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NOD2 genetic variants and sarcoidosis-associated uveitis.

ABSTRACT: Purpose:Identifying genetic risk factors for developing sarcoidosis-associated uveitis could provide insights into its pathogenesis which is poorly understood.We determine if variants in NOD2 confer an increased risk of developing uveitis in adults with sarcoidosis. Methods:In this genetic case-control study, 51 total subjects were enrolled: 39 patients diagnosed with sarcoid-related uveitis and 12 patients with systemic sarcoidosis without ocular involvement as controls. Sanger sequencing of the eleven exons of the NOD2 gene was performed on DNA obtained from whole blood. Sanger sequencing data were aligned against the NOD2 NCBI-RefSeq reference sequence to identify novel mutations in uveitis patients. For common variants, allele frequencies in cases versus controls were compared using the chi-square test. Results:There were no significant differences in NOD2 common variant allele frequencies between sarcoidosis patients with and without uveitis, and none of the pathogenic NOD2 mutations associated with Blau syndrome were found in this cohort. However, four rare, non-synonymous variants were identified in four patients with ocular sarcoidosis and none of the controls. Variants rs149071116, rs35285618, and 16:g.50745164T > C have never been previously reported to be associated with any disease and may be pathogenic. The fourth variant, rs2066845, is associated with Crohn's disease and psoriatic arthritis. Conclusions:Despite the phenotypic overlap between sarcoidosis and Blau syndrome, none of the established pathogenic NOD2 variants were present in adults with sarcoidosis. However, four novel, rare, non-synonymous variants were identified in four cases with ocular sarcoidosis. Further investigation is needed to explore the potential clinical significance of these polymorphisms.

SUBMITTER: Davoudi S

PROVIDER: S-EPMC5757392 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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<i>NOD2</i> genetic variants and sarcoidosis-associated uveitis.

Davoudi Samaneh S Navarro-Gomez Daniel D Shen Lishuang L Ung Cindy C Ren Aiai A Sullivan Lynn L Kwong Mindy M Janessian Maria M Comander Jason J Gai Xiaowu X Lobo Ann-Marie AM Papaliodis George N GN Sobrin Lucia L

American journal of ophthalmology case reports 20160601

<h4>Purpose</h4>Identifying genetic risk factors for developing sarcoidosis-associated uveitis could provide insights into its pathogenesis which is poorly understood.We determine if variants in <i>NOD2</i> confer an increased risk of developing uveitis in adults with sarcoidosis.<h4>Methods</h4>In this genetic case-control study, 51 total subjects were enrolled: 39 patients diagnosed with sarcoid-related uveitis and 12 patients with systemic sarcoidosis without ocular involvement as controls. S ...[more]

PMID: 29503906

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Project description:BackgroundIn case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater risk. However, the importance of these genetic variants if identified in particular individuals within the general population is unknown. We undertook this study to estimate the penetrance of these variants in the general population.MethodsWe genotyped 43,596 individuals from the Danish general population followed between January 1976 and July 2007. Using a logistic regression model, we estimated the risk of Crohn disease in relation to variants of the NOD2/CARD15 gene in the general population. Penetrance was calculated as the fraction of participants in whom Crohn disease was diagnosed before age 50 years.ResultsIn the general population, 89% of participants were noncarriers of the genetic variants of interest (n = 38,594), 11% were heterozygotes (n = 4838), and 0.4% were compound heterozygotes or homozygotes (n = 164). For Crohn disease, multifactorially adjusted odds ratios were 1.2 (95% confidence interval [CI] 0.8-1.9) for heterozygotes and 3.3 (95% CI 0.8-13.6) for compound heterozygotes and homozygotes combined, relative to noncarriers. Only 2 compound heterozygotes received a diagnosis of Crohn disease, and this disease was not diagnosed in any of the homozygotes. The penetrance at age 50 years of NOD2/CARD15 genetic variants of Crohn disease was 0.30% (95% CI 0.29%-0.31%) for heterozygotes and 1.5% (95% CI 1.4%-1.6%) for compound heterozygotes and homozygotes.InterpretationThe penetrance of NOD2/CARD15 genetic variants in relation to risk of Crohn disease for this Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are identified.

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NOD2 genetic variants and sarcoidosis-associated uveitis.

Publications

<i>NOD2</i> genetic variants and sarcoidosis-associated uveitis.

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