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Background  Variation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of the  CARD15  gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since the  CARD15  gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at the  CARD4 ,  CARD8  and  CARD15  loci on the risk for sporadic CRC, using a large patient sample from Northern Germany.    Methods  A total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (≤50 age at diagnosis) were performed for all  CARD  loci and subgroup analyses for diverse age strata were carried out for  CARD15  mutations R702W, G908R and L1007fs. In addition, all SNPs were tested for association with disease presentation and family history of CRC.    Results  No significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (≤45 age at diagnosis) with early disease manifestation the mutant allele of  CARD15  R702W was found to be significantly associated with disease susceptibility (9.7% in cases  vs  4.6% in controls; P allelic  = 0.008, P genotypic  = 0.0008, OR allelic  = 2.22 (1.21-4.05) OR ressessive  = 21.9 (1.96-245.4).    Conclusion  Variation in the innate immunity genes  CARD4 ,  CARD8  and  CARD15  is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution of  CARD15  for CRC patients with very early disease manifestation, mainly driven by variant R702W.

Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer