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

Objectives: 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. Methods: 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. Results: 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). Conclusions: 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.