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  • 1.
    Alenius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hartvig, Per
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 2. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 470-476Article, review/survey (Refereed)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  • 3. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 4. Avery, P. J.
    et al.
    Jorgensen, A.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Pirmohamed, M.
    Kamali, F.
    A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 5, p. 701-706Article in journal (Refereed)
    Abstract [en]

    A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.

  • 5. Becquemont, Laurent
    et al.
    Alfirevic, Ana
    Amstutz, Ursula
    Brauch, Hiltrud
    Jacqz-Aigrain, Evelyne
    Laurent-Puig, Pierre
    Molina, Miguel A
    Niemi, Mikko
    Schwab, Matthias
    Somogyi, Andrew A
    Thervet, Eric
    Maitland-van der Zee, Anke-Hilse
    van Kuilenburg, André Bp
    van Schaik, Ron Hn
    Verstuyft, Céline
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Daly, Ann K
    Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics2011In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 12, no 1, p. 113-124Article, review/survey (Refereed)
    Abstract [en]

    The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.

  • 6. Biss, Tina
    et al.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Avery, Peter
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kamali, Farhad
    Warfarin dose prediction in children using pharmacogenetics information2012In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 159, no 1, p. 106-109Article in journal (Refereed)
  • 7.
    Bloch, K. M.
    et al.
    Univ Liverpool, Liverpool, Merseyside, England..
    Carr, D.
    Univ Liverpool, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Morris, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Maroteau, C.
    Dundee Univ, Dundee, Scotland..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palmer, C.
    Dundee Univ, Dundee, Scotland..
    Alfirevic, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Whole exome sequencing in individuals with statin-induced myopathy2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 1026-1026Article in journal (Other academic)
  • 8. Caudle, Kelly E
    et al.
    Klein, Teri E
    Hoffman, James M
    Muller, Daniel J
    Whirl-Carrillo, Michelle
    Gong, Li
    McDonagh, Ellen M
    Sangkuhl, Katrin
    Thorn, Caroline F
    Schwab, Matthias
    Agundez, Jose A G
    Freimuth, Robert R
    Huser, Vojtech
    Lee, Ming Ta Michael
    Iwuchukwu, Otito F
    Crews, Kristine R
    Scott, Stuart A
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Swen, Jesse J
    Tyndale, Rachel F
    Stein, C Michael
    Roden, Dan
    Relling, Mary V
    Williams, Marc S
    Johnson, Samuel G
    Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process2014In: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Current drug metabolism, Vol. 15, no 2, p. 209-217Article in journal (Refereed)
    Abstract [en]

    The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.

  • 9. Cavallari, Larisa H.
    et al.
    Perera, Minoli
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Deloukas, Panos
    Taube, Gelson
    Patel, Shitalben R.
    Aquino-Michaels, Keston
    Viana, Marlos A. G.
    Shapiro, Nancy L.
    Nutescu, Edith A.
    Association of the GGCX (CAA) 16/17 repeat polymorphism with higher warfarin dose requirements in African Americans2012In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 22, no 2, p. 152-158Article in journal (Refereed)
    Abstract [en]

    Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the gamma-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.

    Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA) n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5mg/day alone and in the context of other variables known to influence dose variability.

    Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P = 0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA) 16 repeat frequency of only 0.27% (P = 0.008 compared with African Americans).

    Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA) 16/17 repeat compared with Caucasians. Pharmacogenetics and Genomics 22: 152-158 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

