CYP2C9 and VKORC1 genotypes in Puerto Ricans: A case for admixture-matching in clinical pharmacogenetic studies

Abstract

Backgrounds: Admixture is of great relevance to the clinical application of pharmacogenetics and personalized medicine, but unfortunately these studies have been scarce in Puerto Ricans. Besides, allele frequencies for clinically relevant genetic markers in warfarin response (i.e., CYP2C9 and VKORC1) have not yet been fully characterized in this population. Accordingly, this study is aimed at investigating whether a correlation between overall genetic similarity and CYP2C9 and/or VKORC1 genotypes could be established.

Methods: 98 DNA samples from Puerto Ricans were genotyped for major CYP2C9 and VKORC1 polymorphisms and tested on a physiogenomic (PG)-array to infer population structure and admixture pattern.

Results: Analysis affirmed that Puerto Ricans are broadly admixed. A genetic distance dendrogram was constructed by clustering those subjects with similar genetic profiles. Individual VKORC1 and CYP2C9 genotypes were visually overlaid atop the three dendrogram sectors. Sector-1, representing Amerindian ancestry, showed higher VKORC1 -1639G>A variant frequency than the rest of the population (p=0.051). Although CYP2C9*3 allele frequencies matched the expected HapMap values, admixture may explain deviations from published findings regarding VKORC1 -1639G>A and CYP2C9*2 allele frequencies in sector-3.

Conclusions: Results suggest that the observed inter-individual variations in ancestral contributions have significant implications for the way each Puerto Rican responds to warfarin therapy. Our findings provide valuable evidence on the importance of controlling for admixture in pharmacogenetic studies of Puerto Rican Hispanics.

Figure 1

Panel A: Individual VKORC1(1639 G→A) genotypes, overlaid on the genetic distance dendrogram for the samples from the Puerto Rican population (dendrogram taken from previously published physiogenomic population analysis[21]). Green color represents G/G genotype; whereas, blue and red colors are for the G/A and A/A genotypes, respectively. P-values were calculated by a chi-squared test comparing observed allele frequencies with expected frequencies given the overall allelic ratios. The VKORC1 SNP 1639 G→A is in high linkage disequilibrium with haplotype A[3], which has been associated with a significant decrease in the warfarin dose per allele. Panel B: Individual CYP2C9 genotypes overlaid on the genetic distance dendrogram for the samples from the Puerto Rican population (dendrogram taken from previously published physiogenomic population analysis [21]). Green color represents wild-type *1/*1 genotype; blue color denotes *1/*2 and red colors indicates the *1/*3 genotype. The yellow rectangle highlights the one *1/*6 genotype observed. P-values were calculated by a chi-squared test comparing observed allele frequencies within the sector with expected frequencies given the overall allelic ratios.

Figure 1

Panel A: Individual VKORC1(1639 G→A) genotypes, overlaid on the genetic distance dendrogram for the samples from the Puerto Rican population (dendrogram taken from previously published physiogenomic population analysis[21]). Green color represents G/G genotype; whereas, blue and red colors are for the G/A and A/A genotypes, respectively. P-values were calculated by a chi-squared test comparing observed allele frequencies with expected frequencies given the overall allelic ratios. The VKORC1 SNP 1639 G→A is in high linkage disequilibrium with haplotype A[3], which has been associated with a significant decrease in the warfarin dose per allele. Panel B: Individual CYP2C9 genotypes overlaid on the genetic distance dendrogram for the samples from the Puerto Rican population (dendrogram taken from previously published physiogenomic population analysis [21]). Green color represents wild-type *1/*1 genotype; blue color denotes *1/*2 and red colors indicates the *1/*3 genotype. The yellow rectangle highlights the one *1/*6 genotype observed. P-values were calculated by a chi-squared test comparing observed allele frequencies within the sector with expected frequencies given the overall allelic ratios.