Genetic variants in the enhancer region of the thymidylate synthase gene in the Chilean population

Abstract

AimsThymidylate synthase (TYMS) is an important target enzyme for the fluoropyrimidines. The TYMS gene enhancer region possesses tandemly repeated ( TSER ) sequences that are polymorphic in humans and different among ethnic g roups. The aims of this study were to estimate the frequencies of the TSER variants in two hospital samples located in the northern (HSJ) and eastern (CLC) parts of Santiago, Chile, and compare them with the frequencies in other populations of different ethnic orig in. MethodsGenotyping of TSER variants in 368 Chilean subjects (HSJ = 178 and CLC = 190) by polymerase chain reaction; products of amplification were electrophoresed, obtaining fragments of 250 bp for allele TSER * 3 and 220 bp for allele TSER * 2. ResultsThe two hospital samples had different degrees of Amerindian admixture (HSJ 34.5%; CLC 15.9%), which was not reflected in the observed frequencies of the CLC TSER * 3 : 56.8% and HSJ TSER * 3 : 53.4%. ConclusionsOur results are unexpected, considering that genetic markers in the Chilean population generally show allele frequencies between those observed in European Caucasians and Amerindians and that the percentage of Amerindian admixture in CLC is lower than in HSJ. Both hospitals should have had greater frequencies of TSER * 3 than were found and the frequency should have been g reater in HSJ than in CLC; the only logical explanation of our results is that the frequency of this allele in aboriginal Chilean people is much lower than the 80% estimated for Mongoloid populations.Thymidylate synthase (TYMS) catalyses the intracellular conversion of deoxyuridine-5 ′ -monophosphate (dUMP) to 2 ′ -deoxythymidine -5 ′ -monophosphate (dTMP), which is essential for DNA replication. TYMS is an important target for cancer chemotherapy drugs such as 5-fluorouracil and raltitrexed. These drugs prevent DNA synthesis by forming stable complexes with TYMS and its folate cofactor, thus blocking the conversion of dUMP to dTMP [1]. Therefore, the in vivo regulation of TYMS is important both in normal tissue biology and in cancer therapeutics [2]. The human TYMS promoter has recently been characterized, identifying several important mechanisms for gene regulation [2,3]. Tandem repeat sequences were identified near the initiation site. Analysis of the 5 ′ -untranslated region of the TYMS gene identified a tandem repeat sequence that is a cis -acting enhancer element. This TYMS enhancer region ( TSER ) was shown to be polymorphic, containing

Correlation between Thymidylate Synthase Gene Variants, RNA and Protein Levels in Primary Colorectal Adenocarcinomas

“…57 The frequency of the 2R/2R, 3R/3R and 2R/3R genotypes was 24%, 15% and 61%, respectively, which is consistent with frequencies previously reported for Caucasians. 28,58,59 Although four to nine repeats of 'R' in the TS enhancer region have been described, 28,29 no alleles with more than three tandem repeats were observed in the present study. The TS genotypes have been found to be identical in normal and tumour tissue of homozygous individuals, suggesting that the genetic variants are stable through carcinogenesis.…”

Distribution of the Most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia

“…The MTHFR C677T polymorphism shows wide regional and ethnic variations among the European population (23.0–41.0%), Asian countries (40.0–44.0%) and Africans (12.0, 6.0%) [ 31 , 32 ]. Inter-population differences have also been documented for TYMS-TSER genetic variants; the frequencies reported for TSER*3 allele within the Asian, indigenous European and African populations were 0.81, 0.60 and 0.52, respectively [ 32 , 33 ].…”

Genetic Variants of Cytochrome <b><i>CYP2D6</i></b> in Two Mixed Chilean Populations

“…EDTA blood samples were acquired from 125 participants from the San José Hospital (HSJ), which belongs to the National Health Service and serves mainly lower socioeconomic classes, and from 125 participants from Clínica Las Condes (CLC), a private hospital serving mainly higher socioeconomic classes. The degree of Amerindian admixture was obtained from the study by Acuña et al [18] , which used the same blood samples. DNA was isolated from peripheral blood using standard methods and stored at 4 ° C until used [19] .…”

“…Hardy-Weinberg equilibrium was analyzed by means of the χ 2 test [26] . The estimations of the percentages of Amerindian mixture of the subpopulations attended by CLC and HSJ were obtained from the paper by Acuña et al [18] . The differences between the allele frequencies among the populations were tested using Fisher's exact test.…”