Polymorphism of the thiopurine S-methyltransferase gene in African- Americans

Abstract

The molecular basis for the genetic polymorphism of thiopurine S -methyltransferase (TPMT) has been estab-lished for Caucasians, but it remains to be elucidated in African populations. In the current study, we determined TPMT genotypes in a population of 248 African-Americans and compared it with allele frequencies in 282 Caucasian Americans. TPMT genotype was determined in all individuals with TPMT activity indicative of a heterozygous genotype (</=10.1 U/ml pRBC, n = 23African-Americans, n = 21 Caucasians) and a control group with TPMT activity indicative of a homozygous wild-type genotype (>10.2 U/ml pRBC, n = 23 African-Americans, n = 21 Caucasians). No mutant alleles were found in the high activity control groups. The overall mutant allele frequencies were similar in African-Americans and Caucasians (4.6 and 3.7% of alleles, respectively). However, while TPMT*3C was the most prevalent mutant allele in African-Americans (52.2% of mutant alleles), it represented only 4.8% of mutant alleles in Caucasians ( P < 0.001). In contrast, TPMT*3A and TPMT*2 were less common in African-Americans (17.4 and 8.7% of mutant alleles), whereas TPMT*3A was the most prevalent mutant allele in Caucasians (85.7% of mutant alleles). A novel allele ( TPMT*8 ), containing a single nucleotide transition (G644A), leading to an amino acid change at codon 215 (Arg-->His), was found in one African-American with intermediate activity. These data indicate that the same TPMT mutant alleles are found in American black and white populations, but that the predominant mutant alleles differ in these two ethnic groups.

Genomic structure and multiple single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene

“…Most of the nucleotide metabolites of these drugs can be methylated and inactivated by TPMT (Elion 1989; Krynetski et al 1995a). Several variant alleles of the TPMT gene that affect its catalytic activity have been reported Otterness et al 1997;Otterness et al 1998;Ameyaw et al 1999;Hon et al 1999). Although the proportion of Asian individuals showing low TPMT activity is similar to that in European or American populations, the frequencies of the known genetic variants are very low in comparison to their frequencies in white and black subjects (Collie-Dugnid et al 1999).…”

“…TPMT*1 corresponds to the wild type, which encodes a highly active product. In earlier studies, the four other alleles accounted for about 80% of white or black subjects whose TPMT activity was low or intermediate Otterness et al 1997;Otterness et al 1998;Ameyaw et al 1999;Hon et al 1999); the TPMT*2 allele includes a G-to-C substitution at nucleotide 238 of the cDNA. TPMT*3 alleles have been classified into three subgroups: TPMT*3A contains two substitutions (G460A and A719G); TPMT*3B has G460A alone; and TPMT*3C contains only the A719G substitution.…”

“…Recent studies have established that differences in the activity of this enzyme reflect variations in the TPMT gene itself (Krynetski et al 1995b), which has been reported to consist of ten exons and to be located on chromosome 6p22.3 (Szumlanski et al 1996). Several variant alleles containing base substitutions have been reported to date, among them five major alleles (TPMT*1, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C) Otterness et al 1997;Otterness et al 1998;Ameyaw et al 1999;Hon et al 1999). TPMT*1 corresponds to the wild type, which encodes a highly active product.…”

Thiopurine methyltransferase phenotypes and genotypes in Brazilians

“…The genetic basis and the molecular mechanisms underlying TPMT polymorphism have been intensively investigated and, to our knowledge, nine nonfunctional mutant alleles have been described to date [2]. Four of these alleles, namely TPMT Ã 2 (238G.C), TPMT Ã 3A (460G.A and 719A.G), TPMT Ã 3B (460G.A) and TPMT Ã 3C (719A.G) account for 78-95% of the lower-activity genotypes in different populations [3,4]. In the present study, phenotyping and genotyping procedures were combined to evaluate the polymorphism of TPMT in 306 healthy Brazilian subjects.…”

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

“…Patients with low or intermediate TPMT activity phenotypes who are treated with standard doses of AZA or 6-MP are at risk of myelosuppression caused by excess accumulation of 6-TGN [73]. Intermediate or low TPMT activity is most frequently associated with TPMT*2, TPMT*3A or TPMT*3C alleles in Caucasians [73], and TPMT*3C in African-Americans [74].…”