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Introduction A loss-of-function variant in deoxyribonuclease 1-like 3 (DNASE1L3), encoding Arg to Cys substitution at position 206 (R206C), was previously identified as a heritable risk factor for systemic sclerosis (SSc), especially SSc with positivity for anti-centromere antibody (ACA). To determine whether this variant is associated with a distinct SSc disease trajectory, we analyzed mortality and end-organ outcomes in SSc patients with or without the risk variant.Material and Methods Mortality in the UTHealth Houston Registry and GENISOS cohort was queried from the U.S. National Death Index and analyzed in a Cox proportional hazards model. Pulmonary hypertension (PH) was ascertained in three independent longitudinal cohorts (GENISOS-U.S., Royal Free College-U.K., and Johns Hopkins-U.S.) in which patients were regularly screened by echocardiogram, and in most cases evaluated by right heart catheterization (RHC) when PH was suspected. >90% of pre-capillary PH cases were adjudicated based on RHC metrics, whereas a minority were adjudicated based on evidence of right ventricular dysfunction and estimated right ventricular systolic pressure greater than 60 mmHg on echocardiogram in the absence of left ventricular failure. Meta-analysis of the three cohorts was performed to determine an overall estimate of the relative risk of pre-capillary PH associated with the DNASE1L3 R206C variant.Results In analyses of all SSc patients (n = 1,234) or restricted to ACA-positive patients (n = 366), mortality was significantly higher in patients with DNASE1L3 R206C after adjustment for age at enrollment and sex (HR 1.23, 95% CI 1.02-1.47 for all SSc; HR 1.43, 95% CI 1.10-1.87 for ACA-positive SSc) ( table 1). Mortality was highest among patients homozygous for the risk variant, consistent with a dose effect (figure 1). In all three longitudinal cohorts, the prevalence of pre-capillary PH was numerically greater in SSc patients with the DNASE1L3 R206C variant, with meta-analysis indicating a significant increase in relative risk (risk ratio of 1.69, 95% CI 1.25-2.27 in SSc overall; risk ratio of 1.81, 95% CI 1.26-2.59 in ACA-positive SSc) (figure 2). Severe interstitial lung disease was uncommon among patients with the DNASE1L3 R206C variant and PH, suggesting that most cases were WHO Group 1 (pulmonary arterial hypertension-PAH).Conclusions Our results reveal a previously unknown impact of DNASE1L3 loss-of-function on a specific end-organ outcome in SSc. The association between loss-of-function of an immunoregulatory gene (DNASE1L3) and PAH susceptibility may provide an opportunity to explore mechanisms underlying the well-recognized but poorly-understood susceptibility of SSc patients to PAH.Abstract OC.42 Table 1Cox regression analyses of mortalityAbstract OC.42 Figure 1Kaplan-Meier curve of survival from time of study enrollment, all SSc (n= 1,234)Abstract OC.42 Figure 2Relative risk of pre-capillary PH among SSc patients with vs. without the DNASE1L3 R206C variant in three longitudinal cohorts. (A) All SSc. (B) ACA-positive SSc