Background/Purpose: Systemic sclerosis (SSc) is a complex disease characterized by substantial genotypic and phenotypic heterogeneity. Four molecular gene expression subsets have been identified from SSc skin, including inflammatory, fibroproliferative, normal-like, and limited. Genome-wide association studies have identified genetic variants associated with disease risk. However, these studies were not designed to interrogate genetic changes underlying specific gene expression subtypes. Here, our objective was, by RNA-seq in SSc skin, to identify potential genetic variants associated with specific gene expression subtypes and disease phenotypes.

Methods: We generated RNA-seq data from skin biopsies of 42 patients with SSc and 14 healthy controls. Variants were detected and filtered by quality, sequencing depth, minor allele frequency, and potential deleterious effects on gene function. Gene burden tests were used to identify susceptibility loci in cases compared to healthy controls, as well as in healthy controls of a European population from the phase III 1000 Genomes Project (N=503). We further quantitated gene expression and used an additive genetic model to identify gene expression associated variants. Variants enriched in each of the SSc molecular subsets were detected by Fisher’s exact test.

Results: We identified 267 potentially deleterious variants in 253 genes in patients with SSc, including 30 genes (e.g. IRF6, NCF2, IL37) enriched in immunological processes and 10 genes (e.g. ITGB4, COL5A1, LAMA3) significantly enriched in extracellular matrix-related pathways. We found variants enriched in each of the inflammatory (35 variants), fibroproliferative (7 variants), and normal-like (45 variants) subsets. Potentially deleterious variants in IL37 were enriched in patients with diffuse skin involvement and were significantly correlated with increased gene expression of IL6 and STAT3 in patient samples. Consistently, HapMap B cell lines harboring deleterious IL37 variants showed increased expression of IL6 upon immune stimulation.

Conclusion: This study demonstrates the value of RNA-seq for identifying genetic variants associated with SSc gene expression subsets. Results indicate genetic variants can be associated with each of the intrinsic gene expression subset and may influence innate immune responses and ECM deposition. The identified IL37 variant may modulate SSc pathogenesis by increasing expression of the IL-6 pathway.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptome-sequencing-reveals-genetic-polymorphisms-associated-with-ssc-gene-expression-subtypes/