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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10067-019-04922-6) contains supplementary material, which is available to authorized users.