Defining genetic risk factors for scleroderma-associated interstitial lung disease: IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5 , and one in each of STAT4 , CD226 and IRAK1 , selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population ( n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10–1.54), p corr = 0.015) and rs10488631 (OR 1.48 (1.14–1.92), p corr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18–1.73), p corr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5 , rs10488631 (OR 1.72 (1.24–2.39), p corr = 0.0098), and rs2004640 (OR 1.39 (1.11–1.75), p corr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45–2.38), p corr = 6.6 × 10 −6 ). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51–0.85), p corr = 0.0084). 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. Key points • We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole. • None of the tested SNPs were risk factors for SSc-ILD specifically. • The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients. • Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.