Background/Purpose: Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad symptoms of symmetric arthritis, dermatitis, and granulomatous recurrent uveitis, similar to that of early onset sarcoidosis. The phenotype of the disease has proven to be more complex than initially thought but most commonly involve cutaneous and arthritis manifestations. Eye disease is rarely the presenting symptom but significant visual impairment has been observed in 46% of patients. Polymorphisms in the nucleotide oligomerization domain 2 (NOD2) are known to be associated with susceptibility to BS, Crohn’s disease and sarcoidosis. Studies have shown that dysregulation of NOD2 signaling is involved in the pathogenesis of a variety of inflammatory disorders and has been implicated in the development of autoimmune disease, allergy, and asthma. As such, the goal of our study was to investigate the involvement of the NOD2 pathway genes by selecting sarcoidosis cases that presented with disease similar to BS in African Americans (AAs) and European Americans (EAs).

Methods: Our AA case-case analysis comprised 51 AA sarcoidosis cases with positive skin and bone/joint involvement (~35.3% also have eye involvement), and 255 AA sarcoidosis cases without any skin and bone/joint involvement. Our EA case-case analysis consisted of 27 EA sarcoidosis cases with positive skin and bone/joint involvement (~14.8% have eye involvement), and 135 EA sarcoidosis cases without any skin and bone/joint involvement. Genotyping was performed at the Oklahoma Medical Research Foundation (OMRF) using the Illumina HumanOmni1-Quad array and imputed using IMPUTE2/gtool. Quality control included removal of SNPs with call rate < 80% and Hardy-Weinberg proportion tests P < 0.001. We evaluated 5,362 SNPs in AAs and 2,639 SNPs in EAs from 30 genes within the NOD2 pathway. Single-marker association test was performed using EMMAX adjusted for sex as a covariate. 

Results: We observed novel significant associations in a TAB1 variant in AAs (rs35506409) and TAB2 variants (rs111447766, rs111576955, rs76778446, and rs79995379) in EAs passing Bonferroni thresholds (P < 3.46x10^-5 in AAs; P < 1.12x10^-4 in EAs). TAB1 is involved in kinase activator activity while TAB2 is involved in polyubiquitin binding molecular functions. Cursory analysis using BioGPS of these genes confirmed their high expression in retina, CD4+ T cells, and CD8+ T cells of human tissues. Previous studies have shown that TAB1 has been found to play a role in skin homeostasis, wound repair, and oncogenesis. Further, both TAB1 and TAB2 genes have been found to be redundantly involved in lipopolysaccharide-induced TAK1 activation in macrophages, and that deletion of either TAB1 or TAB2 results in macrophage death.

Conclusion: Our genetic study of the key players in the NOD2 pathway identified novel genetic associations in TAB1 in AAs and TAB2 in EAs. These findings will give insight into the genetic etiology of BS in adult sarcoidosis cases among AAs and EAs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-nod2-pathway-in-sarcoidosis-cases-with-characteristics-of-blau-syndrome/