NOD2 genetic variants and sarcoidosis-associated uveitis

Abstract

Purpose : To determine if variants in NOD2, a gene that has been associated with autoimmune diseases including a Mendelian disorder similar to early-onset sarcoidosis, confer an increased risk of developing uveitis in adults with sarcoidosis.

Methods : Patients who met the International Workshop on Ocular Sarcoidosis diagnostic criteria for sarcoidosis were prospectively enrolled at the Massachusetts Eye and Ear Infirmary. They were examined for absence or presence of uveitis by fellowship-trained uveitis specialists. Sanger sequencing of the NOD2’s eleven exons was performed on DNA from whole blood. Sanger sequencing data were aligned against the NOD2 NCBI-RefSeq reference file to identify variants. Potential functional significance of novel mutations was quantified using Human BP Codon Resource (HBCR). HBCR uses predicted sequence changes based on Ensembl gene models, and pathogenicity data extracted from a curated database, PolyPhen, SIFT, the dbNSFP resource, and Combined Annotation Dependent Depletion scores. Allele frequencies in cases versus controls were compared using the chi-square test (Stata, College Station, Texas).

Results : 53 participants were enrolled, including 41 patients diagnosed with sarcoid-associated uveitis as cases (mean age of 56.6 years, 73% female) and 12 patients with systemic sarcoidosis without ocular involvement as controls (mean age of 54.2 year, 59% female). There was no significant difference in variant allele frequencies of established pathogenic NOD2 mutations between sarcoid patients with and without uveitis. However, three rare, non-synonymous variants were identified in three patients with severe ocular sarcoidosis. Polymorphisms rs149071116 and rs50745164 have never been previously reported to be associated with any disease. SIFT predicted both variants to be damaging. The third polymorphism, rs35285618, is a rare variant (minor allele frequency = 0.013) located 19 bases downstream of the R702W variant that is associated with Crohn’s disease in African Americans.

Conclusions : Despite the phenotypic overlap between sarcoidosis and Blau syndrome, there were no NOD2 variants significantly present in adult sarcoidosis patients with uveitis. However, three rare, non-synonymous variants were identified in three cases of severe ocular sarcoidosis. Further investigation is needed to explore the potential clinical significance of these polymorphisms.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Table 1. Demographics

 

Table 2. Variant Allele Frequencies