Magnusson Kristinn P, Duan Shan, Sigurdsson Haraldur, Petursson Hjorvar, Yang Zhenglin, Zhao Yu, Bernstein Paul S, Ge Jian, Jonasson Fridbert, Stefansson Einar, Helgadottir Gudleif, Zabriskie Norman A, Jonsson Thorlakur, Björnsson Asgeir, Thorlacius Theodora, Jonsson Palmi V, Thorleifsson Gudmar, Kong Augustine, Stefansson Hreinn, Zhang Kang, Stefansson Kari, Gulcher Jeffrey R
DeCODE Genetics, Reykjavik, Iceland.
PLoS Med. 2006 Jan;3(1):e5. doi: 10.1371/journal.pmed.0030005. Epub 2005 Nov 29.
Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD--or the relationship between them--is unclear.
We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 x 10(-12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 x 10(-9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).
Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.
年龄相关性黄斑变性（AMD）是发达国家不可逆视力损害的最常见原因。晚期AMD的两种形式，即地图样萎缩和新生血管性AMD，代表黄斑区不同的病理过程，可导致中心视力丧失。软性玻璃膜疣的特征是黄斑区有沉积物但无视力丧失，被认为是晚期AMD的前驱病变。最近，有人提出补体因子H（CFH）基因中的一个常见错义变体Y402H会增加晚期AMD的风险。然而，其对软性玻璃膜疣、地图样萎缩或新生血管性AMD的影响，以及它们之间的关系尚不清楚。
我们对581例冰岛晚期AMD患者（278例新生血管性AMD、203例地图样萎缩和100例新生血管性AMD/地图样萎缩混合型）以及435例早期AMD患者（其中220例有软性玻璃膜疣）进行了基因分型。对来自美国犹他州的431例患者组成的第二个队列进行了分析，其中322例晚期AMD患者（244例新生血管性AMD和78例地图样萎缩）以及109例有软性玻璃膜疣的早期AMD病例。我们证实CFH Y402H变体与晚期AMD显著相关，冰岛晚期AMD患者的比值比为2.39（p = 5.9×10⁻¹²），美国犹他州晚期AMD患者的比值比为2.14（p = 2.0×10⁻⁹）。此外，我们表明Y402H变体赋予软性玻璃膜疣以及两种晚期AMD形式（地图样萎缩或新生血管性AMD）相似的风险。
软性玻璃膜疣出现在进展为晚期AMD之前，是新生血管性AMD和地图样萎缩共有的组织学特征。我们的结果表明CFH是软性玻璃膜疣的主要危险因素，进展为晚期AMD可能还需要其他遗传因素和/或环境因素。