  • 10. Chen, Leslie Y.
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gwilliam, Rhian
    Bentley, David
    Deloukas, Panos
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, no 10, p. 3673-4Article in journal (Refereed)
  • 11.
    Cirulli, Elizabeth T.
    et al.
    Duke Univ, Duke Ctr Appl Genom & Precis Med, Durham, NC USA.
    Nicoletti, Paola
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, One Gustave Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT USA.
    Abramson, Karen
    Duke Univ, Duke Mol Physiol Inst, Durham, NC USA.
    Andrade, Raul J.
    Univ Malaga, Hosp Univ Virgen de la Victoria, Ctr Invest Biomed Red Enfermedades Hepat & Digest, UGC Digest,Inst Invest Biomed Malaga IBIMA, Malaga, Spain;Univ Malaga, IBIMA Hosp Univ Virgen de la Victoria, Malaga, Spain;CIBERehd, Madrid, Spain.
    Bjornsson, Einar S.
    Landspitali Univ Hosp, Dept Internal Med, Reykjavik, Iceland.
    Chalasani, Naga
    Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA.
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Yi Ju
    Duke Univ, Duke Mol Physiol Inst, Durham, NC USA;Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA.
    Lucena, M. Isabel
    Univ Malaga, Hosp Univ Virgen de la Victoria, Ctr Invest Biomed Red Enfermedades Hepat & Digest, UGC Digest,Inst Invest Biomed Malaga IBIMA, Malaga, Spain;Univ Malaga, IBIMA Hosp Univ Virgen de la Victoria, Malaga, Spain;CIBERehd, Madrid, Spain.
    Long, Nanye
    Michigan State Univ, Inst Cyber Enabled Res, E Lansing, MI 48824 USA.
    Molokhia, Mariam
    Kings Coll London, Sch Populat Hlth & Environm Sci, London, England;Kings Coll London, London, England.
    Nelson, Matthew R.
    GSK, Target Sci, King Of Prussia, PA USA.
    Odin, Joseph A.
    Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA.
    Pirmohamed, Munir
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
    Rafnar, Thorunn
    deCODE Genet, IS-101 Reykjavik, Iceland.
    Serrano, Jose
    NIDDK, Bethesda, MD 20892 USA.
    Stefansson, Kari
    deCODE Genet, IS-101 Reykjavik, Iceland.
    Stolz, Andrew
    Univ Southern Calif, Los Angeles, CA USA.
    Daly, Ann K.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Aithal, Guruprasad P.
    Nottingham Univ Hosp NHS Trust, Nottingham Digest Dis Ctr, Nottingham, England;Nottingham Univ Hosp NHS Trust, Natl Inst Hlth Res, Nottingham Biomed Res Ctr, Nottingham, England;Univ Nottingham, Nottingham, England;Nottingham Univ Hosp NHS Trust, Nottingham Digest Dis Biomed Res Unit, Natl Inst Hlth Res, Nottingham, England.
    Watkins, Paul B.
    Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC 27515 USA;Univ N Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC USA.
    Bessone, Fernando
    Univ Nacl Rosario, Rosario, Santa Fe, Argentina.
    Bjornsson, Einar
    Natl Univ Hosp Iceland, Dept Internal Med, Div Gastroenterol & Hepatol, Reykjavik, Iceland.
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Inst Expt & Clin Pharmacol, Kiel, Germany.
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland.
    Day, Christopher P.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Hernandez, Nelia
    Univ Republica, Montevideo, Uruguay.
    Ibanez, Luisa
    Hosp Univ Vall dHebron, Barcelona, Spain.
    Kullak-Ublic, Gerd A.
    Univ Zurich, Zurich, Switzerland.
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland.
    Larrey, Dominique
    Hop St Eloi, Montpellier, France.
    Maitland-van der Zee, Anke
    AMC, Amsterdam, Netherlands.
    Martin, Jennifer H.
    Univ Newcastle, Newcastle, NSW, Australia.
    Menzies, Dick
    MUHC, Montreal, PQ, Canada;McGill Univ, Montreal Chest Inst, Montreal, PQ, Canada.
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai, Peoples R China.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury2019In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 156, no 6, p. 1707-1716Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.

    METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.

    RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.

    CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

  • 12. Dias, M M
    et al.
    Pignon, J-P
    Karapetis, C S
    Boige, V
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kweekel, D M
    Lara, P N
    Laurent-Puig, P
    Martinez-Balibrea, E
    Páez, D
    Punt, C J A
    Redman, M W
    Toffoli, G
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    McKinnon, R A
    Sorich, M J
    The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis2014In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 14, no 5, p. 424-431Article in journal (Refereed)
    Abstract [en]

    To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

  • 13.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Prediction of warfarin dose: why, when and how?2012In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, p. 429-440Article, review/survey (Refereed)
    Abstract [en]

    Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

  • 14. Eriksson, Solveig
    et al.
    Berg, Lars M.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cytochrome P450 genotyping by multiplexed real-time DNA sequencing with Pyrosequencing TM technology2002In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 1, no 1, p. 49-59Article in journal (Refereed)
    Abstract [en]

    Individual differences in xenobiotic metabolism influence the therapeutic value of many drugs and are of major concern during the development of new drug candidates. A number of polymorphic cytochrome p450 enzymes account for a significant part of this variation. A better understanding of these genetic factors would be of value for drug development, as well as clinical practice. To fulfill the goal of a personalized medicine, methods for simple and accurate assessment of cytochrome p450 genes are required. We report on the development of multiplex assays for genotyping of the cytochrome p450 drug-metabolizing enzymes CYP2D6, CYP2C9, and CYP2C19 with Pyrosequencing technology. Eleven variable positions, representing 12 of the most frequent alleles, were scored: CYP2D6 alleles *2, *3, *4, *6, *7, *8, and *14, CYP2C19 alleles *2, *3, and *4, and CYP2C9 alleles *2 and *3. Four multiplex Pyrosequencing reactions per patient sample were performed to cover these positions, using either simplex or multiplex PCR for amplification of target DNA sequences. Unequivocal genotypes were obtained for all patient samples, and the results were validated by comparing with results obtained using PCR-RFLP. For positions addressed with both methods, the results were in complete agreement. Pyrosequencing technology offers a highly automated, rapid, and accurate method for identification of cytochrome p450 alleles, which is suitable for pharmacogenomic research, as well as for routine assessment of patient genotypes.

