060, NL-3000 CB0 Rotterdam, Netherlands..
    van Dongen, Jenny
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands..
    Gogarten, Stephanie M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Goyette, Philippe
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland..
    Huikari, Ville
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland..
    Hwang, Shih-Jen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Jaju, Deepali
    Sultan Qaboos Univ Hosp, Dept Clin Physiol, Muscat 123, Oman..
    Kerr, Kathleen F.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Kluttig, Alexander
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, D-06097 Halle, Germany..
    Krijthe, Bouwe P.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Kumar, Jitender
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    van der Laan, Sander W.
    Univ Med Ctr Utrecht, Dept Heart & Lung, Lab Expt Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Maihofer, Adam X.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Minassian, Arpi
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Nivard, Michel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Salvi, Erika
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Stewart, James D.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA..
    Thayer, Julian F.
    Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Zabaneh, Delilah
    Kings Coll London, Inst Psychiat Psychol & Neurosci, De Crespigny Pk, London SE5 8AF, England.;UCL, Genet Inst, London WC1E 6BT, England..
    Zafarmand, Mohammad H.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Obstet & Gynaecol, NL-1105 AZ Amsterdam, Netherlands..
    Abdellaoui, Abdel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Albarwani, Sulayma
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Albert, Christine
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA..
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA..
    Ashar, Foram
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA..
    Auvinen, Juha
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Baker, Dewleen G.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Genet, Ctr Mol Med, NL-3584 CX Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands..
    Barcella, Matteo
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Bayoumi, Riad
    Mohammed Bin Rashid Univ, Coll Med, Dubai Healthcare City, POB 505055, Dubai, U Arab Emirates..
    Bieringa, Rob J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Boomsma, Dorret
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Boucher, Gabrielle
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Britton, Annie R.
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Christophersen, Ingrid E.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Baerum Hosp, Vestre Viken Hosp Trust, Dept Med Res, N-1346 Rud, Norway..
    Dietrich, Andrea
    Univ Groningen, Univ Med Ctr Groningen, Dept Child & Adolescent Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Ehret, George B.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.;Geneva Univ Hosp, Dept Specialties Internal Med, Cardiol, CH-1211 Geneva, Switzerland..
    Ellinor, Patrick T.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Eskola, Markku
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    Felix, Janine F.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Floras, John S.
    Univ Toronto, Univ Hlth Network, Toronto, ON, Canada.;Univ Toronto, Mt Sinai Hosp, Div Cardiol, Dept Med, Toronto, ON, Canada.;Univ Hlth Network, Toronto Gen Res Inst, Toronto, ON M5G 2C4, Canada..
    Franco, Oscar H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Friberg, Peter
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden..
    Gademan, Maaike G. J.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Geyer, Mark A.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hemerich, Daiane
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil..
    Hofman, Albert
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Huikuri, Heikki
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Hutri-Kahonen, Nina
    Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Pediat, Tampere 33014, Finland..
    Jouven, Xavier
    Paris Descartes Univ, INSERM, U970, F-75006 Paris, France..
    Junttila, Juhani
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Juonala, Markus
    Univ Turku, Dept Med, Turku 20520, Finland.;Turku Univ Hosp, Div Med, Turku 20521, Finland..
    Kiviniemi, Antti M.
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Kors, Jan A.
    Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Essex Univ, ISER, Colchester CO4 3SQ, Essex, England..
    Kuznetsova, Tatiana
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Laurie, Cathy C.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Lefrandt, Joop D.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Li, Yong
    Univ Freiburg, Fac Med, Med Center, Div Genet Epidemiol,Inst Med Biometry & Stat, D-79110 Freiburg, Germany..
    Li, Yun
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA..
    Liao, Duanping
    Penn State Univ, Coll Med, Dept Publ Hlth Sci, Div Epidemiol, Hershey, PA 17033 USA..
    Limacher, Marian C.
    Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32611 USA..
    Lin, Henry J.
    Harbor UCLA Med Ctr, Dept Pediat, Los Angeles Biomed Res Inst Harbor, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Div Med Genet, Torrance, CA 90502 USA..
    Lindgren, Cecilia M.
    Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Lubitz, Steven A.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    McKnight, Barbara
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    zu Schwabedissen, Henriette Meyer
    Univ Basel, Dept Pharmaceut Sci, Biopharm, CH-4056 Basel, Switzerland..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Mononen, Nina
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England..
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA..
    Navis, Gerjan
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Neijts, Melanie
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Nikus, Kjell
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    North, Kari E.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA..
    O'Connor, Daniel T.
    Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA..
    Ormel, Johan
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Perz, Siegfried
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland..
    Risbrough, Victoria B.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Sinner, Moritz F.
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Siscovick, David
    New York Acad Med, New York, NY 10029 USA..
    Smit, Johannes H.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Smith, Nicholas L.
    Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA.;Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA..
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA..
    Sotoodehnia, Nona
    Univ Washington, Dept Med & Epidemiol, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Staessen, Jan A.
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Stein, Phyllis K.
    Washington Univ, Heart Rate Variabil Lab, Sch Med, St Louis, MO 63108 USA..
    Stilp, Adrienne M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stolarz-Skrzypek, Katarzyna
    Jagiellonian Univ, Med Coll, Dept Cardiol Intervent Electrocardi & Hypertens 1, PL-31008 Krakow, Poland..
    Strauch, Konstantin
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Sundstrom, Johan
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Swenne, Cees A.
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany..
    Thornton, Timothy A.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Tinker, Lesley E.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Uitterlinden, Andre G.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands.;Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, NL-2300 RC Leiden, Netherlands..
    van Setten, Jessica
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Voss, Andreas
    IGHT Jena Ernst Abbe Hsch, Inst Innovat Hlth Technol, D-07745 Jena, Germany..
    Waldenberger, Melanie
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany..
    Wilhelmsen, Kirk C.
    Univ N Carolina, Dept Genet & Neurol, Chapel Hill, NC 27599 USA.;Renaissance Comp Inst, Chapel Hill, NC 27599 USA..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Wong, Quenna
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Zhang, Zhu-Ming
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA.;Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Cusi, Daniele
    Italian Natl Res Council, CNR, Inst Biomed Technol, I-20090 Milan, Italy.;KOS Genet SRL, I-20091 Milan, Italy..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Greiser, Halina K.
    German Canc Res Ctr, Div Canc Epidemiol, D-69210 Heidelberg, Germany..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hassan, Mohammad
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA..
    Jarvelin, Marjo-Riitta
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland.;Imperial Coll London, Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, St Marys Campus, London, England.;Univ Oulu, Bioctr Oulu, Oulu 90014, Finland..
    Kaab, Stefan
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Lind, Lars
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Nievergelt, Caroline M.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    O'Donnell, Chris J.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Vet Adm Healthcare Boston, Cardiol Sect, Boston, MD 02132 USA..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Penninx, Brenda
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Reiner, Alexander P.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Riese, Harriette
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    van Roon, Arie M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Rioux, John D.
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Sofer, Tamar
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stricker, Bruno H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Inspectorate Hlth Care, NL-2511 VX The Hague, Netherlands..
    Tiemeier, Henning
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Vrijkotte, Tanja G. M.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Asselbergs, Folkert W.
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands..
    Brundel, Bianca J. J. M.
    Vrije Univ Amsterdam, Inst Cardiovasc Res, Dept Physiol, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands..
    Heckbert, Susan R.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Whitsel, Eric A.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA..
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Genetic loci associated with heart rate variability and their effects on cardiac disease risk2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed)
    Abstract [en]

    Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

  • 211.
    Nowak, C.
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Carlsson, A. C.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Östgren, C. J.
    Linkoping Univ, Linkoping, Sweden.
    Nyström, F. H.
    Linkoping Univ, Linkoping, Sweden.
    Alam, M.
    Dalarna Univ, Falun, Sweden.
    Feldreich, T. R.
    Dalarna Univ, Falun, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Roig, J. J. Carrero
    Karolinska Inst, Solna, Sweden.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedberg, Pär O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Cordeiro, A. C.
    Dante Pazzanese Inst Cardiol, Sao Paulo, Brazil.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, E.
    Stanford Univ, Sch Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Arnlöv, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden;Dalarna Univ, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S65-S65Article in journal (Other academic)
  • 212.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Insulin Resistance: Causes, biomarkers and consequences2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.

    The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.

    In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.

    In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.

    List of papers
    1. Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
    Open this publication in new window or tab >>Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
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    2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 1, p. 276-284Article in journal (Refereed) Published
    Abstract [en]

    Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-270825 (URN)10.2337/db15-0881 (DOI)000367424900029 ()26420861 (PubMedID)
    Funder
    Swedish Research Council, 2012-1397Swedish Heart Lung Foundation, 20140422Swedish Diabetes Association, 2013-024Knut and Alice Wallenberg FoundationEU, European Research Council
    Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2017-12-01Bibliographically approved
    2. Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
    Open this publication in new window or tab >>Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
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    2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006379Article in journal (Refereed) Published
    Abstract [en]

    Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-310027 (URN)10.1371/journal.pgen.1006379 (DOI)000386683300041 ()27768686 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, 2015.0327Swedish Diabetes Association, DIA 2013-024Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Heart Lung Foundation, 20120197 20150429 20070481EU, European Research Council, 33595 HEALTH-2009-2.2.1-3/242114 HEALTH-2013-2.4.2-1/602936Swedish Research Council, 2012-1397 2015-03477 M-2005-1112 2016-00250The Karolinska Institutet's Research FoundationNIH (National Institute of Health), DK U01-066134Swedish Foundation for Strategic Research
    Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
    3. Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
    Open this publication in new window or tab >>Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

    National Category
    Cell and Molecular Biology Physiology Endocrinology and Diabetes Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-316886 (URN)
    Note

    Tove Fall and Erik Ingelsson has contributed equally to this work.

    Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-01-13Bibliographically approved
    4. Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization study
    Open this publication in new window or tab >>Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization study
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Type 2 diabetes (T2D) and its hallmarks insulin resistance, impaired insulin secretion, and hyperglycaemia affect over 400 million persons worldwide and are associated with raised cardiovascular risk, but their causal role has been difficult to dissect due to overlap between risk factors. We used Mendelian randomization analysis, which utilises genetic polymorphisms associated with a risk factor, to assess causal effects of T2D, insulin resistance, insulin secretion, and fasting glucose on mortality, ischaemic stroke, and coronary artery disease (CAD) risk in 120,091 adults in the UK Biobank and in the CARDIoGRAMplusC4D consortium (63,746 cases of CAD and 130,681 controls). We found evidence for a causal effect of T2D on raised CAD risk (odds ratio (OR) per doubling in the odds of T2D, 1.07, 95% confidence interval (CI) 1.05 – 1.09, P = 1.2 x 10-9) and for a causal effect of impaired insulin secretion on the risk of CAD (OR per SD-unit decrease, 1.14, 95% CI 1.06 – 1.22, P = 0.002). The genetic score for insulin resistance was associated with increased coronary artery disease risk; however, sensitivity analysis indicated that the instrument might not be appropriate to use for robust causal inference testing. Our results support previous reports of a causal role of T2D and impaired insulin secretion in coronary artery disease and point to a complex relationship between variants affecting insulin resistance and cardiovascular outcomes.

    Keywords
    diabetes, insulin resistance, mendelian randomization, uk biobank, heart disease, cardiovascular disease
    National Category
    Basic Medicine Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-316888 (URN)
    Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-01-13Bibliographically approved
  • 213.
    Nowak, Christoph
    et al.
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Östgren, Carl Johan
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Nyström, Fredrik H.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Alam, Moudud
    Dalarna Univ, Sch Technol & Business Studies Stat, Falun, Sweden.
    Feldreich, Tobias
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carrero, Juan-Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Henriksen, Egil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Cordeiro, Antonio C.
    Dante Pazzanese Inst Cardiol, Dept Hypertens & Nephrol, Sao Paulo, Brazil.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ärnlöv, Johan
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 8, p. 1748-1757Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (< 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

  • 214.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Hetty, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Castillejo-Lopez, Casimiro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Cook, Naomi L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Shen, Xia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8691Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 +/- 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10-and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10-or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.