Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.
BACKGROUND
An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in innate immunity and/or antibody responses to microbial antigens may be valuable in identifying healthy relatives at risk.


METHODS
We investigated 86 families from Belgium and northern France, 45 with at least 3 first-degree relatives with CD, 24 with a single case, and 17 control families without inflammatory bowel disease (IBD). The cohort consisted of 186 CD patients, 290 healthy relatives, and 142 controls (total 618). Genetic (NOD2, NOD1, TLR4, CARD8) and serologic markers (ASCA, ACMA, ALCA, ACCA, ASigmaMA, OmpC, CBir1, I2) were determined in all subjects. All Belgian families were prospectively followed up for 54 months.


RESULTS
In multiple-affected families, an increment of affected first-degree relatives and of positive antibodies were additive risks factors for CD (P < 0.0001), independent of NOD2 mutations. When comparing subjects from multiple-affected families, having 3 additional first-degree relatives with CD and 1 additional positive antibody increased the odds for CD to 9.19 (95% confidence interval [CI]: 4.07-20.80). After a follow-up of 54 months among all Belgian families, a total of 4 new diagnoses of IBD were confirmed in the multiple-affected families only, resulting in a 57-fold increase in incidence within multiple-affected families compared to the known incidence of IBD in our region.


CONCLUSIONS
We found an additive risk increment for CD in subjects from multicase families per additional affected relative and per additional positive antibody, independent of NOD2. Furthermore, a very high disease incidence was observed in these multiple-affected families.
Joossens
Marie
M
Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
Van Steen
Kristel
K
Branche
Julien
J
Sendid
Boualem
B
Rutgeerts
Paul
P
Vasseur
Francis
F
Poulain
Daniel
D
Broly
Franck
F
Colombel
Jean-Frédéric
JF
Vermeire
Séverine
S
Chamaillard
Mathias
M
D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003424:Crohn Disease / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008297:Male; D010375:Pedigree; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
D000942:Antigens, Bacterial; D015415:Biomarkers; D005819:Genetic Markers; D007074:Immunoglobulin G