Profiling of genetic variations in inflammation pathway genes in relation to bladder cancer predisposition

Purpose: Compelling evidence has indicated that inflammation plays an important role in cancer development. We sought to test the hypothesis that common sequence variants in the inflammation pathway modulate bladder cancer risk. Experimental Design: We genotyped 59 potentially functional single nucleotide polymorphisms from 35 candidate inflammation genes in a case-control study including 635 Caucasian bladder cancer patients and 635 matched controls. Results: The most significant finding was in the 3′-untranslated region of PTGS2 (exon10+837T>C, rs5275), which was associated with a significantly reduced risk (odds ratio, 0.68; 95% confidence interval, 0.54-0.87; P = 0.002) and remained significant after multiple comparison adjustment. Consistently, the most common PTGS2 haplotype containing the common allele of exon10+837T>C was associated with a significantly increased risk (odds ratio, 1.27; 95% confidence interval, 1.06-1.52; P = 0.008). In contrast, the haplotypes containing at least one variant allele of exon10+837T>C were all associated with a decreased risk. In a combined analysis to assess the cumulative effects of inflammation single nucleotide polymorphisms on bladder cancer risk, we found that in the anti-inflammation pathway, but not in the proinflammation pathway, when compared with individuals with a few adverse alleles, individuals with more adverse alleles had a significantly increased risk in a dose-dependent manner (P_trend = 0.012). To further elucidate the functional mechanism of these associations, we redefined the adverse alleles based on literature-reported functional results and found that individuals with a higher number of inflammation-enhancing alleles in the anti-inflammation pathway exhibited a greater bladder cancer risk. Conclusions: Our results strongly suggest that common variants in inflammation genes affect bladder cancer susceptibility individually and jointly.