Wang Na, Zhang Qian, Sun Wei, Yang Xiaoyu, Huang Hui, Xu Zuojun
Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Front Oncol. 2022 Sep 8;12:956552. doi: 10.3389/fonc.2022.956552. eCollection 2022.
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.
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.
By WES and SKAT analysis of SSc with and without ILD, only the variants of achieved statistical power ( < 2.51 × 10, P-FDR = 0.025, OR = 15.95). A total of 20 rare functional variants (missense, truncating, splicing) were tested for the gene, and five truncating and damaging missense variants were identified. Carriers showed the older inclusion age ( = 0.02) and the higher frequency use of prednisone (=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 ( = 0.08). In bivariate correlation analysis, we analyzed the relationship between the mutant status of 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, = 0.037).
The variants of 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.
间质性肺疾病（ILD）是系统性硬化症（SSc）肺部受累最常见且可能最具破坏性的表现。然而，系统性硬化症相关间质性肺疾病（SSc-ILD）的发病机制尚不清楚。本研究旨在通过全外显子组测序（WES）探索SSc-ILD的潜在候选基因，并尝试从基因水平分析SSc-ILD可能的发病机制。
通过全外显子组测序（WES）确认变异，并采用SKAT分析来探索差异最大的变异。对选定的变异进行生物学功能、与临床表现的相关性以及下游可能变化的分析。
通过对有或无ILD的SSc进行WES和SKAT分析，仅基因的变异具有统计学意义（<2.51×10，P-FDR = 0.025，OR = 15.95）。对该基因共检测了20个罕见的功能性变异（错义、截短、剪接），并鉴定出5个截短和有害的错义变异。与非携带者相比，携带者的纳入年龄更大（=0.02），泼尼松的使用频率更高（=0.02）。进一步分析表明，与非携带者相比，携带者的睾酮水平较低，但未达到统计学差异（=0.08）。在双变量相关性分析中，在调整年龄混杂因素后，我们分析了基因的突变状态与性激素水平之间的关系。只有睾酮水平与突变状态呈负相关（B = -0.509，=0.037）。
基因的变异可能导致SSc的ILD发展，也可能是SSc-ILD患者睾酮水平降低的一个致病因素，这有助于更好地理解SSc-ILD的病理生物学，雄激素补充可能是这种使人衰弱疾病的一个治疗靶点。
