The results of the largest genome-wide association study (GWAS) to date in patients with systemic sclerosis (SSc) have been published in Nature Communications. The study combined data from 14 independent European cohorts and revealed several new risk loci related to fibrosis and vasculopathy.

“Thanks to a large international collaborative effort, we gathered ~10,000 patients to perform a powerful large-scale genomic analysis of this rare condition,” states co-corresponding author Elena López-Isac. “We have identified 27 independent genome-wide associated signals, including 13 new risk loci, almost doubling the number of genome-wide hits reported for SSc thus far.”

“The study also provides robust evidence to nominate the target genes behind the genetic associations,” adds co-corresponding author Javier Martin. “Some of them point towards molecular pathways linked to vasculopathy (like DDX6, the ability of which to regulate vascular endothelial growth factor under hypoxic conditions has been previously demonstrated), or to fibrosis (like the role of TWSG1, which is involved in transforming growth factor-β signalling in T cells).”

After identifying candidate risk loci in the GWAS screen, the authors used a combination of functional analysis and epigenomic techniques across a variety of cell types to investigate the most relevant genetic associations for the disease. In particular, transcription regulatory functions were uncovered for many genetic variants, and a strong signal for many associations was seen in NK cells, which have been previously linked to SSc pathogenesis.

Importantly, a subtype analysis revealed two unique associations, one for limited cutaneous SSc (MERTK, encoding a tyrosine kinase involved in liver fibrosis) and one for diffuse cutaneous SSc (ANKRD12, the associated variant of which is linked to TWSG1). “For the first time, we identified subtype-specific associated loci outside of the MHC region,” says López-Isac. The authors suggest that the association of fibrotic pathways with diffuse cutaneous SSc is particularly interesting owing to the aggressive nature of this disease subtype.

seven of the identified genes encoded pharmacological targets

The authors also performed a drug target enrichment analysis and found that seven of the identified genes encoded pharmacological targets. Therapeutics are already in clinical trials for SSc for two of these targets (CD80 and BLK), and the authors suggest that the presence of IL12A in the list of genes suggests that ustekinumab might be a candidate to be repurposed for SSc.