IBD5 is a General Risk Factor for Inflammatory Bowel Disease: Replication of Association with Crohn Disease and Identification of a Novel Association with Ulcerative Colitis

Massachusetts General Hospital, Boston, Massachusetts, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2003; 73(1):205-11. DOI: 10.1086/376417
Source: PubMed


Inflammatory bowel disease (IBD) refers to complex chronic relapsing autoimmune disorders of the gastrointestinal tract that have been traditionally classified into Crohn disease (CD) and ulcerative colitis (UC). We have previously reported that genetic variation within a 250-kb haplotype (IBD5) in the 5q31 cytokine gene cluster confers susceptibility to CD in a Canadian population. In the current study, we first replicated this association by examining 368 German trios with CD and demonstrating, by transmission/disequilibrium testing (TDT), that the same haplotype is associated with CD (chi2=5.97; P=.007). Our original association study focused on the role of IBD5 in CD; we next explored the potential contribution of this locus to UC susceptibility in 187 German trios. Given the TDT results in the present cohort with UC, IBD5 may also act as a susceptibility locus for UC (chi2=8.10; P=.002). We then examined locus-locus interactions between IBD5 and CARD15, a locus reported elsewhere to confer risk exclusively to CD. Our current results indicate that the two loci act independently to confer risk to CD but that these two loci may behave in an epistatic fashion to promote the development of UC. Moreover, IBD5 was not associated with particular clinical manifestations upon phenotypic stratification in the current cohort with CD. 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.

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    • "Other early susceptibility loci for Crohn disease included the DLG5 gene on chromosome 10q [91], which has since then been replicated in some, but not all cohorts and a large haplotype block on chromosome 5q31 [92]. Due to strong linkage disequilibrium in the region [93] a combination of functional and genetic evidence was used to implicate SNPs around the SLC22A4/5 genes (solute carrier family 22 (organic cation transporter), member 4/5; encoding for OCTN1/2) genes as potentially causative variants [94]. Both findings were replicated in independent CD cohorts [95] [96] [97], however several negative replication findings [98] [99] [100] have also emphasized the potential heterogeneity of the disease in different populations and the need for large, population-representative replication samples [101] [102]. "
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    ABSTRACT: Recent advances have enabled a comprehensive understanding of the genetic architecture of inflammatory bowel disease (IBD) with over 30 identified and replicated disease loci. The pathophysiological consequences of disease gene variants in Crohn disease and ulcerative colitis, the two main subentities of IBD, so far are only understood on the single disease gene level, yet complex network analyses linking the individual risk factors into a molecular risk map are still missing. In this review, we will focus on recent pathways and cellular functions that emerged from the genetic studies (e.g. innate immunity, autophagy) and delineate the existence of shared (e.g. IL23R, IL12B) and unique (e.g. NOD2 for CD) risk factors for the disease subtypes. Ultimately, the defined molecular profiles may identify individuals at risk early in life and may serve as a guidance to administer personalized interventions for causative therapies and/or early targeted prevention strategies. Due to this comparatively advanced level of molecular understanding in the field, IBD may represent precedent also for future developments of individualized genetic medicine in other polygenic disorders in general.
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    • "They were first used in candidate gene studies and recently, with the growing number of available single nucleotide polymorphisms (SNPs), in genome-wide association studies. There are now studies reporting association of haplotypes to diseases like Crohn's disease [Hugot et al., 2001; Rioux et al., 2001; Giallourakis et al., 2003], autism [Philippi et al., 2005] and bipolar affective disorder [Underwood et al., 2006]. "
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    ABSTRACT: The understanding of complex diseases and insights to improve their medical management may be achieved through the deduction of how specific haplotypes may play a joint effect to change relative risk information. In this paper we describe an ascertainment adjusted likelihood-based method to estimate haplotype relative risks using pooled family data coming from association and/or linkage studies that were used to identify specific haplotypes. Haplotype-based analysis tends to require a large amount of parameters to capture all the information that leads to efficiency problems. An adaptation of the Stochastic Expectation Maximization algorithm is used for haplotypes inference from genotypic data and to reduce the number of nuisance parameters for risk estimation. Using different simulations, we show that this method provides unbiased relative risk estimates even in case of departure from Hardy-Weinberg equilibrium.
    Full-text · Article · Dec 2006 · Genetic Epidemiology
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    • "Genome-wide scans have identified loci with linkage to IBD (Wild and Rioux, 2004) and other loci with suggestive linkage to AD (Bowcock and Cookson, 2004). Although no direct genetic linkage between the two disorders has been identified, a haplotype on chromosome 5q31 that contains a cluster of atopy-related genes including interleukin (IL)-4 and IL-13 is strongly linked to CD and probably also to UC (Giallourakis et al, 2003), and shows linkage to serum IgE levels in AD families (Cookson et al, 2001). "
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    ABSTRACT: AD, atopic dermatitis; CD, Crohn's disease; IBD, inflammatory bowel disease; UC, ulcerative colitis
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