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CYP2C9 Haplotype Structure in European American Warfarin Patients and Association with Clinical Outcomes
Author(s) -
Veenstra David L.,
Blough David K.,
Higashi Mitchell K.,
Farin Frederico M.,
Srinouanprachan Sengkeo,
Rieder Mark J.,
Rettie Allan E.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.01.019
Subject(s) - haplotype , genetics , single nucleotide polymorphism , biology , population , linkage disequilibrium , nonsynonymous substitution , minor allele frequency , allele , gene , genotype , medicine , genome , environmental health
Objective The goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations between CYP2C9 haplotypes and anticoagulation‐related outcomes. Methods Genomic deoxyribonucleic acid from 192 European American patients stabilized on warfarin therapy was resequenced across 60 kilobases of the CYP2C9 genomic region, including all exons, dense sampling of introns, approximately 10 kilobases of the 5′‐flanking region, and approximately 1.7 kilobases of the 3′‐untranslated region. Results A total of 132 single nucleotide polymorphisms (SNPs) were detected, of which 47 were present in the 5′‐flanking promoter region, 11 in the exonic coding region, and 74 in the intron regions. Nine nonsynonymous SNPs in the coding region consisted of CYP2C9*2 , *3 , *9 , *11 , and *12 ; R125H; and 3 new structural variants. Sixty SNPs were present at a minor allele frequency of greater than 5%, and from this subpopulation, 23 haplotypes were inferred. Clustering analysis identified 6 major groups of related haplotypes that were further designated 1A, 1B, 1C, 1D, 2, or 3. The *2 and *3 SNPs appeared exclusively in groups 2 and 3, and these groups combined were associated with significantly reduced warfarin maintenance doses, longer time to stable dosing, and increased risk of bleeding. In contrast, combinations of haplotypes 1A, 1B, 1C, and 1D were not associated with differences in any of these outcomes. Conclusion These data establish a whole‐gene, high‐resolution haplotype structure for CYP2C9 in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for warfarin sensitivity associated with CYP2C9 variants in this population. Clinical Pharmacology & Therapeutics (2005) 77 , 353–364; doi: 10.1016/j.clpt.2005.01.019