Genetic Variability in IkBKB and NFkB1, Interactions with NSAID Use and Risk of Colorectal Cancer in the Colon Cancer Family Registry

Abstract

The NFκB-signaling pathway is involved in promoting inflammation, colorectal carcinogenesis and the reduction of colorectal cancer risk induced by non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesize that genetic variation in two key genes in this pathway, <italic>NFκB1</italic> and <italic>IκBKβ</italic>, may be associated with the risk of colorectal cancer and interact with NSAID use. In a population-based case-unaffected sibling control study of 1,584 incident colorectal cancer cases and 2,516 sibling controls, we investigated the role of 42 <italic>NFκB1</italic> and 10 <italic> IκBKβ</italic> single nucleotide polymorphisms (SNPs). A combined tagSNP and candidate SNP approach was used to maximize screening of genetic variability. In <italic>IκBKβ</italic>, carriers of the variant alleles in rs5029748 (C>A intron 2) and rs10958713 (G>A intron 19) had a 27-38% decreased risk of colon cancer (p-trend = 0.013 and 0.005, respectively) and individuals homozygous for the variant allele of rs9694958 (A>G intron 5) had a 74% decreased risk of colorectal cancer (p = 0.048). No SNP in <italic>NFκB1</italic> was significantly associated with the risk of colorectal cancer. Significant associations between SNPs of both <italic>NFκB1</italic> and <italic> IκBKβ</italic> and CRC risk reported in a previous study were replicated here with similar trends. Two SNPs in <italic>IκBKβ</italic> and three SNPs in <italic>NFκB1</italic> showed statistically significant interactions (p<0.05) with NSAID use. Ultimately, the findings of this study suggest genetic variability in these genes are likely associated with risk of colorectal cancer, with variation in <italic>IκBKβ</italic> particularly associated with a decreased risk of colon cancer. These findings increase evidence that the NFκB-signaling pathway plays a role in colorectal carcinogenesis. Additionally, the significant interactions between NSAID use and polymorphisms in <italic>NFκB1</italic> and <italic>IκBKβ</italic> strengthen the evidence that NSAIDs function, at least partially, through an NFκB-dependent pathway.