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Loss-of-function CYP2C9 variants: finding the correct clinical role for Type 2 diabetes pharmacogenetic testing.

ABSTRACT: Continuing advances in genetic discovery have uncovered several dozen loci that are associated with Type 2 diabetes, including genetic variants that appear to modify responses to commonly prescribed diabetes medications. The use of an individual's genetic information to guide therapy choices raises the possibility of 'personalized medicine', wherein each patient's treatment plan is tailored based on genotype results. However, before such a model of care can be implemented, research is needed to more clearly quantify the association of genetic variation with treatment outcomes and adverse effects. In this article, we review a study examining the association of genetic variation in the cytochrome P450 2C9 enzyme with glycemic response to sulfonylureas in a large cohort of patients with Type 2 diabetes from the Genetics of Diabetes Audit and Research Tayside Study (Go-DARTS).

SUBMITTER: Grant RW

PROVIDER: S-EPMC2852129 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Loss-of-function CYP2C9 variants: finding the correct clinical role for Type 2 diabetes pharmacogenetic testing.

Grant Richard W RW Wexler Deborah J DJ

Expert review of cardiovascular therapy 20100301 3

Continuing advances in genetic discovery have uncovered several dozen loci that are associated with Type 2 diabetes, including genetic variants that appear to modify responses to commonly prescribed diabetes medications. The use of an individual's genetic information to guide therapy choices raises the possibility of 'personalized medicine', wherein each patient's treatment plan is tailored based on genotype results. However, before such a model of care can be implemented, research is needed to ...[more]

PMID: 20222813

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Project description:IntroductionAllelic frequency distribution of drug metabolizing enzyme genes among populations is important to identify risk groups for adverse drug reaction and to select representative populations for clinical trials. Although India emerged as an important hub for clinical trials, information about the pharmacogenetic diversity for this region is still lacking. Here, we investigated genetic diversity of cytochrome-P450-2C9 (CYP2C9) gene which metabolizes wide range of drugs and is highly expressed in the human liver.MethodsIn total, 1278 individuals from 36 diverse Indian populations, 210 individuals from in-house data-repository and 489 other South Asian samples from the 1000 Genomes Project were selected. Variants observed in CYP2C9 gene were subjected to various statistical analyses.ResultsHigh frequency of CYP2C9*3 (~13%) and CYP2C9*3/*3 (~1%) was observed among South Asians, compared to 21 populations living outside the Indian subcontinent. The allelic/genotypic frequency does not correlate with geographical location or linguistic affiliation, except populations speaking Tibeto-Burmans language, who have lower frequency of CYP2C9*3 and CYP2C9*3/*3. Since, South Asians practice strict endogamy, presence of unique mutation and high frequency of homozygous genotypes not surprising. CYP2C9*3 has been associated with therapeutic response.The effect of CYP2C9*3/*3 is more pronounced compared to heterozygous and wild type homozygous genotypes as evident in many in vitro studies. As South Asians have high frequency, it would be interesting to explore potential of CYP2C9*3 as a marker for personalized therapy. Our study revealed several rare functional variants, which form eight novel and rare haplotypes of CYP2C9 (CYP2C9*63-*70). Of which, CYP2C9*64, *65, *66, *68, *69 and *70 haplotypes are South Asian-specific.ConclusionOverall, we find high genetic heterogeneity within South Asians and identified South Asian-specific putative functional CYP2C9 haplotypes. High frequency of CYP2C9*3 and CYP2C9*3/*3 was observed in South Asian populations. Taken together, current study greatly enriches the knowledge of naturally occurring CYP2C9 variants and its diversity in South Asia, which are relevant to further CYP2C9-related functional research and for personalized medicine.

Dataset Information

Loss-of-function CYP2C9 variants: finding the correct clinical role for Type 2 diabetes pharmacogenetic testing.

Publications

Loss-of-function CYP2C9 variants: finding the correct clinical role for Type 2 diabetes pharmacogenetic testing.

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