Genetic Polymorphism of Thiopurine S-Methyltransferase in a Northeastern Thai Population

Abstract

Genetic polymorphism of Thiopurine S-methyltransferase (TPMT) is a

cytosolic enzyme that preferentially catalyzes the S-methylation of thiopurine drugs

including azathioprine, 6-mercaptopurine and thioguanine. TPMT activity exhibits

autosomal codominant genetic polymorphism and patient inheriting TPMT deficiency

are at high risk of potentially fatal hematopoietic toxicity. To date, more than eight

mutant alleles have been reported, with TPMT*2, TPMT*3A and TPMT*3C being

the most common mutant alleles. These variant alleles results from point mutations in

the TPMT open reading frame leading to decrease in enzymatic activity. Ethnic

differences in the frequency of mutant alleles are now recognized. TPMT*3A is the

most prevalent mutant allele in Caucasians, with TPMT*3C and TPMT*2 being rare

allele whereas TPMT*3C is the most prevalent mutant allele in East  Asians. The

aims of the present study were to elucidate the genetic basis for the TPMT

polymorphism in a Northeastern Thai population. TPMT*1 to TPMT*3 were

analyzed using the polymerase chain reaction-restriction fragment length

polymorphism (PCR-RFLP) and allele specific PCR. Among the 200 Northeastern

healthy Thai subjects genotyped, 181 subjects (90.5%) were homozygous wild type

allele (TPMT*1/TPMT*1), 18 subjects (9.0%) were heterozygotes (TPMT*1/

TPMT*3C) and 1 subject (0.5%) was homozygous mutant (TPMT*3C/ TPMT*3C).

Only TPMT*3C variant allele was found in this population and the frequency of this

mutant allele accounts for 5%. This study confirms ethnic differences in TPMT allele

frequency and about 9.5% of a Northeastern Thai population have an increased risk

for thiopurine-induced toxicity.