  • 15.
    Fung, P. P. L.
    et al.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Bedogni, G.
    Liver Res Ctr, Clin Epidemiol Unit, Trieste, Italy..
    Bedogni, A.
    Univ Verona, Dept Maxillofacial Surg, Verona, Italy.;Univ Padua, Dept Maxillofacial Surg, Padua, Italy..
    Petrie, A.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Porter, S.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England..
    Campisi, G.
    Univ Palermo, Dip Discipline Chirurg Oncol & Stomatol, Palermo, Italy..
    Bagan, J.
    Univ Valencia, Univ Gen Hosp, Dept Oral & Maxillofacial Surg, Oral Med, Valencia, Spain..
    Fusco, V.
    Osped SS Antonio & Biagio & C Arrigo, Med Oncol Unit, Dept Oncol & Haematol, Alessandria, Italy..
    Saia, G.
    Univ Padua, Dept Maxillofacial Surg, Padua, Italy..
    Acham, S.
    Med Univ Graz, Dept Oral Surg & Orthodont, Univ Clin Dent Hlth & Oral Med, Graz, Austria..
    Musto, P.
    IRCCS, Sci Direct, Referral Canc Ctr Basilicata, Potenza, Italy..
    Petrucci, M. T.
    Sapienza Univ, Dept Cellular Biotechnol & Haematol, Rome, Italy..
    Diz, P.
    Santiago de Compostela Univ, Sch Med & Dent, Santiago, Spain..
    Colella, G.
    Univ Naples 2, Dept Med Surg & Dent Specialties, Naples, Italy..
    Mignogna, M. D.
    Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Head & Neck Clin Sect, Naples, Italy..
    Pentenero, M.
    Univ Turin, Oral Med & Oral Oncol Unit, Dept Oncol, Turin, Italy..
    Arduino, P.
    Univ Turin, CIR Dent Sch, Turin, Italy..
    Lodi, G.
    Univ Milan, Dipartimento Sci Biomed Chirurg & Odontoiatr, Milan, Italy..
    Maiorana, C.
    Univ Milan, Fdn IRCCS Policlin Ca Granda, Dipartimento Sci Biomed Chirurg & Odontoiatr, Osped Maggiore Policlin, Milan, Italy..
    Manfredi, M.
    Parma Univ, Dipartimento Sci Biomed Biotecnol & Translaz S Bi, Unit Odontostomatol, Parma, Italy..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Takaoka, K.
    Hyogo Coll Med, Dept Oral & Maxillofacial Surg, Nishinomiya, Hyogo, Japan..
    Leung, Y. Y.
    Univ Hong Kong, Oral & Maxillofacial Surg, Fac Dent, Hong Kong, Hong Kong, Peoples R China..
    Bonacina, R.
    Osped Papa Giovanni XXIII, Dept Dent, Bergamo, Italy..
    Schiodt, M.
    Copenhagen Univ Hosp, Dept Oral & Maxillofacial Surg, Rigshosp, Copenhagen, Denmark..
    Lakatos, P.
    Semmelweis Univ, Dept Med 1, Sch Med, Budapest, Hungary..
    Taylor, T.
    Kings Coll Hosp London, Dept Oral Surg, London, England..
    De Riu, G.
    Univ Hosp Sassari, Dept Maxillofacial Surg, Sassari, Italy..
    Favini, G.
    San Francesco Hosp, Dept Dent, Nuoro, Italy..
    Rogers, S. N.
    Aintree Univ Hosp NHS Fdn Trust, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England..
    Nicoletti, P.
    Columbia Univ, Dept Syst Biol, New York, NY USA..
    Fedele, S.
    UCL, Univ Coll London Hosp, Eastman Dent Inst & Hosp, 256 Grays Inn Rd, London WC1X 8LD, England.;NIHR Univ Coll London Hosp, Biomed Res Ctr, London, England..
    Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study2017In: Oral Diseases, ISSN 1354-523X, E-ISSN 1601-0825, Vol. 23, no 4, p. 477-483Article in journal (Refereed)
    Abstract [en]

    Objectives: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients.

    Subjects and Methods: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.

    Results: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n=88) and 2.2years in those treated with zoledronate (n=218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate.

    Conclusions: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

  • 16. Gamazon, E. R.
    et al.
    Daneshjou, R.
    Cavallari, L. H.
    Limdi, N. A.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Johnson, J. A.
    Klein, T. E.
    Scott, S.
    Tsunoda, T.
    Deloukas, P.
    Altman, R.
    Cox, N.
    Perera, M. A.
    Expression Quantitative Trait Loci Analysis of Stable Warfarin Dose Identifies Novel Associations: Finding Signal within the Noise2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 93, no S1, p. S27-S27Article in journal (Other academic)
  • 17.
    Garwicz, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Farmakogenetisk analys kan avslöja risk för statinbiverkningar: [Pharmacogenetic analysis can predict adverse effects of statins]2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 19-20, p. 951-952Article in journal (Refereed)
    Abstract [sv]

    Mer än var tionde vuxen i Sverige behandlas med statiner. 

    Muskelsvaghet, -trötthet och -värk är kända biverkningar. I sällsynta fall ses rabdomyolys, som kan leda till akut njursvikt och någon gång dödsfall. 

    Statiners kemiska egenskaper och serumkoncentration påverkar risken för allvarliga biverkningar. Serumkoncentrationen beror på dos och på patientens förmåga att omsätta läkemedlet.

    Akademiska sjukhuset har som första svenska sjukhus infört analys av en genetisk variant (SLCO1B1*5) som kan förutsäga ökad risk för sällsynta, allvarliga muskelbiverkningar vid statinbehandling.

  • 18.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Garmo, Hans
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Fredriksson, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Byström, P.
    Sørbye, H.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer2011In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 1, p. 61-71Article in journal (Refereed)
    Abstract [en]

    Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

  • 19. Gottlieb, Assaf
    et al.
    Daneshjou, Roxana
    DeGorter, M
    Bourgeois, S
    Svensson, PJ
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Deloukas, P
    Montgomery, SB
    Altman, RB
    Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans2017In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 9, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects.

