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| Session Information |
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| Session Title: Autoimmunity and Complex Traits Session Type: Platform |
| Session Location: Ballroom A Session Time: Fri Nov 14, 2008 08:00AM-10:30AM |
| Abstract Information |
| Program Number: 163 Presentation Time: 09:30AM-09:45AM |
| Keywords: Pharmacogenetics, KW131 - PHARMACOGENETICS, KW080 - GENOME-WIDE ASSOCIATION, KW016 - CARDIOVASCULAR SYSTEM, KW073 - GENETIC EPIDEMIOLOGY, KW076 - GENETIC TESTING |
| Abstract Content |
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Genome-wide association scan for genetic determinants of warfarin dose. R. McGinnis1, F. Takeuchi1, S. Bourgeois1, N. Soranzo1, V. Ranganath1, N. Eriksson2, J. Lindh3, A. Rane3, M. Wadelius2, P. Deloukas1 1) Wellcome Trust Sanger Institute, Cambridge, United Kingdom; 2) Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden; 3) Clinical Pharmacology, Karolinska Institute, Campus Huddinge, Stockholm, Sweden. Warfarin is an anticoagulant that is the most widely prescribed therapy for reducing thromboembolic events that often give rise to stroke, deep vein thrombosis, pulmonary embolism or serious coronary malfunctions. A combination of genetic and non-genetic factors cause Caucasians to exhibit 10-fold interindividual variation in required dose (RD) needed for the usual therapeutic level of anticoagulation (2.0-3.0 PT INR). Thus, in the absence of information (genotypic, clinical, etc.) for predicting each patient's RD, initial prescribed doses may be too low (risking failure to protect the patient) or too high (risking over-anticoagulation and severe bleeding). We were among the first to show that polymorphism in the warfarin drug target (VKORC1) accounts for a major portion (~30%) of the variance in RD and have recently evaluated 1523 Swedish patients from the Warfarin Genetics (WARG) cohort in the largest study to date showing likely patient benefit from genetic forecasting of RD (Wadelius et al. Blood, in press). This study confirmed that SNPs in VKORC1 and CYP2C9 predict at least 40% of RD variance while non-genetic factors (age, gender, etc.) jointly account for another ~15%. We are now searching for additional genetic predictors of RD in a large-scale genome-wide association study (GWAS) of 370,000 SNPs (Illumina 370K) genotyped in >1,000 WARG patients. Our initial GWAS results based on both single marker and haplotype analysis identified CYP4F2 as at least one additional genetic predictor of RD and we have replicated this finding in a further 600 samples (combined p-value of 8.9 x 10-10). We will show that detection of additional genetic predictors critically depends on the statistical technique applied, and will also report on the analysis of CNVs and on additional warfarin-related phenotypes (e.g. over-anticoagulation). |
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