Pulmonary arterial hypertension susceptibility and mortality among patients with systemic sclerosis with the DNASE1L3 rs35677470 (Arg206Cys) variant.

Abstract

A loss-of-function variant in deoxyribonuclease 1-like 3 (DNASE1L3), encoding Arg to Cys substitution at amino acid 206 (R206C), was previously identified as a heritable susceptibility factor for systemic sclerosis (SSc). We analysed mortality and pulmonary outcomes in patients with SSc with or without the DNASE1L3 R206C variant. Mortality, pulmonary hypertension (PH), and interstitial lung disease (ILD) were ascertained in the UTHealth Houston, Royal Free Hospital, and Johns Hopkins University cohorts. Mortality risk and precapillary PH time-to-event from SSc onset were estimated using Cox proportional hazards models. Meta-analyses were performed to generate overall risk estimates. In the mortality analysis (n = 2366 patients, 46.6% of whom were deceased), after adjustment for age of SSc onset and sex, DNASE1L3 R206C was associated with significantly greater mortality (hazard ratio [HR]: 1.16, 95% CI: 1.02-1.32). In the precapillary PH analysis (n = 1170 patients, 20.3% of whom had precapillary PH), after adjustment for age of SSc onset, sex, and the presence of ILD, DNASE1L3 R206C was associated with significantly greater precapillary PH risk (HR: 1.69, 95% CI: 1.31-2.19). The majority of patients with precapillary PH did not have ILD, indicating that they had WHO Group I, ie pulmonary arterial hypertension (PAH). We report a previously unknown impact of DNASE1L3 polymorphism on PAH susceptibility in SSc. The association between loss-of-function of an immunoregulatory gene (DNASE1L3) and PAH susceptibility supports further exploration of downstream sequelae of DNASE1L3 dysfunction in SSc pathogenesis and the mechanisms underlying the well-recognised but poorly understood susceptibility of patients with SSc to PAH.