    METHODS: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals.

    RESULTS: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations.

    CONCLUSIONS: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions.

    MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

  • 20.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Collin, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Preventivt arbete kan minska läkemedelsbiverkningar2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id ERYWArticle in journal (Other academic)
  • 21.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ibanez, Luisa
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Fundacio Inst Catala Farmacol, E-08193 Barcelona, Spain..
    Bondon-Guitton, Emmanuelle
    Univ Toulouse, Serv Pharmacol Med & Clin, Ctr Hosp Univ, Fac Med, Toulouse, France..
    Kreutz, Reinhold
    Charite, Inst Klin Pharmakol & Toxikol, D-13353 Berlin, Germany..
    Carvajal, Alfonso
    Univ Valladolid, Ctr Estudios Seguridad Medicamentos, Valladolid, Spain..
    Isabel Lucena, M.
    Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga, Farmacol Clin S, E-29071 Malaga, Spain.;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain..
    Sancho Ponce, Esther
    Hosp Gen Cataluna, Serv Hematol & Banc Sang, Sant Cugat Del Valles, Spain..
    Molokhia, Mariam
    Guys & St Thomas NHS Fdn Trust, Res Biomed Res Ctr, Natl Inst Hlth, Dept Primary Care & Publ Hlth Sci, London, England.;Kings Coll London, London WC2R 2LS, England..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain..
    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.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 6, p. 507-516Article in journal (Refereed)
    Abstract [en]

    Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.

    Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).

    Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.

    Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.

  • 22.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Martén, Leif
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Possible fluconazole-fentanyl interaction: a case report2006In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, no 6, p. 491-2Article in journal (Refereed)
  • 23.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Nagy, Julia
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Islander, Gunilla
    Norling, Pia
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kämpe, Mary
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Hugosson, Svante
    Yue, Qun-Ying
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough2017In: The Annals of Pharmacotherapy, ISSN 1060-0280, E-ISSN 1542-6270, Vol. 51, no 4, p. 293-300Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.

    OBJECTIVE: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.

    METHODS: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.

    RESULTS: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5). Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.

    CONCLUSION: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

  • 24.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. 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.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norling, Pia
    Sickla Hlth Ctr, Nacka, Sweden..
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population2017In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 3, p. 201-213Article in journal (Refereed)
    Abstract [en]

    Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

  • 25.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smedje, Hans
    Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Daniilidou, Makrina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Öhman, Inger
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Magnusson, Patrik K. E.
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

    METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

    FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

    INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

  • 26.
    Hamberg, Anna Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Barban, M.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pengo, V.
    Padrini, R.
    Jonsson, E. Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 81, no 4, p. 529-538Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.

  • 27.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanséus, Katarina
    Barmhjärtcentrum, Skånes Universietessjukhus, Lund.
    Ekman-Joelsson, Britt-Marie
    Drottnings Silvias Barnsjukhus, Sahlgrenska Universitetssjukhuset, Göteborg.
    Sunnegårdh, Jan
    Drottnings Silvias Barnsjukhus, Sahlgrenska Universitetssjukhuset, Göteborg.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lundell, Bo
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfarin dose prediction in children using pharmacometric bridging: comparison with published pharmacogenetic dosing algorithms2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 6, p. 1275-1283Article in journal (Refereed)
    Abstract [en]

    Purpose

    Numerous studies have investigated causes of warfarin dose variability in adults whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children.

    Method

    An adult population PK/PD-model for warfarin, with CYP2C9 and VKORC1 genotype, age and target INR as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external dataset of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children.

    Results

    Overall, the bridged model predicted INR response well in 64 warfarin treated Swedish children (median age 4.3 years), but with a tendency to over predict INR in children ≤ 2 years old. The bridged model predicted 20 of 49 children (41%) within ± 20% of actual maintenance dose (median age 7.2 years). In comparison the published dosing algorithms predicted 33-41% of the children within ± 20% of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within ± 20% of actual dose to 70%.

    Conclusion

    A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.

  • 28.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hellman, Jacob
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Dahlberg, Jonny
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Jonsson, E Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Bayesian decision support tool for efficient dose individualization of warfarin in adults and children2015In: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 15, no 7Article in journal (Refereed)
    Abstract [en]

    Warfarin is the most widely prescribed anticoagulant for prevention and treatment of thromboembolic events. Although highly effective, the use of warfarin is limited by a narrow therapeutic range combined with a more than ten-fold difference in the dose required for adequate anticoagulation in adults. For each patient, an optimal dose that leads to a favourable balance between the wanted antithrombotic effect and the risk of bleeding, measured as the prothrombin time International Normalised Ratio (INR), must be found. A model capable of describing the time-course of the INR response to warfarin therapy can be used to aid dose selection, both before starting therapy (a priori dose prediction) and after therapy has been initiated (a posteriori dose revision). In this paper we describe the transfer of a population PKPD-model for warfarin developed in NONMEM to a platform independent decision support tool written in Java. The tool proved capable of solving a system of differential equations representing the pharmacokinetics and pharmacodynamics of warfarin, with a performance comparable to NONMEM. To estimate an a priori dose the user provides information on body weight, age, CYP2C9 and VKORC1 genotype, baseline and target INR. With addition of information about previous doses and INR observations, the tool will use a Bayesian forecasting method to suggest an a posteriori dose, i.e. the dose with the highest probability to result in the desired INR. Results are displayed as the predicted dose per day and per week, and graphically as the predicted INR curve. The tool can also be used to predict INR following any given dose regimen, e.g. a loading-dose regimen. We believe it will provide a clinically useful tool for initiating and maintaining warfarin therapy in the clinic. It will ensure consistent dose adjustment practices between prescribers, and provide more efficient individualization of warfarin dosing in both children and adults.

  • 29.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Pharmacogenetics-based warfarin dosing in children2014In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 15, no 3, p. 361-374Article, review/survey (Refereed)
    Abstract [en]

    Clinical factors, demographic variables and variations in two genes, CYP2C9 and VKORC1, have been shown to contribute to the variability in warfarin dose requirements among adult patients. Less is known about their relative importance for dose variability in children. A few small studies have been reported, but the results have been conflicting, especially regarding the impact of genotypes. In this article, we critically review published pharmacogenetic-based prediction models for warfarin dosing in children, and present results from a head-to-head comparison of predictive performance in a distinct cohort of warfarin-treated children. Finally we discuss what properties a prediction model should have, and what knowledge gaps need to be filled, to improve warfarin therapy in children of all ages.

  • 30.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Biss, Tina T
    Kamali, Farhad
    Jonsson, E Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Characterising variability in warfarin dose requirements in children using modelling and simulation2013In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 78, no 1, p. 158-169Article in journal (Refereed)
    Abstract [en]

    AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.

    METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimise a published adult pharmacometric warfarin model for use in children.

    RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.

    CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

  • 31.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Biss, Tina T
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Kamali, Farhad
    icine, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Jonsson, E Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Predicting the relative importance of genetic, clinical and demographic factors on warfarin dose in children using pharmacometric modellingArticle in journal (Other academic)
    Abstract [en]

    It is difficult to predict anticoagulation response to warfarin in children mainly because of a wide inter-individual variability in warfarin dose requirement. The present study objective was to identify important predictors of dose in children and to optimize a previous NONMEM warfarin model for a priori and a posteriori dose and INR predictions in children. Data from 163 warfarin treated children with underlying heart disease (median age 6.3 years) were used. CYP2C9 and VKORC1 genotype caused up to 4-fold and 2-fold differences in warfarin dose requirement, respectively. Other important predictors of warfarin dose were bodyweight, age, baseline and target INR, and time since initiation of therapy with lower doses during the initiation. CYP4F2 genotype had only a marginal effect on dose. The present study findings will aid the development of a personalised approach to warfarin therapy in children, in the pursuit of improving both efficacy and safety of anticoagulation therapy.

  • 32.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lindh, J. D.
    Dahl, Marja- Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Padrini, R.
    Deloukas, P.
    Rane, A.
    Jonsson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Pharmacometric Model Describing the Relationship Between Warfarin Dose and INR Response With Respect to Variations in CYP2C9, VKORC1, and Age2010In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 87, no 6, p. 727-734Article in journal (Refereed)
    Abstract [en]

    The objective of the study was to update a previous NONMEM model to describe the relationship between warfarin dose and international normalized ratio (INR) response, to decrease the dependence of the model on pharmacokinetic (PK) data, and to improve the characterization of rare genotype combinations. The effects of age and CYP2C9 genotype on S-warfarin clearance were estimated from high-quality PK data. Thereafter, a temporal dose-response (K-PD) model was developed from information on dose, INR, age, and CYP2C9 and VKORC1 genotype, with drug clearance as a covariate. Two transit compartment chains accounted for the delay between exposure and response. CYP2C9 genotype was identified as the single most important predictor of required dose, causing a difference of up to 4.2-fold in the maintenance dose. VKORC1 accounted for a difference of up to 2.1-fold in dose, and age reduced the dose requirement by ~6% per decade. This reformulated K-PD model decreases dependence on PK data and enables robust assessment of INR response and dose predictions, even in individuals with rare genotype combinations.

  • 33. Hatch, E.
    et al.
    Wynne, H.
    Avery, P.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kamali, F.
    Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients2008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, p. 1038-1040Article in journal (Refereed)
  • 34. Horne, B D
    et al.
    Lenzini, P A
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jorgensen, A L
    Kimmel, S E
    Ridker, P M
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Anderson, J L
    Pirmohamed, M
    Limdi, N A
    Pendleton, R C
    McMillin, G A
    Burmester, J K
    Kurnik, D
    Stein, C M
    Caldwell, M D
    Eby, C S
    Rane, A
    Lindh, J D
    Shin, J-G
    Kim, H-S
    Angchaisuksiri, P
    Glynn, R J
    Kronquist, K E
    Carlquist, J F
    Grice, G R
    Barrack, R L
    Li, J
    Gage, B F
    Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy2012In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 107, no 2, p. 232-240Article in journal (Refereed)
    Abstract [en]

    By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

  • 35. Howard, Rebecca
    et al.
    Leathart, Julian B S
    French, David J
    Krishan, Elaina
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    van Schie, Rianne
    Verhoef, Talitha
    Maitland-van der Zee, Anke-Hilse
    Daly, Ann K
    Barallon, Rita
    Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon® probes2011In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 412, no 23-24, p. 2063-2069Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Coumarin anticoagulants such as warfarin are used to treat and prevent thromboembolic events in patients. The required dosage is difficult to predict and the risk of over or under anticoagulation are dependent on several environmental and clinical factors, such as concurrent medication, diet, age and genotype for polymorphisms in two genes CYP2C9 and VKORC1.

