Gene variants of interferon induced with helicase C domain 1 in Japanese patients with Dermatomyositis-associated rapidly progressive interstitial lung disease: a genetic association study using whole-exome and Sanger sequencing.

BACKGROUND: Patients with Dermatomyositis (DM) having anti-melanoma differentiation-associated gene 5 (MDA5) antibodies occasionally develop rapidly progressive interstitial lung disease (RP-ILD), a serious inflammatory complication; however, no genetic biomarker has yet been identified for this condition. This study aimed to identify interferon-induced with helicase C domain 1 (also known as MDA5) gene (IFIH1) variants associated with a high risk of DM-associated RP-ILD. METHODS: A total of 204 patients with DM were enrolled from six institutions. Whole-exome sequencing was performed on nine patients with DM-associated interstitial lung disease (ILD) who were positive for anti-MDA5 antibodies, and six single-nucleotide polymorphisms (SNPs) were identified: p.Val194Ala (no reference SNP ID), rs1990760, rs3747517, rs12479043, rs10930046, and rs141134657. Allele frequencies of eight IFIH1 variants-including these six SNPs plus rs117608083 and rs183412282-were analyzed using Sanger sequencing. Statistical analyses included allele frequency comparisons and genotype-based assessments (dominant and recessive models), and the Armitage trend test. RESULTS: Among the 204 patients with DM, 109 (53.4%) had classic DM and 95 (46.6%) had clinically amyopathic DM. A total of 174 patients (85.3%) had ILD, and 62 (30.4%) were positive for anti-MDA5 antibodies. Among the 204 patients with DM, low minor allele frequencies (MAFs) for rs12479043 and rs10930046 were significantly (p < 0.05) associated with high rates of ILD and anti-MDA5 antibodies. Among the 174 patients with ILD, a low MAF for rs141134657 was significantly (p < 0.05) associated with a high incidence of acute onset of ILD within 3 months, in accordance with allele, genotype, and Armitage trend tests, but not the recessive model. A low MAF for rs141134657 tended to be associated with high serum C-reactive protein levels in accordance with the additive and dominant models, but the result was not significant. None of the analyzed IFIH1 variants were significantly associated with serum levels of ferritin, KL-6, and lactate dehydrogenase. CONCLUSION: This study identified genetic biomarkers associated with the risk of RP-ILD in patients with DM. These findings suggest that analysis of IFIH1 variants may serve as a valuable tool for predicting the development of RP-ILD in this patient population.