Genomewide Search in Canadian Families with Inflammatory Bowel Disease Reveals Two Novel Susceptibility Loci

Abstract

The chronic inflammatory bowel diseases (IBDs)-Crohn disease (CD) and ulcerative colitis (UC)-are idiopathic, inflammatory disorders of the gastrointestinal tract. These conditions have a peak incidence in early adulthood and a combined prevalence of approximately 100-200/100,000. Although the etiology of IBD is multifactorial, a significant genetic contribution to disease susceptibility is implied by epidemiological data revealing a sibling risk of approximately 35-fold for CD and approximately 15-fold for UC. To elucidate the genetic basis for these disorders, we undertook a genomewide scan in 158 Canadian sib-pair families and identified three regions of suggestive linkage (3p, 5q31-33, and 6p) and one region of significant linkage to 19p13 (LOD score 4.6). Higher-density mapping in the 5q31-q33 region revealed a locus of genomewide significance (LOD score 3.9) that contributes to CD susceptibility in families with early-onset disease. Both of these genomic regions contain numerous genes that are important to the immune and inflammatory systems and that provide good targets for future candidate-gene studies.

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…It is of some interest that this SNP is associated with earlier age of onset, as this variant maps to the IBD5 region, which in an early study was only of genome-wide significance in families with early-onset disease. 35 A more recent genotype-phenotype analysis of this region has not, however, confirmed this association. 47 In the present study, we have demonstrated that the common mutations in the NOD2/CARD15 gene have a low contribution to CD susceptibility in a Scottish population.…”

“…The Irish CD group comprised 113 patients (77 females and 36 males) with a median age at diagnosis of 27.5 years (IQR [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. This corresponded to 38 patients diagnosed before the age of 40 years (A1) and 21 diagnosed after the age of 40 years (A2).…”

“…34 The human CD14 gene lies on the long arm of chromosome 5 (5q31.1), close to an area of reported linkage in CD (IBD5). 35 Membrane-bound CD14 is expressed on monocytes and macrophages, and the expression of CD14 on mucosal macrophages is upregulated in active IBD. 36,37 A common functional promoter region polymorphism (T-159C) of the CD14 gene has been identified 38 and a weak association with both CD and UC has been demonstrated.…”

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility

“…1 UC is a complex polygenic condition, characterized by an inappropriate mucosal immune response within the gut to the commensal bacterial flora, leading to ulceration of the colonic mucosa. 2 Genome-wide screening in UC has demonstrated replicated linkage to several chromosomal regions, including regions on chromosomes 12 3,4 and 19 5,6 termed IBD2 and IBD6, respectively. Within the IBD2 loci lies the lectin-like natural killer (NK) receptor gene NKG2D (KLRK1) located at 12p13.2-p12.3.…”

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

“…Nevertheless, it is still possible that the RAD50 signal is a result of its LD with other markers within the observed association boundaries. Multiple SNPs in the extended RAD50/IL13 region were previously identified as susceptibility factors for various chronic inflammatory diseases such as Crohn's disease, psoriasis, asthma, and atopic dermatitis (Rioux et al ., 2000; Li et al ., 2008, 2010; Paternoster et al ., 2011). Further studies are therefore needed to identify the functional variant(s) and the underlying molecular mechanisms that predispose(s) to a long and healthy life.…”