The association between common polymorphisms in genes related to inflammatory response and obesity with colorectal cancer in CLUE II

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Background: Several lines of evidence suggest that chronic inflammation and obesity are strongly associated with colorectal cancer. The propensity to mount an innate or adaptive immune response and to regulate energy consumption and metabolism is modified by germ-line variation.
 >Methods: We investigated the association of colorectal cancer with 17 candidate single nucleotide polymorphisms (SNPs) in key immune response related genes (IL1B, IL6, IL8, TNF, IL10, CRP, RNASEL, TLR4) and genes involved in obesity/energy regulation (LEP, ADIPOQ, PPARG, TCF7L2). Haplotype tagging SNPs were also chosen for the CRP, IL10, and TLR4 genes, which showed promising associations in the candidate SNP analysis. Incident colorectal cancer cases (n=208) and matched controls (n=416) were identified between baseline in 1989 and 2002 among participants in a community-based cohort (CLUE II) in Washington County, Maryland. Single-locus association analysis was conducted using conditional logistic regression.
 >Results: Compared with the wild type genotype (AA) at the candidate IL10 -1082 locus (rs1800896), carrying one (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.53 - 1.18) or two (OR, 0.58; 95% CI, 0.35 - 0.95) variant G alleles, a known higher producer of the anti-inflammatory cytokine IL-10, was associated with a lower risk of colorectal cancer (P_trend, 0.03). Carrying at least one variant allele (A) of a SNP in the second intron of adiponectin (ADIPOQ, rs1501299) was associated with an increased risk of colorectal cancer when compared with the CC genotype (OR, 1.42; 95% CI, 0.99 - 2.04; P_trend, 0.09). No other statistically significant associations were observed for the candidate SNPs with colorectal cancer. The candidate SNP associations did not vary greatly by cancer subsite (colon vs. rectum). Evidence for effect modification (P_interaction ≤ 0.07) by body mass index or aspirin/non-steroidal anti-inflammatory drug use was present for several of the candidate SNPs (ADIPOQ, LEP -2548 [rs2167270], TLR4 -11381 [rs11536889], PPARG -Pro¹²Ala [rs1801282], IL8 -251 [rs4073]). Statistically significant associations with colorectal cancer were also observed for several tag-SNPs at the CRP (rs2794521, rs2808630, rs3093077, rs1417938), IL10 (rs1800890, rs3024496, rs3024498) and TLR4 (rs7873784, rs11536891) loci. However, the IL10 tag-SNPs associations were due to high linkage disequilibrium between the tag-SNPs and the candidate IL10 -1082 SNP.
 >Conclusions: Our prospective study suggests that polymorphisms in genes related to the innate or adaptive immune response or in obesity/energy regulation may be associated with risk for colorectal cancer.
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 >Funding: American Institute for Cancer Research, and NCI Contract N01-CO-12400