Research article

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

Nikolaus Möckelmann^{* 1} , Witigo von Schönfels^{* 1} , Stephan Buch^1,2 , Oliver von Kampen¹ , Bence Sipos³ , Jan Hendrik Egberts⁴ , Philip Rosenstiel⁵ , Andre Franke⁵ , Mario Brosch¹ , Sebastian Hinz⁴ , Christian Röder⁶ , Holger Kalthoff⁶ , Ulrich R Fölsch¹ , Michael Krawczak^2,7 , Stefan Schreiber^2,5 , Clemens Dieter Bröring⁴ , Jürgen Tepel⁴ , Clemens Schafmayer^2,4 and Jochen Hampe¹

¹Department of General Internal Medicine Christian-Albrechts-University, Kiel, Germany

²POPGEN Biobank project Christian-Albrechts-University, Kiel, Germany

³Institute for Pathology Christian-Albrechts-University, Kiel, Germany

⁴Department of General and Thoracic Surgery Christian-Albrechts-University, Kiel, Germany

⁵Institute of Clinical Molecular Biology Christian-Albrechts-University, Kiel, Germany

⁶Institute for Experimental Cancer Research/Comprehensiv Cancer Center North Christian-Albrechts-University, Kiel, Germany

⁷Institute of Medical Informatics and Statistics Christian-Albrechts-University, Kiel, Germany

author email corresponding author email* Contributed equally

BMC Gastroenterology 2009, 9:79doi:10.1186/1471-230X-9-79

Published:	20 October 2009

Abstract

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.