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Systemic Sclerosis Study Highlights Immune-Related Genetic Risk Loci

NEW YORK – A Riken Center for Integrative Medical Sciences-led team has tracked down half a dozen new immune cell function-related genetic risk variants involved in systemic sclerosis, a systemic autoimmune condition marked by altered immune system regulation and microvascular changes. These changes lead to fibrotic damage to the lungs, kidneys, and other organs, as well as to connective tissues.

"The etiology of [systemic sclerosis] is complex and is not fully understood, but as with most [autoimmune disorders], it is widely accepted that both environmental and genetic factors contribute to the risk of the disease," senior and corresponding author Chikashi Terao, a researcher affiliated with Riken, Shizuoka General Hospital, and the University of Shizuoka, and colleagues wrote in their study, which was published in Nature Communications on Wednesday.

The researchers began their search for systemic sclerosis culprits through a genome-wide association study that included genotyping data for 1,428 systemic sclerosis cases and nearly 112,600 unaffected control individuals, all from Japan. In addition to directly genotyped variants, they incorporated ones that were imputed with the help of a Japanese reference panel that included more than 3,000 whole-genome sequences.

The initial GWAS search unearthed three previously unappreciated risk variants outside of the HLA region, including systemic sclerosis-associated variants in the AHNAK2-PLD4, TNFAIP3, and FCGR/FCRL gene regions.

The latter risk SNP, which falls in a region coding for Fc-gamma receptor components of the immune system, was also found to be in linkage disequilibrium with a cis-regulatory region that influences the activity of the transcription factor-coding gene IRF8, the team noted.

IRF8 has been implicated in systemic sclerosis in past GWAS done in European ancestry individuals, the investigators explained, noting that the interferon-regulatory factor 8 it encodes is involved in the development of B cells and other immune system components, including dendritic cells, macrophages, and natural killer cells.

"The SNP resides in an enhancer region and forms an IRF8-binding motif, which is crucial for the regulation of immune-related gene expression," Terao and first author Yuki Ishikawa, a statistical and translational genetics researcher at Riken, said in an email. They noted that variants in this region have also been linked to autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis.

When the investigators performed a trans-ethnic GWAS meta-analysis using published data from another 9,095 cases and 17,584 controls of European ancestry, meanwhile, they flagged another 30 loci with significant ties to systemic sclerosis risk, including three risk loci not described in prior studies.

All six of the novel risk variants appeared to have ties to immune cell function which Terao and Ishikawa explained was consistent with a potential causative role for immune-related processes in the pathology of systemic sclerosis. 

The investigators noted that activity of the enhancer-related SNPs appeared to be enriched in B cells in their expression quantitative trait locus analyses. Using available Japanese data for six white blood cell subpopulations, for example, they saw lower-than-usual expression of Fc-gamma receptor genes FCGR2A and FCGR2B genes in the presence of the disease risk-linked SNP rs10917688 in the IRF8 regulatory element.

From these and other findings, the authors suggested that the SNP "may affect the expression of nearby [Fc-gamma receptor] family gene(s) by altering the binding affinity of IRF8 in the target genes, especially B cells."

Likewise, the team's subsequent polygenic risk score (PRS) analyses hinted that the predictive performance of such scores may be enhanced with "the integration of functional annotations in B cells." In particular, Terao and Ishikawa said systemic sclerosis PRS performance appeared to be improved by prioritizing the top 5 percent of SNPs enriched in the IRF8 binding motif.

"Together," the study's authors concluded in the paper, "these data further support the importance of IRF8 and B cells in [systemic sclerosis] development as well as better trans-ancestral portability of PRS by prioritizing SNPs annotated according to TF-binding in tissue and cell type-specific manners."