Two European genome-wide screens for inflammatory bowel disease have identified two significant regions of linkage on chromosomes 16 (IBD1) and 12 (IBD2) and two regions with suggestive levels of significance (chromosomes 3p and 7q).
The present study performed in a Southern European population provides additional support for the conclusion with the IBD1 locus has a clear role in the genetic susceptibility to IBD.
Recent genome scans and replication studies have identified replicated linkage between CD and a locus on chromosome 16 (the IBD1 locus), replicated linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus), and replicated linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus).
In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2).
Methods We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls.
Inflammatory bowel disease (IBD) is a polygenic disorder, as demonstrated by epidemiological evidence, genetic linkage, and the identification of the first susceptibility gene, NOD2.
A case-control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro(268)Ser, Arg(702)Trp, Gly(908)Arg, and Leu(1007)fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls.
Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers.
The new information summarized here includes: the discovery of the association of the NOD2 gene with Crohn's disease; the role of bacteria and the modulating effects of probiotics; the inverse association of appendectomy and ulcerative colitis; progress in imaging based on magnetic resonance imaging and leukocyte scintigraphy; assessment of the value of anti-Saccharomyces cerevisiae antibodies in the screening of inflammatory bowel disease and differentiation between ulcerative colitis and Crohn's disease; and risk factors and management of dysplasia and cancer.
Taken together, our results suggest that IBD5 may act as a general risk factor for IBD, with loci such as CARD15 modifying the clinical characteristics of disease.
In this review, we summarize current information on the genetics of IBD, emphasizing the discovery of CARD15 variants as susceptibility alleles for Crohn's disease and the impact of this discovery on patient care and in delineating pathogenesis of this complex disease.
A significant role for CARD15/NOD2 gene in predisposition to SpA was ruled out, in agreement with the hypothesis that the inflammatory bowel disease in SpA is determined by factors different than those responsible for isolated Crohn's disease.
Together with the mutation-derived truncation and functional change of the NOD2 protein, this could be part of the complex pathophysiology of barrier disruption as it is observed in inflammatory bowel diseases.