Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.
Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.
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DOI：
10.1093/hmg/ddt336
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Wright AF
中科院分区：
文献类型：
--
作者：
Ansari M;McKeigue PM;Skerka C;Hayward C;Rudan I;Vitart V;Polasek O;Armbrecht AM;Yates JR;Vatavuk Z;Bencic G;Kolcic I;Oostra BA;Van Duijn CM;Campbell S;Stanton CM;Huffman J;Shu X;Khan JC;Shahid H;Harding SP;Bishop PN;Deary IJ;Moore AT;Dhillon B;Rudan P;Zipfel PF;Sim RB;Hastie ND;Campbell H;Wright AF
为什么补体因子H （CFH）基因的非编码变异与年龄相关性黄斑变性（AMD）的相关性比直接影响补体途径的功能性编码变异更强，这是一个长期存在的谜题。整个区域的紧密遗传关联使情况变得复杂，包括相邻的cfh相关基因CFHR3和CFHR1，它们本身可能影响替代补体途径，并且包含在与AMD保护相关的共同缺失（CNP147）中。目前尚不清楚这种关联是通过低血浆CFHR1浓度、高血浆CFH还是两者兼有的保护作用介导的。我们在联合病例对照（1256例，1020例对照）和横断面人群（n = 1004）研究中检验了CFH/CFHR3/CFHR1基因型、血浆CFH或CFHR1浓度与AMD易感性之间的三角关系，并开展了血浆CFH和CFHR1浓度的全基因组关联研究。非编码CFH SNP （rs6677604）与CNP147缺失相互之间以及与血浆CFH和CFHR1浓度密切相关。血浆CFH升高rs6677604等位基因和血浆CFH浓度升高均与AMD保护有关。相反，CNP147缺失与AMD的保护性关联不是由低血浆CFHR1介导的，因为无AMD的对照组与对照组相比，血浆CFHR1升高，但它可能是由CNP147与血浆CFH浓度升高的关联介导的。结果与CFH基因32 kb区域内的一个调控位点最为一致，该基因对血浆CFH浓度和AMD易感性有主要影响。
It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.
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