Functional rare and low frequency variants in BLK and BANK contribute to human lupus pathogenesis

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variant found in patients, but not those found exclusively in controls, impair suppression of IRF and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk. 31 SLE Samples, 9 controls

系统性红斑狼疮（Systemic lupus erythematosus, SLE）是原型系统性自身免疫病。学界普遍认为，诸多效应较弱的常见变异基因位点通过加性作用增加个体罹患常见自身免疫病的易感性，而稀有变异的贡献尚不明确。本研究表明，狼疮易感基因中的稀有编码变异在多数系统性红斑狼疮患者与健康对照中均存在。我们证实了相互作用蛋白BLK与BANK上的稀有及低频错义变异所产生的功能影响：这类变异可单独或组合存在于相当比例的狼疮患者体内。仅在患者体内检出的稀有变异（而非仅存在于对照中的变异）会削弱人B细胞系中对干扰素调节因子（Interferon Regulatory Factor, IRF）与I型干扰素（Type I Interferon, IFN-I）的抑制作用，并在狼疮易感小鼠模型中增加致病性淋巴细胞的数量。综上，稀有基因变异在系统性红斑狼疮中颇为常见，且极可能参与了遗传易感风险的形成。本研究共纳入31份系统性红斑狼疮样本与9份健康对照样本。