Medical Genetics and Pediatrics, Cedars-Sinai Research Institute, ... Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
1996 Oxford University Press
Human Molecular Genetics, 1996, Vol. 5, No. 10 1679–1683
Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn’s disease, but not in ulcerative colitis Jeffrey D. Ohmen1,+, Hui-Ying Yang2,+, Karen K. Yamamoto1, Hong-Yu Zhao3, Yuanhong Ma1, L. Gordon Bentley1, Zhihan Huang2, Scott Gerwehr1, Sheila Pressman2, Colleen McElree2, Stephan Targan4, Jerome I. Rotter2 and Nathan Fischel-Ghodsian1,2,* 1GenoMed
Pharmaceuticals, Inc., Suite 360, 150 N. Robertson Blvd, Beverly Hills, CA 90211, USA, 2Departments of Medical Genetics and Pediatrics, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA, 3Department of Biostatistics, UCLA School of Public Health, 10833 LeConte Avenue, Los Angeles, CA 90095, USA and 4Department of Medicine, Division of Gastroenterology, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA Received June 3, 1996; Revised and Accepted July 24, 1996
In the Western world, chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn’s disease (CD) and ulcerative colitis (UC) [Targan,S.R. and Shanahan,F. (1994) In Retford,D.C (ed.), Inflammatory Bowel Disease: From Bench to Bedside. Williams and Wilkins, Baltimore]. Genetic epidemiological studies, the occurrence of rare syndromes associated with IBD, and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD [Yang,H.-Y. and Rotter,J.I. (1995) In Kirsner,J.B. and Shorter,R.G. (eds), Genetic Aspects of Idiopathic inflammatory Bowel Disease. Williams and Wilkins, Baltimore, pp. 301–331]. Recently, a genome-wide search on European families with multiple affected members with CD identified a putative susceptibility locus in the centromeric region of chromosome 16 [Hugot,J.-P. et al. (1996) Nature, 379, 821–823]. We have now tested this region in an independent set of US families, confirmed that this region is likely to contain a gene predisposing to CD, and further refined the chromosomal location of this gene. Most importantly with respect to this locus, our data also seem to indicate that there is heterogeneity both within the CD group, and between the CD and UC groups with respect to this locus. The susceptibility locus appears to be involved only in non-Jewish CD sibpairs and not in our Ashkenazi Jewish CD sibpairs. Additionally, we have tested sibpairs having either only UC or both UC and CD for involvement of this locus, and
have found no evidence that this region predisposes to IBD in these patients. INTRODUCTION Inflammatory bowel disease (IBD) is a complex disease of unknown etiology. The differences in disease frequency between geographic areas and racial/ethnic groups suggest that genetic factors play a role in etiology (2,4). However, data from migrant studies and the increasing incidence of Crohn’s disease (CD) seen in many parts of the world during the past 30 years suggest that environmental agents are also important in disease etiology (5). The high toll of this disease combined with the lack of specific therapeutics has spurred a search for genes that contribute to disease susceptibility. Ulcerative colitis (UC), like CD, is also characterized by inflammatory lesions in the bowel. It is not uncommon for families with an individual afflicted with one form of IBD to have additional siblings afflicted with the other form, and in fact this occurrence is substantially greater than expected from the relative frequency of the two diseases (6). It can be postulated, therefore, that IBD may involve genes in a pathway common to bowel inflammation, and that the phenotypic differences seen between the two diseases result from the expression of additional genes specific to CD or UC. CD is an ideal disease to utilize a genetic approach towards understanding its cellular basis. First, the genetic component is well documented by: (i) the monozygotic twin concordance rates (7–9), (ii) the rarity of IBD concordance in spouses (10) and (iii) the numerous instances of family members with onset separated greatly in time (11–13). Interestingly, there is an increased rate of CD among Ashkenazi Jews, suggesting that within this ethnic group, there may be less genetic heterogeneity for IBD
*To whom correspondence should be addressed at: Department of Pediatrics, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA +Both authors contributed equally to this work
1680 Human Molecular Genetics, 1996, Vol. 5, No. 10 predisposing loci and thus a potentially limited number of genes involved (14–17). Recently, Hugot et al. reported the results of a genome scan for CD using linkage analysis (3). Twenty-five families and ∼41 sibpairs were included in the analysis resulting in the identification of three polymorphic markers on chromosome 16 and one on chromosome 1 as having P values of
