Association study of UGT1A9 promoter polymorphisms with DILI based on systematically regional variation screen in...

Drug-induced liver injury (DILI) is caused by unpredictable adverse drug reaction due mainly to the accumulation of hepatotoxic compounds in the liver resulting in significant damage. Drug-metabolizing enzymes have been prime targets for molecular studies relevant to DILI. The gene UGT1A9 mainly expresses in the liver and has an important role in drug metabolism. The Han Chinese has a very long and complex demographic history, and the population stratification arising from the interplay of different geographic areas may influence the polymorphism pattern. We selected 260 healthy subjects in three different geographic areas (including Xian, Shanghai and Liuzhou) for systemic screening and analysis of single-nucleotide polymorphisms (SNPs) in the promoter region of UGT1A9. Eight SNPs were identified and no regional disparity exists among the three populations. Based on these results, 213 DILI patients from all over the Chinese mainland were further recruited to investigate possible association between UGT1A9 and DILI. We observed statistically significant associations between SNP rs2741045 and DILI at both allele and genotype levels (allele: P=0.032; genotype: P=0.029; after Bonferroni correction). Also, multivariate interaction analysis discovered the interaction between rs2741045 and age associated with DILI significantly. This is the first such screening study to investigate the association between UGT1A9 promoter polymorphisms and DILI in the Chinese population and it could provide the basis for further study of DILI mechanisms.