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.

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population.

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.