Yates John R W, Sepp Tiina, Matharu Baljinder K, Khan Jane C, Thurlby Deborah A, Shahid Humma, Clayton David G, Hayward Caroline, Morgan Joanne, Wright Alan F, Armbrecht Ana Maria, Dhillon Baljean, Deary Ian J, Redmond Elizabeth, Bird Alan C, Moore Anthony T
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
N Engl J Med. 2007 Aug 9;357(6):553-61. doi: 10.1056/NEJMoa072618. Epub 2007 Jul 18.
Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.
年龄相关性黄斑变性是西方人群失明的最常见原因。易感性受年龄、遗传和环境因素影响。补体激活与发病机制有关。
我们在来自英格兰东南部的病例组和对照组中，检测了年龄相关性黄斑变性与跨越补体基因C3和C5的13个单核苷酸多态性（SNP）之间的关联。所有受试者均由眼科医生进行检查，并对眼底照片进行独立分级以确认其疾病状态。为了检验最显著发现的重复性，我们对一组苏格兰病例和对照进行了基因分型。
C3基因中常见的功能性多态性rs2230199（Arg80Gly），对应于电泳变体C3S（慢）和C3F（快），在英格兰组（603例病例和350例对照，P = 5.9×10⁻⁵）和苏格兰组（244例病例和351例对照，P = 5.0×10⁻⁵）中均与年龄相关性黄斑变性密切相关。与C3 S/S纯合子相比，C3 S/F杂合子发生年龄相关性黄斑变性的优势比为1.7（95%置信区间[CI]，1.3至2.1）；对于C3 F/F纯合子，优势比为2.6（95%CI，1.6至4.1）。C3F的估计人群归因风险为22%。
补体C3在年龄相关性黄斑变性的发病机制中起重要作用。这一发现进一步强调了补体途径在该疾病发病机制中的影响。
