M J Rieder1, A P Reiner, A E Rettie. 1. Department of Genome Sciences, Epidemiology, and Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. mrieder@u.washington.edu
Abstract
BACKGROUND: The pharmacogenetic factors contributing to warfarin dosing are of great interest to clinicians, and may have utility in the management of at-risk patients prescribed warfarin. Gamma-glutamyl carboxylase (GGCX), in its role as a key component of the vitamin K cycle, is a potential candidate gene associated with warfarin treatment. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) and correlated GGCX tagSNPs and test for association with warfarin maintenance dose. PATIENTS/ METHODS: A small discovery population of European-descent individuals (n = 23) were resequenced for GGCX SNPs. Polymorphisms identified with > 5% minor allele frequency (MAF) were genotyped in a larger clinical population of 186 European patients. Univariate, multivariate and haplotype-based linear regression were used to assess the impact of GGCX SNPs on warfarin dose. RESULTS: We identified 37 SNPs in GGCX, of which 21 were present at > 5% MAF. These SNPs were binned, based on linkage disequilibrium, and six informative tagSNPs were identified. A single polymorphism at position 12970 (rs11676382; C/G-11%/89%) was associated with a warfarin maintenance dose across all analysis methods. GGCX-12970 explained 2% of the total variance in warfarin dose, in contrast to 21 and 8%, respectively, for VKORC1 and CYP2C9. CONCLUSIONS: The GGCX-12970 SNP had a small, but significant effect, on warfarin maintenance dose. Other polymorphisms in GGCX previously associated with warfarin dose were not confirmed in this study, suggesting that the effects of GGCX are potentially population/treatment-dependent and will not have broad utility for determining warfarin dosing.
BACKGROUND: The pharmacogenetic factors contributing to warfarin dosing are of great interest to clinicians, and may have utility in the management of at-risk patients prescribed warfarin. Gamma-glutamyl carboxylase (GGCX), in its role as a key component of the vitamin K cycle, is a potential candidate gene associated with warfarin treatment. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) and correlated GGCX tagSNPs and test for association with warfarin maintenance dose. PATIENTS/ METHODS: A small discovery population of European-descent individuals (n = 23) were resequenced for GGCX SNPs. Polymorphisms identified with > 5% minor allele frequency (MAF) were genotyped in a larger clinical population of 186 European patients. Univariate, multivariate and haplotype-based linear regression were used to assess the impact of GGCX SNPs on warfarin dose. RESULTS: We identified 37 SNPs in GGCX, of which 21 were present at > 5% MAF. These SNPs were binned, based on linkage disequilibrium, and six informative tagSNPs were identified. A single polymorphism at position 12970 (rs11676382; C/G-11%/89%) was associated with a warfarin maintenance dose across all analysis methods. GGCX-12970 explained 2% of the total variance in warfarin dose, in contrast to 21 and 8%, respectively, for VKORC1 and CYP2C9. CONCLUSIONS: The GGCX-12970 SNP had a small, but significant effect, on warfarin maintenance dose. Other polymorphisms in GGCX previously associated with warfarin dose were not confirmed in this study, suggesting that the effects of GGCX are potentially population/treatment-dependent and will not have broad utility for determining warfarin dosing.
Authors: Hedi Schelleman; Colleen M Brensinger; Jinbo Chen; Brian S Finkelman; Mark J Rieder; Stephen E Kimmel Journal: Br J Clin Pharmacol Date: 2010-09 Impact factor: 4.335
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Authors: Stuart A Scott; Manishkumar Patel; Suparna Martis; Steven A Lubitz; Sarina van der Zee; Chang Yoo; Lisa Edelmann; Jonathan L Halperin; Robert J Desnick Journal: Pharmacogenomics Date: 2011-12-21 Impact factor: 2.533