Association of immune response- and obesity-related genes with prostate cancer in CLUE II

B79

Background: Chronic intra-prostatic inflammation and obesity are thought to play a role in the pathogenesis of prostate cancer. Thus, polymorphisms in genes related to the host innate or adaptive immune response or in energy regulation, including insulin secretion and sensitivity, could alter the risk of prostate cancer. Methods: 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG and TCF7L2 were genotyped in 264 prostate cancer cases and 264 matched controls nested in the prospective CLUE II cohort of Washington County, MD. Single-locus association analyses were conducted by conditional logistic regression. TagSNPs were selected (exclusive of the candidate SNPs) in IL10 (n=7), CRP (n=4), and TLR4 (n=8) and haplotype analyses were conducted. Results: Carrying the variant allele of IL10 -1082G>A (rs1800896), a known lower producer of the inflammation-inhibitory cytokine IL-10, was associated with an increased risk of prostate cancer when compared with the homozygous wild type (AG: OR, 1.69; 95% CI 1.10-2.60, AA: OR, 1.81; 95% CI, 1.11-2.96, P_trend=0.02). The direction of the association did not vary by stage or grade, although it was strongest among cases that were both organ-confined and low stage (AA/AG vs GG: OR, 2.67, 95% CI, 1.04-6.82). The IL10 -1082G>A (rs1800896) association with total prostate cancer was stronger among users of non-steroidal anti-inflammatory drugs (OR, 3.02; 95% CI, 1.34-6.78) than nonusers (OR, 1.40; 95% CI, 0.88-2.23) and stronger among men who were lean (OR, 2.35; 95% CI, 1.16-4.79) than men who were overweight (OR, 1.49; 95% CI, 0.92-2.40), although the interactions were not statistically significant. Several IL10 haplotypes were associated with total prostate cancer when compared with the most common haplotype. However, these associations were due to high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and IL10 -1082G>A. A candidate SNP (rs4986790; ≥ 1 variant allele vs. 0: OR, 0.60; 95% CI 0.33-1.08, P_trend=0.09) and a tagSNP (rs10116253, OR, 3.05; 95% CI, 1.11-8.41) in TLR4 were weakly associated with prostate cancer risk. None of the other candidate SNPs, nor the TLR4 and CRP haplotypes, were statistically significantly associated with prostate cancer overall. Conclusions: Our prospective study suggests that genetic polymorphisms in IL10 and possibly TLR4 may be associated with risk of prostate cancer. Although none of the candidate SNPs in the genes related to obesity was statistically significantly associated with prostate cancer, this does not rule out the complex role of obesity and its metabolic perturbations in the etiology of prostate cancer.