Thiopurine S-methyltransferase alleles, TPMT*2, *3B, and *3C, and genotype frequencies in an indian population

Thiopurine S-methyltransferase (tpmt) catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including thiopurine drugs such as 6-mercapto-purine, 6-thioguanine and azathioprine. tpmt activity exhibits genetic variation and shows tri-modal distribution with 89-94% of individuals possessing high activity, 6-11% intermediate activity and approximately 0.3% low activity. Patients with intermediate or defcient TPMT activity exposed to thiopurine drugs show severe hematopoietic toxicity. three single nucleotide polymorphisms (Snps) in TPMT (nm_000367.2:c.238G>c, nm_000367.2:c.460G>a and NM_000367.2:c.719A>G) defne the most prevalent mutant alleles associated with loss of catalytic activity reported in several populations. The present study investigated, for the frst time, the frequency distribution of these three Snps of TPMT, their alleles and genotypes in a Southern indian population. peripheral blood was obtained from 326 individuals of a Southern indian population, and genomic dna was isolated from total peripheral white blood cells. the genotypes at the polymorphic loci were determined by allele-specifc polymerase chain reaction, restriction fragment length polymorphism and confrmatory DNA sequencing. The estimated genotype frequency for homozygous TPMT*1/*1 was 97.24%, for heterozygous TPMT*1/*2 and TPMT*1/*3B, 0.61% each, and for heterozygous TPMT*1/*3C, 1.53%. the frequency of heterozygous mutants in the studied indian population was 2.76%. This study demonstrated signifcant variations in TPMT gene polymorphisms in an indian population in relation to other human populations and may help to predict both clinical effcacy and drug toxicity of thiopurine drugs.