Genetic variants associated with Crohn's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Michail S
PROVIDER: S-EPMC3735034 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Genetic variants associated with Crohn's disease.
Michail Sonia S Bultron Gilberto G Depaolo R William RW
The application of clinical genetics 20130716
Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks ...[more]
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Project description: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.
| S-EPMC5215692 | biostudies-literature
Project description:BACKGROUND: Crohn's Disease (CD) has a heterogeneous presentation, and is typically classified according to extent and location of disease. The genetic susceptibility to CD is well known and genome-wide association scans (GWAS) and meta-analysis thereof have identified over 30 susceptibility loci. Except for the association between ileal CD and NOD2 mutations, efforts in trying to link CD genetics to clinical subphenotypes have not been very successful. We hypothesized that the large number of confirmed genetic variants enables (better) classification of CD patients. METHODOLOGY/PRINCIPAL FINDINGS: To look for genetic-based subgroups, genotyping results of 46 SNPs identified from CD GWAS were analyzed by Latent Class Analysis (LCA) in CD patients and in healthy controls. Six genetic-based subgroups were identified in CD patients, which were significantly different from the five subgroups found in healthy controls. The identified CD-specific clusters are therefore likely to contribute to disease behavior. We then looked at whether we could relate the genetic-based subgroups to the currently used clinical parameters. Although modest differences in prevalence of disease location and behavior could be observed among the CD clusters, Random Forest analysis showed that patients could not be allocated to one of the 6 genetic-based subgroups based on the typically used clinical parameters alone. This points to a poor relationship between the genetic-based subgroups and the used clinical subphenotypes. CONCLUSIONS/SIGNIFICANCE: This approach serves as a first step to reclassify Crohn's disease. The used technique can be applied to other common complex diseases as well, and will help to complete patient characterization, in order to evolve towards personalized medicine.
| S-EPMC2944846 | biostudies-literature
Project description:Genome-wide association studies have identified multiple Crohn's disease (CD) susceptibility loci, including association with non-coding intergenic single-nucleotide polymorphisms (SNPs) at 10q21.To fine-map the 10q21 locus, the authors genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single-marker and conditional analyses using logistic regression.Association with CD risk spanning 11 SNPs (p<0.001) was observed. The most significant association observed was at the non-synonymous SNP, rs7076156 (Ala62Thr), in ZNF365. The alanine allele was over-represented in CD (p=5.23×10??; OR=1.39 (95% CI 1.22 to 1.58)); allele frequency of 76% in CD and 69.7% in controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified, and rs7076156 is located in an exon unique to ZNF365 isoform D. The authors demonstrated, using reverse transcription-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. Markedly reduced mean expression levels of ZNF365D were identified in Epstein-Barr virus-transformed lymphoblastoid cell lines from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD.Collectively, these data support the hypothesis that the non-synonymous Ala62Thr SNP, rs7076156, underlies the association between 10q21 and CD risk and suggest that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.
| S-EPMC3250380 | biostudies-literature
Project description:BACKGROUND: Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p?=?1.95×10??; OR 1.49 [1.34-1.79]) and UC (p?=?3.87×10?², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p?=?1.30×10?³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p?=?7.53×10?²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p?=?6.62×10?³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p?=?0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p?=?4.68×10?³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-?B, C/EBP, and E4BP4. CONCLUSIONS/SIGNIFICANCE: Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.
| S-EPMC3310077 | biostudies-literature
Project description:Predisposition to psoriasis is known to be affected by genetic variation in HLA-C, IL12B and IL23R, but other genetic risk factors also exist. We recently reported three psoriasis-associated single nucleotide polymorphisms (SNPs) in the 5q31 locus, a region of high linkage disequilibrium laden with inflammatory pathway genes. The aim of this study was to assess whether other variants in the 5q31 region are causal to these SNPs or make independent contributions to psoriasis risk by genotyping a comprehensive set of tagging SNPs in a 725 kb region bounded by IL3 and IL4 and testing for disease association. Ninety SNPs, capturing 86.4% of the genetic diversity, were tested in one case-control sample set (467 cases/460 controls) and significant markers (P(allelic) < 0.05) (n = 9) were then tested in two other sample sets (981 cases/925 controls). All nine SNPs were significant in a meta-analysis of the combined sample sets. Pair-wise conditional association tests showed rs1800925, an intergenic SNP located just upstream of IL13 (Mantel-Haenszel P(combined) = 1.5 x 10(-4), OR = 0.77 [0.67-0.88]), could account for observed significant association of all but one other SNP, rs11568506 in SLC22A4 [Mantel-Haenszel P(combined) = 0.043, OR = 0.68 (0.47-0.99)]. Haplotype analysis of these two SNPs showed increased significance for the two common haplotypes (rs11568506-rs1800925: GC, P(combined) = 5.67 x 10(-6), OR = 1.37; GT, P(combined) = 6.01 x 10(-5), OR = 0.75; global haplotype P = 8.93 x 10(-5)). Several 5q31-region SNPs strongly associated with Crohn's disease (CD) in the recent WTCCC study were not significant in the psoriasis sample sets tested here. These results identify the most significant 5q31 risk variants for psoriasis and suggest that distinct 5q31 variants contribute to CD and psoriasis risk.
| S-EPMC2536504 | biostudies-literature
Project description:Background & aimsRecent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms.MethodA cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations.ResultsThe NOD2 rare variants were associated with an earlier age at diagnosis (p?=?0.0001) and an ileal involvement (OR?=?2.25[1.49-3.41] and 2.77 [1.71-4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR?=?2.25 [1.13-4.51]) and 6q21 rs7746082 (OR?=?1.60 [1.10-2.34] and negatively associated with the risk alleles of IRGM rs13361189 (OR?=?0.29 [0.11-0.74]) and DEFB1 rs11362 (OR?=?0.50 [0.30-0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR?=?1.75 [1.22-2.53] and OR?=?1.50 [1.04-2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p?=?0.03).ConclusionsIt is not recommended to genotype the studied polymorphisms in routine practice.
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Project description:Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.
| S-EPMC2637978 | biostudies-literature
Project description:Crohn's Disease (CD) is one of the predominant forms of inflammatory bowel disease (IBD). A combination of genetic and non-genetic risk factors have been reported to contribute to the development of CD. Many high-throughput omics studies have been conducted to identify disease associated risk variants that might contribute to CD, such as genome-wide association studies (GWAS) and next generation sequencing studies. A pressing need remains to prioritize and characterize candidate genes that underlie the etiology of CD. In this study, we collected a comprehensive multi-dimensional data from GWAS, gene expression, and methylation studies and generated transcriptome-wide association study (TWAS) data to further interpret the GWAS association results. We applied our previously developed method called mega-analysis of Odds Ratio (MegaOR) to prioritize CD candidate genes (CDgenes). As a result, we identified consensus sets of CDgenes (62-235 genes) based on the evidence matrix. We demonstrated that these CDgenes were significantly more frequently interact with each other than randomly expected. Functional annotation of these genes highlighted critical immune-related processes such as immune response, MHC class II receptor activity, and immunological disorders. In particular, the constitutive photomorphogenesis 9 (COP9) signalosome related genes were found to be significantly enriched in CDgenes, implying a potential role of COP9 signalosome involved in the pathogenesis of CD. Finally, we found some of the CDgenes shared biological functions with known drug targets of CD, such as the regulation of inflammatory response and the leukocyte adhesion to vascular endothelial cell. In summary, we identified highly confident CDgenes from multi-dimensional evidence, providing insights for the understanding of CD etiology.
| S-EPMC6467075 | biostudies-literature
Project description:Genetic variations were successfully associated among patients with coronary artery disease using Illumina Cardiometabochip containing 1,96,725 SNPs Illumina Cardio-metabochip is a custom designed SNP microarray containing 1,96,725 SNPs designed by several GWAS and consortia
2021-01-11 | GSE109068 | GEO
Project description:Hepatocyte nuclear 4 alpha (HNF4?), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4? genetic variants and Crohn's disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the HNF4A gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case-control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33; P<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P<2.09 × 10(-4) for combined cohorts). This is the first report showing that the HNF4A locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD.
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