Study identifies three genes that may influence sarcoidosis risk
Findings could help with development of potential therapy targets
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Three genes not previously established as major genetic contributors to sarcoidosis — RFTN2, FAM117B, and RNF215 — may influence a person’s susceptibility to the inflammatory disease, according to a large genetic analysis.
Using genetic information from more than 5,000 people living with sarcoidosis and nearly 500,000 without the disease, who served as controls, researchers found that genetically predicted higher activity of RFTN2 and FAM117B was associated with a lower risk of sarcoidosis, whereas higher RNF215 activity was associated with greater disease risk.
Further analyses supported these three genes as the strongest candidates and showed that the genetic signals were concentrated in immune cells called macrophages found in granulomas, tiny clusters of white blood cells that form in sarcoidosis.
The findings expand “the genetic landscape of sarcoidosis” and identify three genes as “promising candidate targets for future functional studies and therapeutic development in sarcoidosis,” researchers wrote.
The study, “Cross-Tissue Transcriptomic and Spatial Mapping Analyses Identify Novel Non-HLA Candidate Causal Genes for Sarcoidosis,” was published in the International Journal of Clinical Practice.
RNF215 activity associated with increased sarcoidosis risk
Sarcoidosis is an inflammatory condition that can affect any organ. Exactly why sarcoidosis develops remains unclear. Both environmental and genetic factors are thought to contribute, and some of the known genetic associations occur in the human leukocyte antigen (HLA) region, a cluster of genes involved in immune responses.
However, genetic factors outside this region remain less well understood. Identifying them could reveal biological pathways that contribute to abnormal immune activation and potentially uncover new treatment targets.
In this study, researchers in China and the U.K. sought to identify genes outside this region to provide “a deeper understanding of the genetic variations associated with sarcoidosis.”
They combined genetic data from 5,411 people with sarcoidosis and 492,311 controls with gene activity data from 49 tissues. Additional analyses were then used to narrow the results to genes with stronger evidence of a role in sarcoidosis risk and to specifically determine which cells are more strongly associated.
Six genes — RFTN2, FAM117B, RNF215, SF3B1, PLCL1, and MIR4435-2HG — were associated with sarcoidosis. Additional analyses particularly supported RFTN2, FAM117B, and RNF215 in several tissues.
Specifically, as genetically predicted, higher RFTN2 activity was associated with a lower risk of sarcoidosis in several tissues, including the lungs, spleen, and thyroid. Higher FAM117B activity was similarly linked to lower risk in tissues including the lungs, spleen, and blood.
Collectively, our work not only expands the known genetic architecture of sarcoidosis but also delivers a prioritized set of candidate molecular targets that may inform the development of future therapeutic strategies for this enigmatic disease.
In contrast, higher RNF215 activity was associated with increased sarcoidosis risk in the tibial artery tissue in the lower leg.
To better determine where the identified genetic signals might be most relevant, the researchers next used spatial transcriptomics, a technology that maps gene activity in intact tissue samples, using samples from people with muscular sarcoidosis.
Among different cell populations, granuloma-associated macrophages showed the strongest association with genetic susceptibility to sarcoidosis. RFTN2, FAM117B and RNF215, along with two other candidate genes (SF3B1 and PLCL1), had high activity in these macrophages and in areas of immune-cell infiltration.
Macrophages are immune cells that engulf foreign material and help coordinate inflammation. In sarcoidosis, they accumulate together with other immune cells to form granulomas.
Among the study limitations noted by the scientists were its computational nature and the fact that genetic data came solely from people of European ancestry.
“Collectively, our work not only expands the known genetic architecture of sarcoidosis but also delivers a prioritized set of candidate molecular targets that may inform the development of future therapeutic strategies for this enigmatic disease,” the team concluded.
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