Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.
The first gene associated with Crohn disease (CD) has been identified as CARD15 (16q12). Three variants, R702W, G908R and 1007fsinsC are strongly and independently associated with the disease. A second gene, conveying a smaller risk for inflammatory bowel disease (IBD), has been identified as DLG5 (10q23). We assess the frequency of the CARD15 SNPs and of the R30Q mutation in DLG5 and their contribution to the development of CD in a cohort of unrelated IBD patients (151 CD, 325 ulcerative colitis (UC)) and healthy controls (236) from South-east Norway (IBSEN cohort). Genotype-based tests of population differentiation using 23 SNPs across CARD15, together with estimates of F(ST), indicated that the German and Norwegian background populations could be differentiated at the CARD15 locus. The Norwegian and German CD samples exhibited particularly strong differentiation at the three predisposing loci and those marking their background haplotype. There were significantly lower frequencies of the CARD15 SNPs and no significant association with CD in the Norwegian samples. Only a marginal association was observed for the subphenotypes ileitis and ileocolitis vs colitis (P=0.048). The population attributable risk percentage (PAR%) for CARD15 variants in the Norwegian cohort is the lowest reported for a European population (1.88%), except Iceland. Similarly, the DLG5 variant showed no association with CD or IBD, however, there was a negative correlation with stricture (P=0.035). The present results are consistent with an emerging pattern of a low frequency of the CARD15 variants in Northern countries where the prevalence of IBD is greatest.
Department of General and Internal Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-University, Schittenhelmstrasse 12, Kiel 24105, Germany.
Valentina
V
Medici
Silvia
S
Mascheretti
Peter J P
PJ
Croucher
Monika
M
Stoll
Jochen
J
Hampe
Jochen
J
Grebe
Giacomo C
GC
Sturniolo
Camilla
C
Solberg
Jorgen
J
Jahnsen
Bjorn
B
Moum
Stefan
S
Schreiber
Morten H
MH
Vatn
D000328:Adult; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D009664:Norway; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C114461:DLG5 protein, human; D008565:Membrane Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D025521:Tumor Suppressor Proteins