NOD2/CARD15 genotype and common gastrointestinal diseases in 43,600 individuals.
OBJECTIVE
NOD2/CARD15 is involved in the innate immune response and three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with risk of the rare Crohn's disease. We tested the hypothesis that polymorphisms in NOD2/CARD15 associate with risk of nine common gastrointestinal diseases.


METHODS
We genotyped 43 596 white individuals from the Danish general population followed for 31 years, during which time 782 developed oesophagitis and reflux, 1395 ulcus ventriculi and duodeni, 1384 gastritis and dyspepsia, 1407 appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas.


RESULTS
Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95%CI 1.4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst homozygotes appeared to be similar amongst both men and women and amongst those below or above 60 years, and likely included both upper gastrointestinal cancer and colorectal cancer.


CONCLUSIONS
NOD2/CARD15 polymorphisms are not major risk factors for common gastrointestinal diseases; however, we cannot completely exclude association with appendicitis, anal fissure, fistula and abscess, and gastrointestinal cancer.
Yazdanyar
S
S
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, DK-2730 Herlev, Denmark.
Nordestgaard
B G
BG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005767:Gastrointestinal Diseases / Q000453:epidemiology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D011110:Polymorphism, Genetic; D055815:Young Adult
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein