Genetics of psoriatic arthritis

Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families and possess overlapping clinical features. The pathogenesis of SpA encompasses a complex array of genetic, immunological and environmental factors. In this article, we will briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the major histocompatibility complex (MHC) region, which accounts for approximately one-third of the genetic contribution of PsV and PsA. To date, 36 genes have reached genome-wide significance, accounting for approximately 22% of psoriasis (PsV) heritability. Prominent genes identified via GWAS include HLA-Cw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1. Genes identified in psoriatic arthritis (PsA) has largely echoed those in PsV and include HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL. The lack of identified genetic susceptibility loci is largely attributed to the much smaller number of PsA patients and the greater clinical heterogeneity of PsA. Searching for different types of genetic variants such as small CNVs and/or insertions/deletions has also led to the identification of several genes with a function relative to PsV in particular including DEFB4, LCE3C_LCE3B, and IL-22 gene (exon 1). The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprised of barrier integrity, innate immune response and adaptive immune response, mediated primarily by Th-17 and Th-1 signalling. While GWAS studies have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine-mapping and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases. That searching solely for common variants by GWAS will identify only a fraction of the entire genetic burden of disease, a concerted effort is underway to search for highly penetrant but rare disease alleles in families with PsV and PsA, using next-generation sequencing and through epigenetic investigations.