Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer.
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 (<or=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 (<or=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).


CONCLUSIONS
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.
Department of General Internal Medicine Christian-Albrechts-University, Kiel, Germany. nikomoeckelmann@googlemail.com
Nikolaus
N
Möckelmann
Witigo
W
von Schönfels
Stephan
S
Buch
Oliver
O
von Kampen
Bence
B
Sipos
Jan Hendrik
JH
Egberts
Philip
P
Rosenstiel
Andre
A
Franke
Mario
M
Brosch
Sebastian
S
Hinz
Christian
C
Röder
Holger
H
Kalthoff
Ulrich R
UR
Fölsch
Michael
M
Krawczak
Stefan
S
Schreiber
Clemens Dieter
CD
Bröring
Jürgen
J
Tepel
Clemens
C
Schafmayer
Jochen
J
Hampe
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D004273:DNA, Neoplasm; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D009363:Neoplasm Proteins; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein