Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
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ABSTRACT:
SUBMITTER: Parkes M
PROVIDER: S-EPMC2628541 | biostudies-literature | 2007 Jul
REPOSITORIES: biostudies-literature
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Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
Parkes Miles M Barrett Jeffrey C JC Prescott Natalie J NJ Tremelling Mark M Anderson Carl A CA Fisher Sheila A SA Roberts Roland G RG Nimmo Elaine R ER Cummings Fraser R FR Soars Dianne D Drummond Hazel H Lees Charlie W CW Khawaja Saud A SA Bagnall Richard R Burke Denis A DA Todhunter Catherine E CE Ahmad Tariq T Onnie Clive M CM McArdle Wendy W Strachan David D Bethel Graeme G Bryan Claire C Lewis Cathryn M CM Deloukas Panos P Forbes Alastair A Sanderson Jeremy J Jewell Derek P DP Satsangi Jack J Mansfield John C JC Cardon Lon L Mathew Christopher G CG
Nature genetics 20070606 7
A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13. ...[more]
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Project description:The aim of the present meta-analysis was to evaluate the correlation between a common polymorphism, rs13361189 C>T in the immunity-related GTPase M (IRGM) gene, and susceptibility to Crohn's disease (CD). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were investigated from database inception through to October 1, 2013 without the application of any language restrictions. The meta-analysis was performed using STATA 12.0 software and the relative risk (RR) with a 95% confidence interval (CI) was calculated. Seven case-control studies were included with a total of 3,093 CD patients and 3,227 healthy control subjects. The results of the meta-analysis revealed that the IRGM rs13361189 polymorphism correlates with an increased risk of CD (T allele versus C allele: RR=1.25 with 95% CI, 1.04-1.50; P=0.016 and CT + TT versus CC: RR=1.21 with 95% CI, 1.03-1.42; P=0.018). A subgroup analysis conducted using a genotyping method indicated that the IRGM rs13361189 polymorphism was correlated with an increased risk of CD in the TaqMan® (T allele versus C allele: RR=1.32 with 95% CI, 1.01-1.73; P=0.042) and the polymerase chain reaction-restriction fragment length polymorphism subgroups (T allele versus C allele: RR=1.80 with 95% CI, 1.32-2.45; P<0.001 and CT + TT versus CC: RR=1.61 with 95% CI, 1.19-2.18; P=0.018). However, no correlation was observed in the direct sequencing subgroup (P>0.05). Further subgroup analysis by sample size demonstrated significant correlations between the IRGM rs13361189 polymorphism and an increased risk of CD in the large sample-size subgroup (T allele versus C allele: RR=1.46 with 95% CI, 1.26-1.68; P<0.001 and CT + TT versus CC: RR=1.40 with 95% CI, 1.21-1.62; P<0.001). However, no correlation was identified between the IRGM rs13361189 polymorphism and CD risk in the small sample-size subgroup (P>0.05). The present meta-analysis indicated that the IRGM rs13361189 polymorphism may contribute to susceptibility to CD. Thus, IRGM rs13361189 polymorphism may be a potential biomarker for the early diagnosis of CD.
| S-EPMC4079410 | biostudies-literature
Project description:BackgroundPolymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results.Methodology/ principal findingsThe PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn's disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2 × 10(-10), OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC).Conclusions/ significanceThese results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.
| S-EPMC3827440 | biostudies-literature
Project description:We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
| S-EPMC2728932 | biostudies-literature
Project description:Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
| S-EPMC2731799 | biostudies-literature
Project description:DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5' untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 x 10(-5) to 1.40 x 10(-9)), and that the CNV and the 5'-untranslated region variant -308(GTTT)(5) contribute independently to CD susceptibility (P = 2.6 x 10(-7) and P = 2 x 10(-5), respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10(-12)) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.
| S-EPMC2850616 | biostudies-literature
Project description:Background & aimsGenome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.Methodology/principal findingsGenomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction.Conclusions/significanceOur results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.
| S-EPMC3554777 | biostudies-literature
Project description:Background:To date, studies have shown that polymorphisms in an autophagy-related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods:Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves' disease, 292 with Hashimoto's thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results:T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves' disease patients than controls, and the ORs were OR = 1.207 (P = 0.022), OR = 1.207 (P = 0.027), and OR = 1.200 (P = 0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P = 0.033) and 1.33 (P = 0.024), while the adjusted ORs for rs13361189 were 1.19 (P = 0.042) and 1.33 (P = 0.026), respectively. No significant difference was found between Hashimoto's thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves' disease patients (OR = 1.195, P = 0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves' disease patients (OR = 0.861, P = 0.044; OR = 0.816, P = 0.017). Conclusions:Our study reveals IRGM as a susceptibility gene of AITD and Graves' disease for the first time.
| S-EPMC6016217 | biostudies-literature
Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is an increasingly recognized comorbidity in Crohn's disease (CD), but the mechanisms are poorly understood. Autophagy is a highly conserved process regulating innate immunity that contributes to CD susceptibility. Emerging data suggest that variants in the autophagy-governing IRGM gene may contribute to the accumulation of visceral adipose tissue (VAT) and hepatic fat. Our objective was to characterize the relationship between VAT, IRGM gene variants, and NAFLD risk in patients with CD.MethodsWe included all CD patients in the Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM) without history of alcohol abuse or liver disease. Hepatic fat was quantified by liver attenuation (LA) on computed tomography, with NAFLD defined by the validated liver:spleen (L:S) ratio. NAFLD severity was estimated by the FIB-4 Index and alanine aminotransferase (ALT). Using logistic regression modeling, we examined the relationship between VAT, autophagy gene variants, and NAFLD risk.ResultsAmong 462 patients, 52% had NAFLD. Increasing VAT quartile was associated with reduced LA (mean change, -7.43; 95% confidence interval [CI], -10.05 to -4.81; Ptrend < 0.0001). In the fully adjusted model, patients in the highest VAT quartile had a 2.2-fold increased NAFLD risk (95% CI, 1.21 to 4.14; Ptrend = 0.032) and a 4.2-fold increased risk of ALT>upper limit of normal (ULN) (95% CI, 1.19 to 14.76; Ptrend = 0.017). The relationship between VAT and NAFLD was modified by IRGM variants rs4958847 and rs13361189 (Pinteraction = 0.005 and Pinteraction < 0.001, respectively).ConclusionsIn a large CD cohort, VAT was directly associated with prevalent NAFLD, and this relationship was augmented by functionally annotated IRGM variants associated with impaired autophagy.
| S-EPMC6230523 | biostudies-literature
Project description:Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
| S-EPMC3832895 | biostudies-literature
Project description:Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.
| S-EPMC6372082 | biostudies-literature