[en] 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. Inflamm Bowel Dis 2010.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Joossens, Marie
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Branche, Julien
Sendid, Boualem
Rutgeerts, Paul
Vasseur, Francis
Poulain, Daniel
Broly, Franck
Colombel, Jean*-Frederic
Vermeire, Severine
Chamaillard, Mathias
Language :
English
Title :
Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.
Publication date :
2010
Journal title :
Inflammatory Bowel Diseases
ISSN :
1078-0998
eISSN :
1536-4844
Publisher :
Lippincott Williams & Wilkins, Hagerstown, United States - Maryland
Russell RK, Satsangi J. IBD: a family affair. Best Pract Res Clin Gastroenterol. 2004;18:525-539.
Monsen U, Bernell O, Johansson C, et al. Prevalence of inflammatory bowel disease among relatives of patients with Crohn's disease. Scand J Gastroenterol. 1991;26:302-306.
Probert CSJ, Jayanthi V, Hughes AO, et al. Prevalence and family risk of ulcerative colitis and Crohn's disease - an epidemiologic study among Europeans and South Asians in Leicestershire. Gut. 1993;34:1547-1551.
Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324:84-88.
Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology. 1996;111:597-603.
Yang H, Mcelree C, Roth MP, et al. Familial empirical risks for inflammatory bowel disease - differences between Jews and non-Jews. Gut. 1993;34:517-524.
Freeman HJ. Familial Crohn's disease in single or multiple first-degree relatives. J Clin Gastroenterol. 2002;35:9-13.
Satsangi J, Grootscholten C, Holt H, et al. Clinical patterns of familial inflammatory bowel disease. Gut. 1996;38:738-741.
Gower Rousseau C, Grandbastien B, Cortot A, et al. Epidemiology of inflammatory bowel disease: is there a "Belgian-French exception?" Acta Gastroenterol Belg. 1996;59:2.
Van Kruiningen HJ, Joossens M, Vermeire S, et al. Environmental factors in familial Crohn's disease in Belgium. Inflamm Bowel Dis. 2005;11:360-365.
Comes MC, Gower Rousseau C, Colombel JF, et al. Inflammatory bowel disease in married-couples - 10 cases in Nord-Pas-De-Calais region of France and Liege County of Belgium. Gut. 1994;35:1316-1318.
Laharie D, Debeugny S, Peeters M, et al. Inflammatory bowel disease in spouses and their offspring. Gastroenterology. 2001;120:816-819.
Bennett RA, Rubin PH, Present DH. Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease. Gastroenterology. 1991;100:1638-1643.
Colombel JF, Grandbastien B, Gower Rousseau C, et al. Clinical characteristics of Crohn's disease in 72 families. Gastroenterology. 1996; 111:604-607.
Polito JM, Childs B, Mellits ED, et al. Crohn's disease: Influence of age at diagnosis on site and clinical type of disease. Gastroenterology. 1996;111:580-586.
Polito JMII, Rees RC, Childs B, et al. Preliminary evidence for genetic anticipation in Crohn's disease. Lancet. 1996;347:798-800.
Grandbastien B, Peeters M, Franchimont D, et al. Anticipation in familial Crohn's disease. Gut. 1998;42:170-174.
Hopper JL, Bishop DT, Easton DF. Genetic epidemiology 6 - population-based family studies in genetic epidemiology. Lancet. 2005;366:1397-1406.
Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99:2393-2404.
Sendid B, Colombel JF, Jacquinot PM, et al. Specific antibody response to oligomannosidic epitopes in Crohn's disease. Clin Diagn Lab Immunol. 1996;3:219-226.
Peeters M, Vermeire S, Joossens S, et al. Diagnostic value of ASCA (anti-saccharomyces cerevisae antibodies) and pANCA (perinuclear antineutrophil cytoplasmic antibodies) in inflammatory bowel disease. Gastroenterology. 2000;118:A105.
Ferrante M, Henckaerts L, Joossens M, et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007;56:1394-1403.
Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut. 2005;54:1232-1236.
Mow WS, Vasiliauskas EA, Lin YC, et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. Gastroenterology. 2004;126:414-424.
Targan SR, Landers CJ, Yang HY, et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease. Gastroenterology. 2005;128:2020-2028.
Dubinsky MC, Taylor K, Targan SR, et al. Immunogenetic phenotypes in inflammatory bowel disease. World J Gastroenterol. 2006;12:3645-3650.
Bayless TM, Tokayer AZ, Polito JM, et al. Crohn's disease: Concordance for site and clinical type in affected family members - potential hereditary influences. Gastroenterology. 1996;111:573-579.
Standaert-Vitse A, Chamaillard M, Joossens M, et al. Candida Albicans carriage and Asca in familial Crohn's disease. Am J Gastroenterol. (in press).
Khoury PVE, Colombel JF, Joossens S, et al. Detection of antisynthetic mannoside antibodies (A Sigma MA) reveals heterogeneity in the ASCA response of Crohn's disease patients and contributes to differential diagnosis, stratification, and prediction. Am J Gastroenterol. 2008;103:949-957.
Langholz B, Ziogas A, Thomas DC, et al. Ascertainment bias in rate ratio estimation from case-sibling control studies of variable age-at-onset diseases. Biometrics. 1999;55:1129-1136.
Abecasis GR, Cherny SS, Cookson WO, et al. Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002;30:97-101.
Epi info (FBAT/PBAT). http://biosun1.harvard.edu/~fbat/fbat.htm 2008.
Martin ER, Ritchie MD, Hahn L, et al. A novel method to identify gene-gene effects in nuclear families: The MDR-PDT. Genet Epidemiol. 2006;30:111-123.
Epi info (S.A.G.E. 2008). Statistical Analysis for Genetic Epidemiology. http://darwin.cwru.edu/2008.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons; 1987.
Shivananda S, Lennard Jones J, Logan R, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European collaborative study on inflammatory bowel disease (EC-IBD). Gut. 1996;39:690-697.
