การศึกษาความผันแปรทางพันธุกรรมของยีน UGT3A1 ในตัวแทนประชากรมุสลิมในจังหวัดสงขลา

Abstract

UDP-glucuronosyltransferases (UGTs) are the important enzymes in phase II drug metabolism. UGTs are currently divided into 4 families: UGT1, UGT2, UGT3 and UGT8. There are two types of UGT3: UGT3A1 and UGT3A2. The main substrates of UGT3A1 are ursodeoxycholic acid (UDCA), a bile acids and 7ẞ-hydroxycholesterol, the main component of oxLDL which is the cause of plaque in arterial blood vessels. Thus, the mutation of the UGT3A1 gene may lead to abnormalities in the metabolism of bile acids, then may cause gallstones in the gallbladder and may increase the risk of artherosclerosis. Therefore, this study aims to investigate the mutation of UGT3A1 gene in muslim population in Songkhla province. To detect the allele frequency in the genetic variation in promoter, exon 1 and exon 4 area in 97 samples of neonates umbilical cord blood who was born at Songkhla Hospital, Songkhla province. The primer and PCR were used to increase the numbers of gene fragments and to determine the size of gene fragments by 1.5% agarose gel electrophoresis and DNA sequencing to detect the mutation. The results of the study revealed two mutations in the UGT3A1 gene: 1 novel SNPs at promoter region (-219A> G) and 1 known SNPs at exon 4 region (361T> G) (C121G). The mutation in exon 4 has genotype frequency of homozygous mutation ( 0.044) and heterozygous mutation (0.332) and the mutation at -219A> G, the genotype frequency of homozygous mutation is 0.011. Allele frequency of the two mutations, ranging from high to low are 361T>G (0.21) and -219A> G (0.01). Based on the analysis of the Hardy-Weinberg equilibrium of both UGT3A1 mutation, the mutation in exon 4 (361T> G) was followed to the Hardy-Weinberg equilibrium and at the promoter (-219A>G) was not followed to the Hardy- Weinberg equilibrium. It can be concluded that the allele frequency of UGT3A1 gene mutation at 361T>G (allele frequency (0.249)) in neonates born at Songkhla Hospital was not differences from other Asian people such as Japan and China (allele frequency (0.20)). The mutation of the UGT3A1 gene at this location causes an inactive enzyme. So the elimination of bile acid is abolished. This may result in congestion of the bile more easily than people who have normal gene. It may also be an indicator of artherosclerosis risk. However, UGT3A1 gene should be screened before treatment with a substrate of UGT3A1 to prevent adverse effects which may cause worsening of gallstone.