Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective.

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual’s genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.

Effect of CYP2C9 AND VKORC1 genetic polymorphisms on warfarin dose requirement in south indian population.

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genetic polymorphisms were strongly associated with warfarin dose requirement in Caucasians, African Americans and other populations. Our aim was to evaluate the effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirement in south Indian population. A total of 150 patients on warfarin with stable INR (2- 3.5) for the past 3 months were recruited. The genotypes of CYP2C9*2 and *3 and VKORC1 -1639G>A were compared with mean daily warfarin dose (MDWD). The variant allele frequency of VKORC1 -1639G>A was found to be 10.4% and CYP2C9*2 and CYP2C9*3 were found to be 4.5% and 6.6%, respectively. Our study showed that the mean daily warfarin dose is higher in patients with wild type genotypes of CYP2C9 and VKORC1 compared to those with variant genotypes. Multivariate regression analysis revealed that age, body mass index (BMI), duration of therapy and genetic polymorphisms of CYP2C9 and VKORC1 together contribute to 36.1% variability in MDWD in south Indian population.

Inter and intra ethnic variation of vitamin K epoxide reductase complex and cytochrome P450 4F2 genetic polymorphisms and their prevalence in South Indian population.

BACKGROUND: Genetic variation in the vitamin K epoxide reductase complex (VKORC1) and cytochrome P450 4F2 (CYP4F2) genes were found to be strongly associated with the oral anticoagulant (OA) dose requirement. The distribution of genetic variation in these two genes was found to show large inter‑ and intra‑ethnic difference. MATERIALS AND METHODS: A total of 470 unrelated, healthy volunteers of South Indians of either sex (age: 18‑60 years) were enrolled for the study. A 5 ml of venous blood was collected and the genomic deoxyribonucleic acid (DNA) was extracted by using phenol‑chloroform extraction method. Real‑time quantitative polymerase chain reaction (RT‑PCR) method was used for genotyping. RESULTS: The variant allele frequencies of VKORC1 rs2359612 (T), rs8050894 (C), rs9934438 (T) and rs9923231 (A) were found to be 11.0%, 11.8%, 11.7% and 12.0%, respectively. The variant allele VKORC1 rs7294 was (80.1%) more frequent and the variant allele CYP4F2 * 3 was found to be 41.8% in South Indians. The allele, genotype and haplotype frequencies of VKORC1 and CYP4F2 gene were distinct from other compared HapMap populations (P < 0.0001). CONCLUSION: The findings of our study provide the basic genetic information for further pharmacogenetic based investigation of OA therapy in the population.

Genetic analysis of OCT1 gene polymorphisms in an Indian population.

BACKGROUND: Genetic variants of the organic cation transporter (OCT1) gene could influence interindividual variation in clinical response to metformin therapy. The genetic basis for the single-nucleotide polymorphism (SNP) of OCT1 gene has been established in other populations, but it remains to be elucidated in the Indian population. This study is focused on OCT1 gene variants rs2282143 (P341L, 1022C>T), rs628031 (M408V, 1222A>G) and rs622342 (1386C>A) frequency distributions in the South Indian Tamilian population. MATERIALS AND METHODS: A total of 112 unrelated healthy subjects of South Indian Tamilian origin, aged 18–60 years, of either sex were recruited for the study. Genotyping was determined using the quantitative real time-polymerase chain reaction and polymerase chain reaction followed by restriction fragment length polymorphism methods. RESULTS: Allele frequencies of rs2282143, rs628031and rs622342 polymorphisms were 8.9%, 80.3% and 24.5%, respectively. Interethnic differences in the genotype and allele frequencies of OCT1 gene polymorphism were observed when compared with other major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5–16.8% and 76.2–81%) and African Americans (8.2% and 73.5%) than in Caucasians (0–2% and 57.4–60%). CONCLUSION: This is the first time the frequency of OCT1 gene polymorphism was determined in the Indian population, and is similar to the frequencies observed in African-Americans and other Asian populations but different from those in Caucasians. The data observed in this study would justify further pharmacogenetic studies to potentially evaluate the role of OCT1 gene polymorphism in the therapeutic efficacy of metformin.