Detection of one single mutation predicts thiopurine S-methyltransferase activity in a population of Saami in northern Norway

Abstract

Thiopurine S-methyltransferase (TPMT) activity exhibits genetic polymorphism. The purpose of this investigation was to identify TPMT mutant alleles in the Saami population as a basis of developing genotyping tests for prediction of TPMT activity. The most predominant allele in Saamis (n = 194) was the TPMT*3C allele (A719G mutation) representing 92% of the mutant alleles, with an estimated allelic frequency of 3.3%. The most frequent allele in Caucasians (n = 66) living in the same geographic area was the TPMT*3A (A719G and G460A mutations) representing 91% of the mutant alleles, with an estimated allelic frequency of 3.4%. A test for one mutation, A719G, may prospectively identify more than 90% of the Saami individuals who require reduction in thiopurine dose to avoid hematopoietic toxicity. In a Norwegian population, comprising both the major Caucasian population and a minor Saami population, the same genotyping tests (eg, tests for the A719G and G460A mutations) may be used.

Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease

“…These previous investigations identified TPMT*3A as the most frequently occurring nonfunctional allele, followed by TPMT*3C, with allele frequencies of 3.4 -4.5% and 0.25-3.3%, respectively (21,24,33 ). However, for TPMT*2 we obtained an eightfold lower allele frequency (0.06% vs 0.5%) compared with a previous estimate (24 ).…”

“…This is the most frequent nonfunctional TPMT allele among Caucasians in Europe and America, with ϳ10% of the population carrying a nonfunctional allele (3,(21)(22)(23)(24). In Asia, the overall frequency of nonfunctional TPMT alleles is comparatively lower.…”

Thiopurine methyltransferase polymorphisms in a Brazilian population

“…36 The TPMT*3C allele (A719G), with a frequency of 1.0%, has been previously shown in several other ethnic groups including the Saamis, Kenyans, Ghanaians, AfricanAmerican and Asians. [22][23][24]29,30 Finally, the very uncommon allele TPMT*3B (G460A) was found in only one subject, thus indicating this allele to be a rare one. 11,16,23 To date, of the two strategies used to identify TPMT-deficient and heterozygous patients, TPMT genotype can easily be performed.…”

“…20 Furthermore, bimodal or trimodal activity patterns have been shown in several populations. 16,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] Since ethnic differences have been demonstrated worldwide, it remains to be elucidated in Brazil, the fifth largest populated country in the world. The present-day Brazilian populations reflects the result of five centuries of interethnic crosses between peoples from almost all continents (Europeans, African, Asians) as well as autochthonous Amerindians, all forming one of the most heterogeneous populations in the world.…”

Thiopurine S-Methyltransferase Pharmacogenetics: Genotype to Phenotype Correlation in the Slovenian Population

“…Individuals with intermediate or defi cient TPMT activity thus have a higher risk for toxic events such as life-threatening myelosuppression and/or secondary tumor development after receiving standard doses of thiopurine drugs [22] . Therefore, a reduction to 6-14 and 50-100% of the standard dosage of thiopurine drugs is required for homozygous and heterozygous patients, respectively [23][24][25] . On the other hand, patients with a very high TPMT activity may be undertreated and/or have a greater risk of early leukemia relapse [26,27] .…”