Natural Variations in Genes May Increase PF Susceptibility in Systemic Sclerosis Patients

Natural gene variants, called polymorphisms, may explain why some patients with systemic sclerosis also develop pulmonary fibrosis (PF).

The study, “The status of pulmonary fibrosis in systemic sclerosis is associated with IRF5, STAT4, IRAK1, and CTGF polymorphisms,” appeared in the journal Rheumatology International.

PF is one of the leading causes of death in patients with systemic sclerosis. However, about 40 percent of people with this disease never get PF. This suggests that factors beyond those underlying autoimmunity must play a role in triggering PF.

“Despite intense research efforts, the pathogenesis of PF in systemic sclerosis remains elusive and effective therapies to systemic sclerosis-related PF are still missing,” researchers wrote.

Now, researchers aimed to find out if there is a genetic basis for why certain patients with systemic sclerosis develop PF. Specifically, they set out to investigate potential susceptibility genes controlling the status of PF in these patients.

The team searched for published studies on the PubMed database, using as a first search keyword “systemic sclerosis genetic association.” In total, and after filtering the results for their intended objective, it selected 17 articles for further analysis. The team identified eight susceptibility gene variants, known as genetic polymorphisms, of systemic sclerosis.

To determine whether the eight systemic sclerosis-associated genetic polymorphisms were associated with PF status, researchers performed a comprehensive meta-analysis by comparing PF-positive and PF-negative systemic sclerosis patients.

Out of the eight initial identified polymorphisms, only four of them were found to associate with the status of PF in systemic sclerosis. These were the gene IRF5 (rs2004640 polymorphism), STAT4 (rs7574865 polymorphism), CTGF (G-945C polymorphism) and IRAK1 (rs1059702 polymorphism).

IRF5 and STAT4 are transcription factors regulating innate immune responses. The IRAK1 gene is also important for the immune system, encoding essential molecules of innate immunity. Contrary to a general role in immunity, the CTGF gene is not expressed in immune cells but in connective tissues, especially in fibroblasts. Its function is linked to regulating extracellular matrix (ECM) synthesis in wound healing and fibrotic diseases.

Overall, wrote researchers, these results “suggest that a group of genes involved in the regulation of innate immunity or ECM synthesis are associated with the status of PF in systemic sclerosis. This result suggests a role of innate immunity and ECM synthesis in the manifestation of pulmonary fibrosis in systemic sclerosis.”