Prevalence of CARD15/NOD2 Mutations in Caucasian Healthy People

Authors: Hugot, Jean-Pierre¹; Zaccaria, Isabelle²; Cavanaugh, Juleen³; Yang, Huiying⁴; Vermeire, Séverine⁵; Lappalainen, Maarit⁶; Schreiber, Stefan⁷; Annese, Vito⁸; Jewell, Derek P.⁹; Fowler, Elizabeth V.¹⁰; Brant, Steven R.¹¹; Silverberg, Mark S.¹²; Cho, Judy¹³; Rioux, John D.¹⁴; Satsangi, Jack¹⁵; Parkes, Miles¹⁶

Source: The American Journal of Gastroenterology, Volume 102, Number 6, June 2007 , pp. 1259-1267(9)

Publisher: Blackwell Publishing

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Abstract:

BACKGROUND: Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels.

SUBJECTS AND METHODS: The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using χ² tests.

RESULTS: The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P < 0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low.

CONCLUSION: Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.

(Am J Gastroenterol 2007;102:1-9)

Document Type: Research article

DOI: 10.1111/j.1572-0241.2007.01149.x

Affiliations: 1: INSERM Avenir U763; AP-HP; Université Paris 7, Hôpital Robert Debré, Paris, France 2: INSERM CIE 5, Unit of Clinical Epidemiology; AP-HP; Université Paris 7, Hôpital Robert Debré, Paris, France 3: Medical Genetics Research Unit, Medical School, Australian National University, Canberra, Australia 4: Medical Genetics Institute, Cedars-Sinai Medical Center, UCLA, School of Medicine, Los Angeles, California 5: Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium 6: Department of Medicine and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland 7: Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany 8: Dipartimento di Medicina Generale e Specialistica, U.O. Gastroenterologia, Ospedale CSS-IRCCS, S.Giovanni Rotondo, Italy 9: Gastroenterology Unit, Radcliffe Infirmary, Oxford, United Kingdom 10: Crohn's and Colitis Laboratory, Royal Brisbane and Women's Hospital Research Foundation Clinical Research Centre, Queensland Institute of Medical Research, Brisbane, Australia 11: Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 12: Departments of Medicine and Surgery, University of Toronto, Mount Sinai Hospital IBD Centre, Toronto, Canada 13: The Martin Boyer Genetics Research Laboratories, Gastroenterology Section, Department of Medicine, The University of Chicago Hospitals, Chicago, Illinois 14: Université de Montréal et l'Institut de Cardiologie de Montréal, Montreal, Québec, Canada; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 15: Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom 16: Gastroenterology Unit, Addenbrooke's Hospital, Cambridge, United Kingdom

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