HNF4 alpha and CDH1 Are Associated with Ulcerative Colitis in a Dutch Cohort

Department of Genetics, University Medical Center Groningen, The Netherlands.
Inflammatory Bowel Diseases (Impact Factor: 4.46). 08/2011; 17(8):1714-8. DOI: 10.1002/ibd.21541
Source: PubMed


Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are complex disorders with multiple genes contributing to disease pathogenesis. A recent genome-wide association scan identified three novel susceptibility loci for UC: HNF4α, CDH1, and LAMB1. We performed an analysis of these three loci in an independent cohort.
In all, 821 UC patients and 1260 healthy controls of central European Caucasian descent were genotyped for single nucleotide polymorphisms (SNPs): rs6017342 (HNF4α), rs1728785 (CDH1), and rs6949033 (LAMB1). Differences in allele and genotype distribution in cases and controls were tested for significance with the χ² test.
Allelic association analysis showed that SNP rs6017342 in the HNF4α locus was strongly associated with UC (P = 1,04 × 10(-11) , odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.37-1.77) and SNP rs1728785 (CDH1) was associated with P = 0.01 (OR = 1.23, 95% CI = 1.05-1.44). SNP rs6949033 in LAMB1 was not associated in our cohort (P = 0.12, OR = 1.11, 95% CI = 0.97-1.26). We found an association for SNP rs6949033 (LAMB1) for disease limited to the rectum (P = 0.02). However, this association was lost after correcting for multiple testing. No further specific subphenotype associations were identified.
This is the first independent study to replicate the HNF4α and CDH1 loci as susceptibility loci for UC. The main candidate genes in these risk loci play important roles in the maintenance of the integrity of the epithelial barrier, highlighting the importance of the mucosal barrier function for UC pathogenesis.

Download full-text

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: High myopia, which is extremely prevalent in the Chinese population, is one of the leading causes of blindness in the world. Genetic factors play a critical role in the development of the condition. To identify the genetic variants associated with high myopia in the Han Chinese, we conducted a genome-wide association study (GWAS) of 493,947 SNPs in 1088 individuals (419 cases and 669 controls) from a Han Chinese cohort and followed up on signals that were associated with p < 1.0 × 10(-4) in three independent cohorts (combined, 2803 cases and 5642 controls). We identified a significant association between high myopia and a variant at 13q12.12 (rs9318086, combined p = 1.91 × 10(-16), heterozygous odds ratio = 1.32, and homozygous odds ratio = 1.64). Furthermore, five additional SNPs (rs9510902, rs3794338, rs1886970, rs7325450, and rs7331047) in the same linkage disequilibrium (LD) block with rs9318086 also proved to be significantly associated with high myopia in the Han Chinese population; p values ranged from 5.46 × 10(-11) to 6.16 × 10(-16). This associated locus contains three genes-MIPEP, C1QTNF9B-AS1, and C1QTNF9B. MIPEP and C1QTNF9B were found to be expressed in the retina and retinal pigment epithelium (RPE) and are more likely than C1QTNF9B-AS1 to be associated with high myopia given the evidence of retinal signaling that controls eye growth. Our results suggest that the variants at 13q12.12 are associated with high myopia.
    The American Journal of Human Genetics 06/2011; 88(6):805-13. DOI:10.1016/j.ajhg.2011.04.022 · 10.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute infectious diarrhea is a frequent occurrence both in the developing world, where it results in considerable mortality, and in developed countries, where it accounts for a significant number of health visits, hospitalizations, and medical and non-medical losses. Recent evidence in basic, clinical, and epidemiological science domains has emerged that suggest that the burden caused by these infections is not limited to the acute illness, but may result in triggering or contributing to the pathogenesis of a number of chronic health problems. This review considers the breadth of this information for the purpose of consolidating what is currently known, identifying gaps in knowledge, and describing future directions and policy implications related to the chronic consequences of acute infectious diarrhea. A unifying hypothesis of this review is that infections may trigger a number of long-lasting changes in gut physiology and immunity that can increase the risk to a variety of chronic gastrointestinal diseases, particularly in genetically susceptible individuals.
    The American Journal of Gastroenterology 04/2012; 107(7):981-9. DOI:10.1038/ajg.2012.65 · 10.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) symptoms often overlap. In some IBS cases there are subtle inflammatory changes similar to the immune-mediated pathophysiology of IBD, and the risk of both increases after infectious gastroenteritis (IGE). To evaluate the effect of IBS and IGE on IBD risk utilizing US Department of Defense medical encounter data, active duty personnel with IBS were matched to subjects without IBS. Medical encounter history was analyzed to assess for incident IBD. IGE was identified from documented medical encounters and by self-report. Relative risks were calculated using Poisson regression models. We identified 9,341 incident IBS cases and 18,678 matched non-IBS subjects and found an 8.6-fold higher incidence (p < 0.0001) of IBD among those with IBS (238.1 per 100,000 person-years) compared to our referent population (27.8 per 100,000 person-years). In a subset (n = 2,205) of well-defined IBS cases, IBD risk was 15 times that of subjects without IBS. The median time between IBS and IBD diagnoses was 2.1 years. IGE also increased IBD risk approximately 2-fold ( p < 0.05) after controlling for IBS. These data reflect a complex interaction between illness presentation and diagnosis of IBS and IBD and suggest intercurrent IGE may increase IBD risk in IBS patients. Additional studies are needed to determine whether IBS lies on the causal pathway for IBD or whether the two are on a pathophysiological spectrum of the same clinical illness. These data suggest consideration of risk reduction interventions for IGE among IBS patients at high disease risk.
    BMC Gastroenterology 05/2012; 12(1):55. DOI:10.1186/1471-230X-12-55 · 2.37 Impact Factor
Show more