    METHODS: A novel fluorescent PCR genotyping assay using HyBeacon® probes, was developed to enable clinical staff to genotype the CYP2C9*2 and CYP2C9*3 alleles and the VKORC1 G-1639A polymorphism directly from unextracted blood samples. A prototype PCR instrument, Genie 1, suitable for point of care use was developed to carry out the assays. The panel of tests was validated by analysing blood samples from 156 individuals and comparing genotypes with data obtained using DNA samples from the same individuals. The accuracy of genotypes obtained with the Genie 1 was compared against results from well validated real time PCR and PCR-restriction fragment length polymorphism analysis.

    RESULTS: Identical results were obtained for the newly developed HyBeacon® method and the validation method in all cases except for one where no result was obtained for the VKORC1 polymorphism on the Genie instrument. The samples used for validation represented all six possible *2 and *3 allele-related CYP2C9 genotypes and all three VKORC1 G-1639A genotypes.

    CONCLUSIONS: We observed excellent accuracy for the newly developed method which can determine genotype in less than 2 h.

  • 36.
    Jacobson, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?2004In: BMC Blood Disorders, ISSN 1471-2326, Vol. 4, no 1, p. 5-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.

  • 37. Johnson, J. A.
    et al.
    Gong, L.
    Whirl-Carrillo, M.
    Gage, B. F.
    Scott, S. A.
    Stein, C. M.
    Anderson, J. L.
    Kimmel, S. E.
    Lee, M. T. M.
    Pirmohamed, M.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Klein, T. E.
    Altman, R. B.
    Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 4, p. 625-629Article, review/survey (Refereed)
    Abstract [en]

    Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for similar to 50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.

  • 38. Johnson, JA
    et al.
    Caudle, KE
    Gong, L
    Whirl-Carrillo, M
    Stein, CM
    Scott, SA
    Lee, MT
    Gage, BF
    Kimmel, SE
    Perera, MA
    Anderson, JL
    Pirmohamed, M
    Klein, TE
    Limdi, NA
    Cavallari, LH
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 3, p. 397-404Article, review/survey (Refereed)
    Abstract [en]

    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

  • 39. Josefsson, Ann
    et al.
    Sydsjö, Gunilla
    Berg, Göran
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Nordin, Conny
    CYP2D6 genotypes and depressive symptoms during late pregnancy and postpartum2004In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 58, no 1, p. 61-4Article in journal (Refereed)
    Abstract [en]

    The aim of this exploratory was to investigate the theory of a relation between cytochrome P450 2D6 (CYP2D6) genotype and depressive symptoms in late pregnancy and/or postpartum. We studied 145 women with depressive symptoms. CYP2D6 genotype was analysed in leukocyte DNA by polymerase chain reaction (PCR). There were no significant differences in CYP2D6 genotypes between the groups of women being depressed during and/or after pregnancy. The frequencies of CYP2D6 genotypes did not differ from other European studies. This study cannot confirm that depressive symptoms in late pregnancy and postpartum are connected with CYP2D6 genotype. It is, however, noteworthy that the frequency of ultrarapid metabolizers was higher than in a general Caucasian population. This warrants further exploration in a greater study sample, but should also be investigated in a general population with major depression.

  • 40.
    Karlsson Sundbaum, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lehto, Niklas
    Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice2019In: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, no 7, p. 1226-1232Article in journal (Refereed)
    Abstract [en]

    Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

    Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis.

    Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

    Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

  • 41.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Schilcher, Jorg
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala Univ, Dept Med Sci, Uppsala, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture2019In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed)
    Abstract [en]

    Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

  • 42. Klein, T. E.
    et al.
    Altman, R. B.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gage, B. F.
    Kimmel, S. E.
    Lee, M-T. M.
    Limdi, N. A.
    Page, D.
    Roden, D. M.
    Wagner, M. J.
    Caldwell, M. D.
    Johnson, J. A.
    Estimation of the warfarin dose with clinical and pharmacogenetic data2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 8, p. 753-764Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

    METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

    RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).

    CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

  • 43.
    Kohnke, Hugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Scordo, Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pengo, Vittorio
    Padrini, Roberto
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Apolipoprotein E (APOE) and warfarin dosing in an Italian population2005In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 61, no 10, p. 781-3Article in journal (Refereed)
  • 44.
    Kohnke, Hugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Sörlin, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Granath, Göran
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfarin dose related to apolipoprotein E (APOE) genotype2005In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 61, no 5-6, p. 381-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Warfarin is an anticoagulant which acts through interference with the recycling of vitamin K in the liver, leading to reduced activation of several clotting factors. Apolipoprotein E plays a central role in the uptake of the lipid-soluble vitamin K. The apolipoprotein E (APOE) alleles E2, E3 and E4 encode the three major isoforms of apolipoprotein E. The aim of this project was to evaluate whether variation in the APOE gene influences warfarin dose.METHODS: We genotyped APOE in 183 warfarin-treated patients. Information about warfarin dose, prothrombin time, age, gender, body weight, treatment indication and duration, other diseases and concurrent medication was taken from the patients' medical records. Cytochrome P(450) 2C9 genotyping had been performed previously, and patients were stratified according to CYP2C9 genotype.RESULTS: Patients homozygous for APOE*E4 tended to receive higher warfarin doses than others. Among CYP2C9 extensive metabolisers, APOE*E4 homozygous patients received significantly higher warfarin doses than patients with one or no E4 alleles; 56.9 compared with 34.3 and 34.6 mg/week, (Bonferroni corrected P=0.008 and 0.007, respectively). APOE genotype explains 6% of warfarin dose variance among CYP2C9 extensive metabolisers (analysis of variance, P=0.009).CONCLUSION: Previous studies have shown that individuals carrying the APOE*E4 allele have a faster uptake of lipoproteins into the liver and lower levels of circulating vitamin K than others. It is therefore plausible that patients carrying E4 alleles have an enhanced uptake of vitamin K into the liver and require higher doses of warfarin to compensate for this.

  • 45.
    Kowalec, K.
    et al.
    Univ British Columbia, Vancouver, BC, Canada..
    Wright, G. E. B.
    Univ British Columbia, Vancouver, BC, Canada..
    Drogemoller, B. I.
    Univ British Columbia, Vancouver, BC, Canada..
    Aminkeng, F.
    Univ British Columbia, Vancouver, BC, Canada..
    Bhavsar, A. P.
    Univ British Columbia, Vancouver, BC, Canada..
    Kingwell, E.
    Univ British Columbia, Vancouver, BC, Canada..
    Yoshida, E. M.
    Univ British Columbia, Vancouver, BC, Canada..
    Traboulsee, A.
    Univ British Columbia, Vancouver, BC, Canada..
    Marrie, R. A.
    Univ Manitoba, Winnipeg, MB, Canada..
    Kremenchutzky, M.
    Western Univ, London, ON, Canada..
    Campbell, T.
    Dalhousie Multiple Sclerosis Res Unit, Halifax, NS, Canada..
    Duquette, P.
    Ctr Hosp Univ Montreal, Montreal, PQ, Canada..
    Chalasani, N.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Xia, Z.
    Univ Pittsburgh, Sch Med, Pittsburgh, PA USA..
    De Jager, P.
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA..
    Ross, C. J. D.
    Univ British Columbia, Vancouver, BC, Canada..
    Tremlett, H.
    Univ British Columbia, Vancouver, BC, Canada..
    Carleton, B.
    Univ British Columbia, Vancouver, BC, Canada..
    Genome-wide scan identifies association between an interferon regulatory factor-related variant and interferon-beta induced liver injury in multiple sclerosis patients2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no 3, p. 834-836Article in journal (Refereed)
  • 46. Kowalec, Kaarina
    et al.
    Kingwell, Elaine
    Yoshida, Eric M.
    Marrie, Ruth Ann
    Kremenchutzky, Marcelo
    Campbell, Trudy L.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Carleton, Bruce
    Tremlett, Helen
    Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients2014In: Expert Opinion on Drug Safety, ISSN 1474-0338, E-ISSN 1744-764X, Vol. 13, no 10, p. 1305-1317Article, review/survey (Refereed)
    Abstract [en]

    Objective: To identify and characterize drug-induced liver injury (DILI) associated with IFN-beta in multiple sclerosis (MS) using recommended criteria. Methods: This retrospective, mixed methods design included a cohort of IFN-beta exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-beta product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites. Results: In BC, 18/942 (1.9%) of IFN-beta exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-beta-1a SC (44 mcg 3 x weekly) (adjusted Hazard Ratios: 3.15; 95% CI: 0.72 - 13.72, p = 0.13 and 6.26; 95% CI: 0.78 - 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006). Conclusions: Approximately 1 in 50 IFN-beta exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.

  • 47.
    Kowalec, Kaarina
    et al.
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada.
    Wright, Galen E. B.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Dept Med Genet, Fac Med, Vancouver, BC, Canada.
    Drogemoller, Britt I.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Aminkeng, Folefac
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore;Agcy Sci Res & Technol, Translat Lab Genet Med, Singapore, Singapore.
    Bhavsar, Amit P.
    British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada;Univ Alberta, Fac Med & Dent, Dept Med Microbiol & Immunol, Edmonton, AB, Canada.
    Kingwell, Elaine
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Yoshida, Eric M.
    Univ British Columbia, Div Gastroenterol, Fac Med, Vancouver, BC, Canada.
    Traboulsee, Anthony
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Marrie, Ruth Ann
    Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Internal Med, Winnipeg, MB, Canada;Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Community Hlth Sci, Winnipeg, MB, Canada.
    Kremenchutzky, Marcelo
    Western Univ, Fac Med, London Hlth Sci Ctr, London, ON, Canada;Western Univ, Fac Med, Dept Clin Neurol Sci, London, ON, Canada.
    Campbell, Trudy L.
    Dalhousie Univ, Dalhousie Multiple Sclerosis Res Uni, Halifax, NS, Canada;Dalhousie Univ, Sch Nursing, Halifax, NS, Canada.
    Duquette, Pierre
    Univ Montreal, Dept Neurosci, Montreal, PQ, Canada.
    Chalasani, Naga
    Indiana Univ Sch Med, Div Gastroenterol Hepatol, Indianapolis, IN 46202 USA.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xia, Zongqi
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.
    De Jager, Philip L.
    Columbia Univ, Med Ctr, Dept Neurol, Ctr Translat & Computat Neuroimmunol, New York, NY USA.;Columbia Univ, Med Ctr, Dept Neurol, Multiple Sclerosis Ctr, New York, NY USA.;Broad Inst, Cambridge, MA USA.
    Denny, Joshua C.
    Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA.;Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Davis, Mary F.
    Brigham Young Univ, Dept Microbiol & Mol Biol, Provo, UT 84602 USA.
    Ross, Colin J. D.
    British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada.;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.
    Tremlett, Helen
    Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC, Canada.
    Carleton, Bruce C.
    Univ British Columbia, Div Translat Therapeut, Dept Pediat, Vancouver, BC, Canada.;British Columbia Childrens Hosp Res Inst, Vancouver, BC, Canada.
    Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 8, p. 1081-+Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P= 2.3 × 10–8, odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P= 7.6 × 10–5) and alkaline phosphatase (P= 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.

