Dataset Information

Crohn's Disease Localization Displays Different Predisposing Genetic Variants.

ABSTRACT: Crohn's disease (CD) is a pathologic condition with different clinical expressions that may reflect an interplay between genetics and environmental factors. Recently, it has been highlighted that three genetic markers, NOD2, MHC and MST1, were associated to distinct CD sites, supporting the concept that genetic variations may contribute to localize CD. Genetic markers, previously shown to be associated with inflammatory bowel disease (IBD), were tested in CD patients with the aim to better dissect the genetic relationship between ileal, ileocolonic and colonic CD and ascertain whether a different genetic background would support the three disease sites as independent entities.A panel of 29 SNPs of 19 IBD loci were analyzed by TaqMan SNP allelic discrimination method both evaluating their distinct contribute and analyzing all markers jointly.Seven hundred and eight CD patients and 537 healthy controls were included in the study. Of the overall population of patients, 237 patients had an ileal involvement (L1), 171 a colonic localization (L2), and the 300 remaining an ileocolon location (L3). We confirmed the association for 23 of 29 variations (P < 0.05). Compared to healthy controls, 16 variations emerged as associated to an ileum disease, 7 with a colonic disease and 14 with an ileocolonic site (P < 0.05). Comparing ileum to colonic CD, 5 SNPs (17%) were differentially associated (P < 0.05). A genetic model score that aggregated the risks of 23 SNPs and their odds ratios (ORs), yielded an Area Under the Curve (AUC) of 0.70 for the overall CD patients. By analyzing each CD location, the AUC remained at the same level for the ileal and ileocolonic sites (0.73 and 0.72, respectively), but dropped to a 0,66 value in patients with colon localization.Our findings reaffirm the existence of at least three different subgroups of CD patients, with a genetic signature distinctive for the three main CD sites.

SUBMITTER: Palmieri O

PROVIDER: S-EPMC5215692 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Crohn's Disease Localization Displays Different Predisposing Genetic Variants.

Palmieri Orazio O Bossa Fabrizio F Valvano Maria Rosa MR Corritore Giuseppe G Latiano Tiziana T Martino Giuseppina G D'Incà Renata R Cucchiara Salvatore S Pastore Maria M D'Altilia Mario M Scimeca Daniela D Biscaglia Giuseppe G Andriulli Angelo A Latiano Anna A

PloS one 20170104 1

<h4>Background</h4>Crohn's disease (CD) is a pathologic condition with different clinical expressions that may reflect an interplay between genetics and environmental factors. Recently, it has been highlighted that three genetic markers, NOD2, MHC and MST1, were associated to distinct CD sites, supporting the concept that genetic variations may contribute to localize CD. Genetic markers, previously shown to be associated with inflammatory bowel disease (IBD), were tested in CD patients with the ...[more]

PMID: 28052082

Similar Datasets

Project description:BackgroundInflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Recent discoveries have brought much attention to the genetic predisposition of patients with IBD. Here we evaluate the interaction between IBD genetic risk factors susceptibility and CD occurrence in an IBD pediatric patient population, performing a clinical exome survey.MethodsFrom February 2018 to April 2019, we collected blood samples from 7 pediatric patients with IBD concerns from several collaborating health centers and/or hospitals. Blood samples were processed by extracting and sequencing DNA for a clinical exome survey. Shophia-DDM-v3-4 platform allowed sequenced reads alignment on hg19 genome as well as genetic variant calling. Both IBD risk and pathogenic genetic variants covered by at least 20 reads were selected for subjacent analysis.ResultsNormality and Bartlett tests of both risk and pathogenic genetic variants suggested random and heterogeneous distribution of these variants in this group of IBD pediatric patients. P value clustering analysis by processing 157 IBD risk factors revealed genetic heterogeneity in IBD population and suggested two pathways influencing IBD development. In particular, (1) genetic variants associated with autoimmune and (2) metabolic diseases and CD risk factors (rs2066844 and rs2241880 single nucleotide polymorphism variants, respectively, of genes NOD2 and ATG16L) were identified in distinct clusters of IBD patients (P < .05). Moreover, the heterogeneous distribution of the following variants rs10065172 (IRGM), rs1805010 (IL4R), rs5030737 (MBL2), and rs33995883 (LRRK2) in this group of IBD patients was consistent with their random distribution in that population.ConclusionOur study revealed specific genetic variants linked to CD susceptibility, autoimmune and/or innate immunodeficiency as well as to metabolic defects, as favoring factors of IBD, suggesting the valuable role of next generation sequencing (NGS) approaches in IBD molecular diagnostic procedures.

Project description:Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6 × 10(-10), odds ratio (OR)?= 0.74, 95% CI:0.68-0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6 × 10(-4). OR = 0.86 (95% CI:0.79-0.93); rs744166, P = 2.6 × 10(-5), OR = 0.84 (95% CI:0.77-0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2 × 10(-5), OR = 0.65 (95% CI:0.54-0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2 × 10(-5), OR = 0.83 (95% CI:0.76-0.91)), CDKAL1 (rs6908425, P = 1.1 × 10(-4), OR = 0.82 (95% CI:0.74-0.91)), LRRK2/MUC19 (rs11175593, P = 9.9 × 10(-5), OR = 1.92 (95% CI: 1.38-2.67)), and chr13q14 (rs3764147, P =?5.9 × 10(-4), OR = 1.19 (95% CI: 1.08-1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.

Project description:Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn's disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European CEU HapMap population (P=0.0007) and European Human Genome Diversity Panel populations (P?0.01). To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high-density microarray data in a sample of 1,868 Crohn's disease cases and 5,550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease (odds ratio [OR]: 1.05, P=0.21). In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three genes (OR: 1.24, P=2.6×10(-8)), as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn's disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn's disease patients (P=0.0006) and no significant difference in expression of OCTN1. Collectively, these data indicate that the 503F variant has increased in frequency due to recent positive selection and that disease-causing variants in linkage disequilibrium with 503F have hitchhiked to relatively high frequency, thus forming the IBD5 risk haplotype. Finally, our association results and expression data support IRF1 as a strong candidate for Crohn's disease causation.

Dataset Information

Crohn's Disease Localization Displays Different Predisposing Genetic Variants.

Publications

Crohn's Disease Localization Displays Different Predisposing Genetic Variants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets