Genetic control of the alternative pathway of complement in humans and age-related macular degeneration
Genetic control of the alternative pathway of complement in humans and age-related macular degeneration
复制标题
DOI：
10.1093/hmg/ddp472
复制
发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Oppermann, Martin
中科院分区：
文献类型：
--
作者：
Hecker, Laura A.;Edwards, Albert O.;Oppermann, Martin
补体旁路途径的激活涉及常见的神经退行性疾病，包括年龄相关性黄斑变性（AMD）。我们探讨了编码旁路途径蛋白质的基因的常见变异对人血液和AMD中补体激活的影响。确定了编码补体因子H（CFH）、因子B（CF B）和组分3（C3）的基因间的遗传变异。在定量基因组关联研究中确定了定义转录和翻译单位的常见单倍型对血液中补体激活的影响。CFH和CFB中的个体单倍型与对人血液中补体旁路途径的前体、调节剂和活化产物的血浆水平的独特和新颖的影响相关。此外，CFH中的遗传变异被认为影响补体的细胞表面调节，但不改变人血液中的血浆补体水平。慢性激活的血浆标志物（分裂产物Ba和C3d）和激活酶（因子D）在AMD受试者中升高。AMD的大部分升高是由控制人类血液中补体激活的遗传变异引起的。血液中补体旁路途径的激活受遗传控制，并随年龄增长而增加。与人类血液中补体激活增加相关的遗传变异也增加了AMD的风险。我们的数据与疾病模型一致，其中补体系统中的遗传变异通过全身补体激活和局部组织中补体激活的异常调节的组合增加AMD的风险。
Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.