Variant in STAT4 Gene Protects Patients Against SSc-ILD Development, Study Suggests

A specific variant in the STAT4 gene protects people with scleroderma against the development of interstitial lung disease (ILD), a new study in patients of European descent suggests.

However, more and larger studies are needed to identify the genetic risk factors that make some people with scleroderma more likely to have ILD, the researchers said.

The study, titled “Defining genetic risk factors for scleroderma-associated interstitial lung disease,” was published in the journal Clinical Rheumatology.

Scleroderma, also called systemic sclerosis (SSc), is a complex condition resulting from the combination of environmental and genetic factors.

Suggesting the existence of genetic predisposition, patients often have a family member with another autoimmune disease. Notably, the likelihood of developing scleroderma varies between ethnic groups. In the U.S., African-Americans and Native Americans are more often affected by the connective tissue disease than are Caucasians.

The most severe of all complications associated with scleroderma is ILD, a group of lung disorders that generally involve inflammation and progressive scarring of the lungs, along with pulmonary arterial hypertension.

Very little is known about the genetic susceptibility to SSc-associated ILD. Many of the genetic variants studied have given conflicting results in separate populations, and rather than focusing on SSc-ILD specifically, research to date has assessed scleroderma as a whole, the scientists said.

Also, few studies have sought to detect genetic risk factors for ILD outcomes, including lung function decline.

To address this gap, a team of researchers from the U.K. and Italy assessed 612 people with scleroderma, 394 of whom had ILD. These patients were seen at the Royal Brompton Hospital and the Royal Free London hospital, both in London. For comparison, the study also included a control group of 503 individuals of European descent.

The genetic screening specifically focused on seven small genetic variations — four in the IRF5 gene, and one each in the STAT4, CD226 and IRAK1 genes – which had robust evidence of an association with SSc-ILD.

All of these genes are involved in the functioning of the immune system and also have been associated with other autoimmune diseases.

The results revealed that three of the tested variants, called single nucleotide polymorphisms (SNPs, pronounced “snips”), were significantly associated with scleroderma. Specifically, these were rs2004640 T allele and rs10488631 C allele in IRF5, and rs7574865 T allele in STAT4. SNPs are the most common type of genetic variation among people, with each one representing a difference in a single DNA building block, called a nucleotide.

An allele refers to one of the two gene copies inherited from each parent. A, G, T, and C designate the different nucleotides. So, for instance, if an individual carries the rs2004640 T allele in IRF5, this means that person has a gene copy of IRF5 with the “DNA letter” T at the specific position identified as rs2004640.

However, none of the tested genetic variants were risk factors for SSc-ILD.

Two variations in IRF5 — rs10488631 C allele and rs2004640 T allele — and the change in STAT4 (rs7574865 T allele) were more frequent in patients without ILD than in controls.

The only significant difference between scleroderma with and without ILD was in the variant rs7574865 T allele in STAT4, which was less common in scleroderma patients with ILD. This indicates that this variation was protective against the development of lung fibrosis, or scarring, in people with scleroderma.

None of the seven tested SNPs were significantly associated with mortality or the course of the disease, as measured by time-to-lung-function decline.

“In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD,” the researchers said.

The scientists said these findings draw attention to the need for more studies on genetic susceptibility to SSc-ILD.