Ramos Paula S, Silver Richard M, Feghali-Bostwick Carol A
aDivision of Rheumatology and Immunology, Department of Medicine bDepartment of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
Curr Opin Rheumatol. 2015 Nov;27(6):521-9. doi: 10.1097/BOR.0000000000000214.
Large-scale and follow-up genetic association studies in systemic sclerosis (SSc) have implicated over 40 regions in disease risk, 15 of which with robust associations. Nevertheless, the causal variants and the functional mechanisms underlying the genetic associations remain elusive, and the reasons for the higher disease burden in African Americans unknown. Incorporating tools from diverse fields is beginning to unveil the role of genetic diversity and regulatory variation in SSc susceptibility. This review will summarize recent advances in SSc genetics, including autoimmune disease overlap, evidence of natural selection, and current progress towards the dissection of the functional role of associated risk variants.
In the past year, multiple large-scale studies reported novel strong and suggestive SSc associations. These results, coupled with the regions shared with other autoimmune diseases, emphasize the role of dysregulation of immune pathways as a key causative factor in SSc pathogenesis. Strong evidence implicates natural selection as a mechanism contributing to the maintenance of some of these SSc alleles in the population. Studies integrating genomic, transcriptomic, and epigenomic datasets in specific cell types to identify causal autoimmune disease variants are emerging.
The identification and comprehensive understanding of the factors and mechanisms contributing to SSc will contribute to improved diagnosis and disease management.
系统性硬化症（SSc）的大规模及随访基因关联研究已发现40多个与疾病风险相关的区域，其中15个具有较强的关联性。然而，基因关联背后的因果变异和功能机制仍不明确，非裔美国人疾病负担较高的原因也不清楚。整合不同领域的工具开始揭示遗传多样性和调控变异在SSc易感性中的作用。本综述将总结SSc遗传学的最新进展，包括自身免疫性疾病重叠、自然选择的证据以及当前在剖析相关风险变异功能作用方面的进展。
在过去一年中，多项大规模研究报告了新的、强烈且具有提示性的SSc关联。这些结果，再加上与其他自身免疫性疾病共有的区域，强调了免疫途径失调作为SSc发病机制关键致病因素的作用。有力证据表明自然选择是导致人群中某些SSc等位基因得以维持的一种机制。整合特定细胞类型的基因组、转录组和表观基因组数据集以识别因果自身免疫性疾病变异的研究正在兴起。
对导致SSc的因素和机制的识别与全面理解将有助于改善诊断和疾病管理。
