Genetic and Genomic Analysis of Systemic Sclerosis: A Narrative Review of the Recent Advancement

Systemic sclerosis (SSc) is one of the systemic autoimmune diseases characterized by disease-specific autoantibodies and generalized fibrosis in connective tissues and internal organs, resulting from microvascular and immune dysfunctions, which lead to premature death in affected individuals. The etiology of SSc is complex and poorly understood; however, as with most autoimmune conditions, it is widely accepted that both environmental and genetic factors interact and contribute to disease development. Over the last decade, genome-wide association studies (GWAS) have identified multiple genetic markers associated with SSc, and a number of causal variants have also been fine-mapped using state-of-the-art statistical techniques. Furthermore, the latest East Asian GWAS identified novel risk variants that were not as strongly represented in Europeans as in East Asians, and also provided additional novel risk variants, highlighting the importance of enrolling a diverse population for the analysis of complex traits. The association of human leukocyte antigen regions has been clarified mainly in individuals of European descent, with the identification of clinical subtype-specific associations of certain alleles. The associations in East Asian SSc are currently being analyzed by our team. Recent advances in single-cell ribonucleic acid (RNA) sequence technology have enabled the identification of transcriptomic changes at the single-cell level in a cell type or tissue-specific manner, allowing for the identification of disease-relevant cells or transcriptomes. To date, multiple single-cell RNA sequence studies have been conducted, primarily focusing on cells and transcriptomes in peripheral blood, skin, or lung. Despite the remarkable advances in state-of-the-art technology for both genetics and transcriptomics, gene expression regulations, especially by enhancers, enriched for disease heritability and thus critical for SSc development, remain unresolved. Integrative analysis using multi-omics approaches, combined with deep phenotyping of study cohorts, is imperative to fully characterize the genetic component of this disease and to identify causal variants, which may lead to more targeted and effective treatment of SSc.