Abstract
Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis (UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Hampe J, Cuthbert A, Croucher PJP et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations Lancet 2001 357: 1925–1928
Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease Nature 2001 411: 599–603
Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease Nature 2001 411: 603–606
Hugot JP, Laurent-Puig P, Gower-Rousseau C et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16 Nature 1996 379: 821–823
Satsangi J, Parkes M, Louis E et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12 Nat Genet 1996 14: 199–202
Cho JH, Nicolae DL, Gold LH et al. Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q and 4q: evidence for epistatis between 1p and IBD1 Proc Natl Acad Sci USA 1998 95: 7502–7507
Ma Y, Ohmen JD, Li Z et al. A genome-wide search identifies potential new susceptibility loci for Crohn's disease Inflam Bowel Dis 1999 5: 271–278
Duerr RH, Barmada MM, Zhang L, Pfützer R, Weeks DE . High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12 Am J Hum Genet 2000 66: 1857–1862
Hampe J, Schreiber S, Shaw SH et al. A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort Am J Hum Genet 1999 64: 808–816
Hampe J, Shaw SH, Saiz R et al. Linkage of inflammatory bowel disease to human chromosome 6p Am J Hum Genet 1999 65: 1647–1655
Rioux JD, Silverberg MS, Daly MJ et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci Am J Hum Genet 2000 66: 1863–1870
Forabosco P, Collins A, Latiano A et al. Combined segregation and linkage analysis of inflammatory bowel disease in the IBD1 region using severity to characterise Crohn's disease and ulcerative colitis Eur J Hum Genet 2000 8: 846–852
Parkes M, Barmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH . The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn's disease Am J Hum Genet 2000 67: 1605–1610
Brant SR, Panhuysen CIM, Bailey-Wilson JE et al. Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity Gastroenterology 2000 119: 1483–1490
de la Concha EG, Fernandez-Arquero M, Lopez-Nava G et al. Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL Gastroenterology 2000 119: 1491–1495
Vermeire S, Satsangi J, Peeters M et al. Evidence for inflammatory bowel disease of a susceptibility locus on the X chromosome Gastroenterology 2001 120: 834–840
Ekbom A, Helmick C, Zack M, Adami HO . The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden Gastroenterology 1991 100: 350–358
Paterson AD, Petronis A . Age and sex based genetic locus heterogeneity in type 1 diabetes J Med Genet 2000 37: 186–191
O'Donnell CJ, Lindpaintner K, Larson MG et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study Circulation 1998 97: 1766–1772
Loughlin J, Mustafa Z, Smith A et al. Linkage analysis of chromosome 2q in osteoarthritis Rheumatology 2000 39: 377–381
Wise LH, Lanchbury JS, Lewis CM . Meta-analysis of genome searches Ann Hum Genet 1999 63: 263–272
Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests Am J Hum Genet 1997 61: 1179–1188
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247
Satsangi J, Welsh KI, Bunce M et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease Lancet 1996 347: 1212–1217
Yang H, Plevy SE, Taylor K et al. Linkage of Crohn's disease to the major histocompatibility complex region is detected by multiple non-parametric analyses Gut 1999 44: 519–526
Kawasaki A, Tsuchiya N, Hagiwara K, Takazoe M, Tokunaga K . Independent contribution of HLA-DRB1 and TNF alpha promoter polymorphisms to the susceptibility to Crohn's disease Genes Immun 2000 1: 351–357
Trachtenberg EA, Yang H, Hayes E et al. HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations Hum Immunol 2000 61: 326–333
Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP . Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies Genes Immun 2000 1: 185–190
Bouma G, Oudkerk Pool M et al. Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD) Clin Exp Immunol 1997 109: 175–179
Cucca F, Goy JV, Kawaguchi Y et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients Nat Genet 1998 19: 301–302
Celius EG, Harbo HF, Egeland T, Vartdal F, Vandvik B, Spurkiand A . Sex and age at diagnosis are correlated with the HLA-DR2,DQ6 haplotype in multiple sclerosis J Neurol Sci 2000 178: 132–135
Hajeer A, John S, Ollier WE et al. Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA J Rheumatol 1997 24: 217–219
Leal SM, Ott J . Effects of stratification in the analysis of affected sib-pair data: benefits and costs Am J Hum Genet 2000 66: 567–575
Vingsbo-Lundberg C, Nordquist N, Olofsson P et al. Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats Nat Genet 1998 20: 401–404
Melanitou E, Joly F, Lathrop M, Boitard C, Avner P . Evidence for the presence of insulin-dependent diabetes-associated alleles on the distal part of mouse chromosomes 6 Genome Res 1998 8: 608–620
Petronis A, Petroniene R . Epigenetics of inflammatory bowel disease Gut 2000 47: 302–306
Acknowledgements
This work was supported in the UK by the Wellcome Trust, the Generation Trust and Axys Pharmaceuticals Inc. In Germany, support was from the Deutsche Forschungsgemeinschaft (For423), a Training and Mobility of Research (TMR) Network grant of the European Union (ERB-4061-PL-97-0389), a Competence Network ‘Chronisch-entzündliche Darmerkrankungen’, the German Human Genome Project (DHGP) and the National Genome Research Network (all funded by the German Federal Department for Research and Education).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fisher, S., Hampe, J., Macpherson, A. et al. Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6. Eur J Hum Genet 10, 259–265 (2002). https://doi.org/10.1038/sj.ejhg.5200792
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200792
Keywords
This article is cited by
-
Sex-specific differences in peripheral blood leukocyte transcriptional response to LPS are enriched for HLA region and X chromosome genes
Scientific Reports (2021)
-
De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease
Genome Medicine (2017)
-
An extensive analysis of the hereditary hemochromatosis gene HFE and neighboring histone genes: associations with childhood leukemia
Annals of Hematology (2010)
-
HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility
Cell Stress and Chaperones (2010)
-
The sex-specific genetic architecture of quantitative traits in humans
Nature Genetics (2006)