Abstract 916: Functional significance of sulfotransferase 1A1 polymorphisms in the 3’ untranslated region in determination of enzymatic activity

Abstract

Abstract SULT1A1 is the most highly expressed hepatic sulfotransferase and is involved in the biotransformation of a wide variety of endo-and xenobiotics. The inter-individual variation of SULT1A1 enzyme activity can markedly influence drug toxicity and/or treatment efficacy in the clinical setting. We and others have examined a common SNP in the coding region of SULT1A1 (Arg213His, SULT1A1*1/2), as well as several SNPs in the proximal promoter that were associated with altered enzymatic activity. However, the SNPs account for only a small proportion of variation of SULT1A1 activity in human populations. In order to identify SNPs that markedly affect SULT1A1 activity, we resequenced the 3’UTR of SULT1A1 in 97 liver samples. Direct sequencing revealed 2 SNPs (902A>G, 973C>T) in the 3’UTR and 1 SNP (1307G>A) in the 3’ flanking region. Interestingly, we found these SNPs are in absolute linkage disequilibrium and are closely associated with SULT1A1 expression and enzymatic activity. To further elucidate the important role of SNPs in 3’UTR, we performed haplotype analysis to predict the collective effects of functional genetic variants in the 3’ UTR regions, the SULT1A1*1/2 polymorphism and copy number variation on SULT1A1 enzymatic activity. Notably, two major haplotypes (ACGG and GTAA) were significantly correlated with SULT1A1 activity, Copy number did not influence on SULT1A1 activity in liver samples. 3’UTR SNPs are in linkage disequilibrium with SULT1A1*1/2 polymorphism, so to examine the effect of the SULT1A1*1/2 polymorphism, we performed haplotype-activity assay in 499 Caucasian and 129 African American subjects. Haplotype and regression analysis both strongly suggest that the 3’UTR SNPs are the pivotal predictor of SULT1A1 activity. MicroInspector predicts 3116C>T influences the binding of miR-631 to SULT1A1 3’UTR. Furthermore, in vitro luciferase reporter assays and overexpression of miRNA mimics and inhibitors indicated that SULT1A1 is a direct target of miR-631 and miR-631 differentially regulates the C and T alleles of rs1042157. The results suggest, for the first time, that allele-specific regulation of SULT1A1 by miR-631 contributes to the activity variation of SULT1A1 in population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 916.