Linkage of inflammatory bowel disease to human chromosome 6p

Jochen Hampe, Sarah H. Shaw, Robert Saiz, Nancy Leysens, Annette Lantermann, Silvia Mascheretti, Nicholas J. Lynch, Andrew J. S. MacPherson, Stephen Bridger, Sander van Deventer, Pieter Stokkers, Phil Morin, Mudasser M. Mirza, Alastair Forbes, John E. Lennard-Jones, Christopher G. Mathew, Mark E. Curran, Stefan Schreiber

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193 Citations (Scopus)

Abstract

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Given the immunologic dysregulation in IBD, the human-leukocyte-antigen region on chromosome 6p is of significant interest. Previous association and linkage analysis has provided conflicting evidence as to the existence of an IBD-susceptibility locus in this region. Here we report on a two-stage linkage and association analysis of both a basic population of 353 affected sibling pairs (ASPs) and an extension of this population to 428 white ASPs of northern European extraction. Twenty-eight microsatellite markers on chromosome 6 were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of five single-nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for association of these important candidate genes with IBD. In summary, we provide firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.
Original languageEnglish
Pages (from-to)1647-1655
Number of pages9
JournalAmerican Journal of Human Genetics
Volume65
Issue number6
DOIs
Publication statusPublished - Dec 1999

Keywords

  • Alleles
  • Chromosomes, Human, Pair 6
  • Cohort Studies
  • Colitis, Ulcerative
  • Crohn Disease
  • Europe
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Inflammatory Bowel Diseases
  • Likelihood Functions
  • Lymphotoxin-alpha
  • Male
  • Microsatellite Repeats
  • Nuclear Family
  • Phenotype
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Tumor Necrosis Factor-alpha

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