  • 48. Lenzini, P.
    et al.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kimmel, S.
    Anderson, J. L.
    Jorgensen, A. L.
    Pirmohamed, M.
    Caldwell, M. D.
    Limdi, N.
    Burmester, J. K.
    Dowd, M. B.
    Angchaisuksiri, P.
    Bass, A. R.
    Chen, J.
    Eriksson, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Rane, A.
    Lindh, J. D.
    Carlquist, J. F.
    Horne, B. D.
    Grice, G.
    Milligan, P. E.
    Eby, C.
    Shin, J.
    Kim, H.
    Kurnik, D.
    Stein, C. M.
    McMillin, G.
    Pendleton, R. C.
    Berg, R. L.
    Deloukas, P.
    Gage, B. F.
    Integration of genetic, clinical, and INR data to refine warfarin dosing2010In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 87, no 5, p. 572-578Article in journal (Refereed)
    Abstract [en]

    Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

  • 49. Limdi, Nita A.
    et al.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Cavallari, Larissa
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Crawford, Dana C.
    Lee, Ming-Ta M.
    Chen, Chien-Hsiun
    Motsinger-Reif, Alison
    Sagreiya, Hersh
    Liu, Nianjun
    Wu, Alan H. B.
    Gage, Brian F.
    Jorgensen, Andrea
    Pirmohamed, Munir
    Shin, Jae-Gook
    Suarez-Kurtz, Guilherme
    Kimmel, Stephen E.
    Johnson, Julie A.
    Klein, Teri E.
    Wagner, Michael J.
    Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across three racial groups2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 18, p. 3827-3834Article in journal (Refereed)
    Abstract [en]

    Warfarin dosing algorithms incorporating CYP2C9 and VKORC1-1639G>A improve dose prediction compared to algorithms based solely on clinical and demographic factors. However these algorithms better capture dose variability among Whites compared to Asians or Blacks. Herein we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1-1639G>A among Asians (n=1103), Blacks (n=670) and Whites (n=3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 SNPs and haplotypes on warfarin dose employed both univariate and multivariable linear regression. VKORC1-1639G>A and 1173C>T individually explained the greatest variance in dose in all three racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among Whites as compared to Blacks and Asians. Differences in the percent variance in dose explained by VKORC1 across race was largely accounted for by the frequency of the -1639 A (or 1173 T) allele. Thus, clinicians should recognize that although at a population level, the contribution of VKORC1 towards dose requirements is higher in Whites compared to non-whites; genotype predicts similar dose requirements across racial groups.

  • 50.
    Lind, Anna-Britta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Klinisk farmakologi.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Darj, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Finnström, Niklas
    Lundgren, Stefan
    Rane, Anders
    Gene expression of cytochrome P450 1B1 and 2D6 in leukocytes in human pregnancy2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, no 6, p. 295-9Article in journal (Refereed)
    Abstract [en]

    We investigated the influence of human pregnancy on gene expression of two cytochrome P450 enzymes in white blood cells. Cytochrome P450 1B1 (CYP1B1) catalyses oestradiol 4-hydroxylation, and may participate in the endocrine regulation of oestrogens. Cytochrome P450 2D6 (CYP2D6) metabolises many commonly used drugs, and previous studies have suggested that it is induced during pregnancy. CYP1B1 and CYP2D6 were therefore considered to be of interest in human pregnancy. As it is not ethically possible to take liver biopsies from healthy mothers during pregnancy, easily accessible cells that express the genes were used as a surrogate tissue. White blood cells were collected from eighteen pregnant women, and were used to measure CYP1B1 and CYP2D6 ribonucleic acid (RNA). The analysis was repeated after pregnancy, the women, thus, serving as their own controls. Real-time reverse transcriptase - polymerase chain reaction methods were used with 18S ribosomal RNA as an internal control. A slight, but not significant, increase in gene activity of CYP1B1 was detected during pregnancy. Expression of CYP2D6 in blood was extremely low, and induction of CYP2D6 during pregnancy could not be confirmed. In conclusion, gene expression of CYP1B1 and CYP2D6 in leukocytes was not significantly up-regulated in the third trimester of pregnancy, but a trend indicating an altered metabolism during pregnancy was detected.

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