engleski

Thymidylate Synthase Gene Polymorphisms in Croatian Population

Thymidylate synthase (TS) is crucial enzyme in the nucleotide biosynthetic pathway because it calalyzes the reductive methylation of dUMP by 5, 10-MTHFR to form dTMP. TS gene has been an important target for a variety of chemotherapeutics such as 5-FU. The human TS promoter region includes polymorphic enhancer containing two or three 28-bp tandem repeats and has been implicated in affecting on TS mRNA expression. The majority of individual human TS alleles harbor either a double repeat (2R) or a triple repeat (3R) for this polymorphism, creating genotypes of 2R/2R, 2R/3R i 3R/3R. Individuals homozygous for the 3R were found to have elevated intratumoral TS mRNA and protein level. Recently identified G→ C SNP in the second repeat of the 3R alleles has shown that the 3R sequence with G has three to four times greater efficiency of translation than the 3R with C and the 2R sequence. Due to associations of the TS polymorphisms with the prognosis of several tumor types, we performed a study to determine the distribution of TS polymorphisms in Croatian population. A total of 125 healthy unrelated individuals were genotyped for the TS 5' UTR polymorphisms using PCR-RFLP method with HaeIII restriction enzyme. Genotype frequencies for 5’ UTR TS polymorphisms were 26, 4 %, 16%, 2, 4%, 42, 4%, 8, 8% and 4% for 2R/3G, 3G/3C, 3G/3G, 2R/2R, 2R/3C, 3C/3C genotype respectively. Our results showed that in Croatian population low TS expression genotypes were more frequent (55.2%) than high TS expression genotypes (44.8%) but not significant.

thymidylate synthase; polymorphisms; pharmacogenetics

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