A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration
A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration
复制标题
DOI：
10.1073/pnas.0501536102
复制
发表时间：
2005-05-17
影响因子：
11.1
通讯作者：
Allikmets, R
中科院分区：
文献类型：
--
作者：
Hageman, GS;Anderson, DH;Allikmets, R
年龄相关性黄斑变性（AMD）是发达国家老年人不可逆失明的最常见原因。我们先前的研究表明补体激活与玻璃膜疣的形成有关，玻璃膜疣是AMD的标志性病变。在此，我们发现因子H（HF1），即替代补体途径的主要抑制剂，在玻璃膜疣内积聚，并由视网膜色素上皮细胞合成。由于先前的连锁分析确定了包含因子H基因（HF1/CFH）的1q25 - 32号染色体为AMD的易感位点，我们在两个独立的队列中分析了HF1的基因变异，这两个队列约包含900例AMD患者和400例匹配的对照。我们发现8个常见的HF1单核苷酸多态性（SNP）与AMD相关；两个常见的错义变异呈现出高度显著的相关性（162V，卡方值 = 26.1，P = 3.2×10⁻⁷；Y402H，卡方值 = 54.4，P = 1.6×10⁻¹³）。单倍型分析显示，多个HF1变异会增加或降低AMD的风险。一种常见的风险单倍型在AMD患者中的频率为50%，在对照中为29%[比值比（OR）= 2.46，95%置信区间（1.95 - 3.11）]。这种单倍型的纯合子在患者中占24%，在对照中占8%[OR = 3.51，95%置信区间（2.13 - 5.78）]。还确定了几种保护性单倍型（OR = 0.44 - 0.55），这进一步表明HF1在AMD的发病机制中起作用。我们提出，当替代补体途径的调节因子发生基因变异，并与感染等触发事件相结合时，是人类人群中大部分AMD的基础病因。
Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of approximate to 900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (162V, chi(2) = 26.1 and P = 3.2 x 10(-7) and Y402H, chi(2) = 54.4 and P = 1.6 x 10(-13)). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.