Browsing by Author "Wadelius, Mia"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study
    (Elsevier, 2017-04) Nicoletti, Paola; Aithal, Guruprasad P.; Bjornsson, Einar S.; Andrade, Raul J.; Sawle, Ashley; Arrese, Marco; Barnhart, Huiman X.; Bondon-Guitton, Emmanuelle; Hayashi, Paul H.; Bessone, Fernando; Carvajal, Alfonso; Cascorbi, Ingolf; Cirulli, Elizabeth T.; Chalasani, Naga; Conforti, Anita; Coulthard, Sally A.; Daly, Mark J.; Day, Christopher P.; Dillon, John F.; Fontana, Robert J.; Grove, Jane I.; Hallberg, Pär; Hernández, Nelia; Ibáñez, Luisa; Kullak-Ublick, Gerd A.; Laitinen, Tarja; Larrey, Dominique; Lucena, M. Isabel; Maitland-van der Zee, Anke H.; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Powell, Elizabeth E.; Qin, Shengying; Serrano, Jose; Stephens, Camilla; Stolz, Andrew; Wadelius, Mia; Watkins, Paul B.; Floratos, Aris; Shen, Yufeng; Nelson, Matthew R.; Urban, Thomas J.; Daly, Ann K.; International Drug-Induced Liver Injury Consortium; Drug-Induced Liver Injury Network Investigators; International Serious Adverse Events Consortium; Medicine, School of Medicine
    BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
  • Thumbnail Image
    Item
    Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis
    (Springer Nature, 2018-08) Kowalec, Kaarina; Wright, Galen E.B.; Drögemöller, Britt I.; Aminkeng, Folefac; Bhavsar, Amit P.; Kingwell, Elaine; Yoshida, Eric M.; Traboulsee, Anthony; Marrie, Ruth Ann; Kremenchutzky, Marcelo; Campbell, Trudy L.; Duquette, Pierre; Chalasani, Naga; Wadelius, Mia; Hallberg, Pär; Xia, Zongqi; Jager, Philip L. De; Denny, Joshua C.; Davis, Mary F.; Ross, Colin J.D.; Tremlett, Helen; Carleton, Bruce C.; Medicine, School of Medicine
    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.
  • Thumbnail Image
    Item
    PharmVar GeneFocus: CYP2C9
    (Wiley, 2021-09) Sangkuhl, Katrin; Claudio‐Campos, Karla; Cavallari, Larisa H.; Agundez, Jose A.G.; Whirl‐Carrillo, Michelle; Duconge, Jorge; Del Tredici, Andria L.; Wadelius, Mia; Rodrigues Botton, Mariana; Woodahl, Erica L.; Scott, Stuart A.; Klein, Teri E.; Pratt, Victoria M.; Daly, Ann K.; Gaedigk, Andrea; Medical and Molecular Genetics, School of Medicine
    The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs including NSAIDs, phenytoin, anti-diabetic agents and angiotensin receptor blocker. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).