Exome sequencing link mutation in RGPD4 with systemic sclerosis-associated interstitial lung disease and the low level of testosterone-an exploration study

Background Interstitial lung disease (ILD) is the most common and potentially most devastating manifestation of SSc in pulmonary involvement. However, the mechanism for systemic sclerosis-associated ILD (SSc-ILD) is unclear. This work aims to explore the potential candidates for SSc-ILD upon whole exome sequencing (WES) and attempts to analyze the possible pathogenesis of SSc-ILD from the perspective of the genetic level. Materials Variants were confirmed by whole exome sequencing (WES), and SKAT analysis was employed to explore the most differential variants. Targeted variants were performed in biological functions, associated with clinical manifestations, and the probable change of downstream. Results By WES and SKAT analysis of SSc with and without ILD, only the variants of RGPD4 achieved statistical power (P < 2.51 x 10(-6), P-FDR = 0.025, OR = 15.95). A total of 20 rare functional variants (missense, truncating, splicing) were tested for the RGPD4 gene, and five truncating and damaging missense variants were identified. Carriers showed the older inclusion age (P = 0.02) and the higher frequency use of prednisone (P=0.02) compared to the non-carriers. Further analysis illustrated that carriers showed lower levels of TES in comparison to non-carriers but did not reach statistical difference (P = 0.08). In bivariate correlation analysis, we analyzed the relationship between the mutant status of RGPD4 and the levels of sex hormones after adjusting for age confounders. Only the level of TES showed a negative correlation with the mutant status (B = -0.509, P = 0.037). Conclusion The variants of RGPD4 might contribute to the ILD development of SSc and might also be a causative factor of lower TES among SSc-ILD, which provided insight to a better understanding of pathobiology of SSc-ILD, and androgen hormone supplement might be a therapeutic target in this debilitating disease.