Murugesan Raju, Vahab Saadi Abdul, Patra Satyajit, Rao Rekha, Rao Jyothi, Rai Padmalatha, Gopinath P M, Satyamoorthy Kapaettu
Manipal Life Sciences Center, Manipal University, Manipal 576104, India.
Exp Ther Med. 2010 Jan;1(1):121-127. doi: 10.3892/etm_00000021. Epub 2010 Jan 1.
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including thiopurine drugs such as 6-mercaptopurine, 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 deficient 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) define the most prevalent mutant alleles associated with loss of catalytic activity reported in several populations. The present study investigated, for the first 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-specific polymerase chain reaction, restriction fragment length polymorphism and confirmatory 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 significant variations in TPMT gene polymorphisms in an Indian population in relation to other human populations and may help to predict both clinical efficacy and drug toxicity of thiopurine drugs.
硫嘌呤甲基转移酶（TPMT）催化芳香族和杂环巯基化合物的S-甲基化反应，这些化合物包括硫嘌呤类药物，如6-巯基嘌呤、6-硫鸟嘌呤和硫唑嘌呤。TPMT活性存在遗传变异，呈三峰分布，89-94%的个体具有高活性，6-11%具有中等活性，约0.3%具有低活性。暴露于硫嘌呤类药物的TPMT活性中等或缺乏的患者会出现严重的造血毒性。TPMT基因（NM_000367.2:c.238G>C、NM_000367.2:c.460G>A和NM_000367.2:c.719A>G）中的三个单核苷酸多态性（SNP）定义了在多个群体中报道的与催化活性丧失相关的最常见突变等位基因。本研究首次调查了印度南部人群中TPMT这三个SNP及其等位基因和基因型的频率分布。从326名印度南部人群个体中采集外周血，并从外周全血白细胞中分离基因组DNA。通过等位基因特异性聚合酶链反应、限制性片段长度多态性和验证性DNA测序确定多态性位点的基因型。纯合TPMT（）1/（）1的估计基因型频率为97.24%，杂合TPMT（）1/（）2和TPMT（）1/（）3B的频率均为0.61%，杂合TPMT（）1/（）3C的频率为1.53%。在研究的印度人群中，杂合突变体的频率为2.76%。这项研究表明，印度人群中TPMT基因多态性与其他人群相比存在显著差异，这可能有助于预测硫嘌呤类药物的临床疗效和药物毒性。
