Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Human Molecular Genetics (Impact Factor: 6.39). 01/2012; 21(8):1918-30. DOI: 10.1093/hmg/ddr619
Source: PubMed


A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44-0.69, P = 3.3 × 10(-7)). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.

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Available from: Ludmila Prokunina-Olsson,
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    • "Interestingly, the UGT1A8 and UGT2B4 genotypes, associated with decreased UGT enzyme activity and increased unconjugated bilirubin levels, were also significantly associated with increased risk of esophageal cancer (Dura et al., 2012). In another study, the UGT1A gene cluster on chromosome 2q37.1 was identified in a cohort of patients with bladder cancer suggesting that enhanced UGT1A may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium (Tang et al., 2012). In a meta-analysis of 21 case-control studies cancer risk was associated with intermediate, and low activity of UGT1A7 genotypes, found predominantly in Asians (Lu et al., 2011). "
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