小柯机器人

哈佛医学院Steven A. McCarroll和英国伦敦国王学院Timothy J. Vyse研究组合作取得一项新成果。经过不懈努力，他们揭示补体基因在多种疾病中造成性别差异的原因。2020年5月11日，《自然》在线发表了这一成果。

研究人员发现与具有正常补体成分4（C4）基因型的个体相比，C4A和C4B的变异（其位于主要组织相容性复合体（MHC）所在位点）与精神分裂症发病风险增加相关，并且增加了7倍系统性红斑狼疮（SLE）发病的风险，在Sjögren综合征产生16倍的变化，在这两种疾病中，C4A的保护作用均强于C4B。同样的等位基因会增加精神分裂症的风险，从而大大降低SLE和Sjögren综合征的风险。

在所有三种疾病中，C4等位基因在男性中的作用要强于女性：在男性中，常见的C4A和C4B组合会使SLE产生的风险增加14倍、Sjögren’s综合征产生的风险增加31倍、精神分裂症的风险增加1.7倍（女性患病风险分别为6倍、15倍和1.26倍）。在蛋白质水平上，年龄在20至50岁之间的成年人中，男性脑脊液和血浆中C4及其效应物C3的含量均高于女性，这与相应的易感疾病年龄相对应。补体蛋白水平的性别差异可能有助于解释C4等位基因在男性中更强的作用、女性患SLE和Sjögren综合征的风险更高以及男性更易患精神分裂症。这些结果暗示补体系统是多种易患疾病性别二态性的来源。

研究人员表示，尚不确定为什么许多常见疾病对男人和女人的影响不同。例如，自身免疫性疾病SLE和Sjögren综合征对女性的影响是男性的9倍，而精神分裂症在男性中的发病率和严重性则比女性要高。这三种疾病在MHC基因座中具有最强的共同遗传关联。长期以来，人们一直认为SLE和Sjögren综合征是由该基因座上的人类白细胞抗原（HLA）基因等位基因引起的。

附：英文原文

Title: Complement genes contribute sex-biased vulnerability in diverse disorders

Author: Nolan Kamitaki, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W. Whelan, Philip Tombleson, Loes M. Olde Loohuis, Michael Boehnke, Robert P. Kimberly, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Christine E. Seidman, Michele T. Pato, Carlos N. Pato, Roel A. Ophoff, Robert R. Graham, Lindsey A. Criswell, Timothy J. Vyse, Steven A. McCarroll

Issue&Volume: 2020-05-11

Abstract: Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjgren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjgren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3,4,5,6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjgren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjgren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjgren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjgren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

DOI: 10.1038/s41586-020-2277-x

Source: https://www.nature.com/articles/s41586-020-2277-x

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