Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

Peter, Inga; Mitchell, Adele A.; Ozelius, Laurie J.; Erazo, Monica; Hu, Jianzhong; Doheny, Dana; Abreu, María T.; Present, Daniel H.; Ullman, Thomas; Benkov, Keith; Korelitz, Burton I.; Mayer, Lloyd; Desnick, Robert J.

doi:10.1186/1471-2350-12-63

Cited by 42 publications

(40 citation statements)

References 46 publications

(76 reference statements)

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“…In accordance with our results, the SNP rs1000113 has been associated with Crohn's disease in both German and Ashkenazi Jewish populations [31], [32]. Consistent with our finding where the OR for Crohn's disease association with the minor T allele of rs1000113 was 1.46, a previous study in an Italian population of IBD patients indicated rs1000113 as a CD susceptibility locus with OR of 1.62 (Confidence interval 1.29–2.03) [28].…”

Section: Discussionsupporting

confidence: 92%

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

2014

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BackgroundMutations in the IRGM gene have been associated with Crohn's disease in several populations but have not been explored in Indian patients with this disease. This study examined the association of IRGM mutations with ulcerative colitis and Crohn's disease in Indian patients with inflammatory bowel disease.MethodsThe IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn's disease, 39 ulcerative colitis, and 20 healthy controls). Ten single nucleotide polymorphisms (SNP) were genotyped in 1200 participants (352 Crohn's disease, 400 ulcerative colitis, and 448 healthy controls) using Sequenom MassARRAY iPLEX. Disease associations were evaluated for each of the ten SNPs.ResultsThirty one mutations were identified in the IRGM gene, of which two had not hitherto been reported (150226250- ss947429272 & 150227858- ss947429273). Ten SNPs (6 from the above and 4 from the literature) were evaluated. Significant associations with Crohn's disease were noted with the T allele of rs1000113 (OR 1.46, 95% CI 1.12–1.90), T allele of rs9637876 (OR 1.25, 95% CI 1.005–1.561) and C allele of rs 13361189 (OR 1.33, 95% CI 1.07–1.669). Two SNPs – rs11747270 and rs180802994 – did not exhibit Hardy-Weinberg equilibrium but were associated with both Crohn's disease and ulcerative colitis in this population. The remaining SNPs did not show significant associations with either Crohn's disease or ulcerative colitis.ConclusionsAssociation of IRGM gene SNPs with Crohn's disease is reported for the first time in Indian patients. We also report, for the first time, an association of rs 9637876 in the IRGM gene with Crohn's disease.

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Section: Discussionsupporting

confidence: 92%

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

2014

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“…Consequently, IRGM may particularly affect the onset, severity, and relapse of CD (Lapaquette et al, 2010). Several SNPs in the IRGM gene such as rs13361189 (C>T), rs10065172 (C>T), and rs4958847 (A>G) have been investigated previously (Waterman et al, 2011;Peter et al, 2011;Moon et al, 2013). Previous studies have shown that these 3 polymorphisms may impact the normal expression of the IRGM gene, thus contributing to the susceptibility to CD (Palomino-Morales et al, 2009;Glas et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Correlation between IRGM genetic polymorphisms and Crohn’s disease risk: a meta-analysis of case-control studies

Yao

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This meta-analysis was performed to evaluate the relationships between single-nucleotide polymorphisms (SNPs) in the immunity-related GTPase M (IRGM) gene and the risk of Crohn's disease (CD). Eleven case-control studies were included, for a total of 5183 CD patients and 5571 healthy controls. Three common SNPs (rs13361189 C>T, rs10065172 C>T, and rs4958847 A>G) in the IRGM gene were assessed. We found that the IRGM rs13361189 polymorphism was significantly associated with an increased risk of CD [C allele vs T allele: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.05-1.61, P = 0.017; CC + CT vs TT: OR = 1.32, 95%CI = 1.06-1.64, P = 0.013]. However, we observed no correlation between the rs10065172 and rs4958847 polymorphisms in the IRGM gene with susceptibility to CD (all P > 0.05). Subgroup analysis by ethnicity revealed significant associations between IRGM genetic polymorphisms and an increased risk of CD among Caucasian populations (C allele vs T allele: OR = 1.22, 95%CI = 1.07-1.40, P = 0.004; CC + CT vs TT: OR = 1.22, 95%CI = 1.05-1.41, P = 0.009), but not among Asian populations (all P > 0.05). Meta-regression analysis also confirmed that ethnic differences may be an important source of heterogeneity (P = 0.003). Our meta-analysis results indicate that the IRGM rs13361189 polymorphism contributes to the susceptibility to CD. Thus, the IRGM rs13361189 polymorphism is promising as a biomarker for early diagnosis of CD. However, the IRGM rs10065172 and rs4958847 polymorphisms may not be the major determinants of CD risk.

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“…The top association signals were then replicated in an independent cohort of 589 CD cases and 1,019 controls, recruited throughout North America, Europe, and Israel. Disease diagnosis was confirmed using standard criteria as described elsewhere and full Ashkenazi Jewish ancestry was validated using principal components analysis (11, 44). Our second stage genetic association analysis included a total of 8,619 independent Ashkenazi Jewish and 16,401 independent non-Jewish participants comprising CD cases, PD cases, and healthy controls, genotyped in previous studies (45, 46).…”

Section: Methodsmentioning

confidence: 99%

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of non-synonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2,066 CD cases and 3,633 healthy controls. We detected association signals in the LRRK2 gene that conferred CD risk (N2081D variant, P=9.5×10−10) or protection (N551K variant, tagging R1398H-associated haplotype, P=3.3×10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant is associated with increased kinase activity, whereas neither N551K nor R1398H on the protective haplotype altered kinase activity. R1398H, but not N551K, increased GTPase activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

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Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

Cited by 42 publications

References 46 publications

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

Correlation between IRGM genetic polymorphisms and Crohn’s disease risk: a meta-analysis of case-control studies

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

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