การศึกษาการกลายพันธุ์ของยีน UGT2B17 ในตัวแทนประชากรไทยมุสลิมที่จังหวัดสงขลา

Abstract

The human UDP glucuronosyltransferase 2B17 (UGT2B17) enzyme play an important role in phase II drug metabolism, that catalyze the glucuronidation of various substrates, including endogenous as well as xenobiotic, such as steroid hormones (testosterone and its metabolites), exemestane and vorinostat. UGT2B17 is encoded by the UGT2B17 gene. The mutation of the UGT2B17 gene may affect to loss of enzyme activity or no enzyme activity. Although the polymorphic gene deletion of UGT2B17 gene has a high prevalence in Asian (67%), there is no report in Thai population. The aim of this study was to determine the genetic polymorphism of UGT2B17 in promoter and exon 1 regions in representative Thai-Muslim population in Songkhla province. Ninety-nine genomic DNAs were extracted from Thai-Muslim neonates cord blood samples, which were collected at Songkhla hospital and then were amplified the promoter and exon 1 regions of UGT2B17 gene by PCR. The mutations of UGT2B17 gene were detected by direct sequencing. The result showed that 53 samples (53.54%) were homozygous deletion (del/del), 41 samples (41.41%) were heterozygous deletion (del/ins), and 5 samples (5.05%) were wild-type homozygous insertion (ins/ins) of UGT2B17 gene. Two known SNPs were found in promoter region (-198G>A and 15C>T) of wild type UGT2B17 gene. The nucleotide sequence of UGT2B17 deletion polymorphism was similar to UGT2B15 gene, which indicated that this sample lack of UGT2B17 gene. One known SNPs (253T>G, YPD) and 1 novel SNPs (643T>G, M L ) were found in exon 1 region of UGT2B15 gene. The genotype frequency of homozygous mutation (G/G) and heterozygous mutation (T/G) for 253T>G region were 0.1698 and 0.5849, respectively (40/53 72, 75.47%). The genotype frequency of heterozygous mutation (A/T) for 643A>T region was 0.0377 (2/53 91, 3.77%). Allele frequency of the two mutations arranged in descending order are 0.4623 (253T>G) and 0.0189 (643T>G). One SNPs (253T>G) was in Hardy-Weinberg equilibrium (p>0.05). On the other hand, 643T>G was not followed to the Hardy-Weinberg equilibrium (p<0.05). Conclusion, Homozygous deletion (del/del) of the UGT2B17 is the highest prevalence in representative Thai-Muslim population which is similar to other Asians (Japanese, Korean and Chinese). The polymorphic gene deletion of the UGT2B17 leads to a lack of enzyme activity, which alters glucuronidation of steroid hormones (testosterone and its metabolites) and associated to increase the risk of prostate cancer. Moreover, UGT2B17 deletion polymorphism has been found associated to increase the risk of upper aero digestive tract (UADT) cancer. However, it should be considered other factors which may related with disease development such as gender, age or environment etc.