Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.
Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.
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DOI：
10.1016/j.ajhg.2021.05.015
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发表时间：
2021-08-05
影响因子：
9.8
通讯作者：
Unwin RD
中科院分区：
文献类型：
--
作者：
Cipriani V;Tierney A;Griffiths JR;Zuber V;Sergouniotis PI;Yates JRW;Moore AT;Bishop PN;Clark SJ;Unwin RD
视网膜相关性黄斑变性（AMD）是视力丧失的主要原因;补体因子H（CFH）基因座具有很强的遗传易感性。该基因座编码一系列补体调节因子：H因子（FH）、剪接变体H因子样1（FHL-1）和五种H因子相关蛋白（FHR-1至FHR-5），所有这些都参与补体因子C3 b周转的调节。关于该位点的AMD相关变异如何影响FHL-1和FHR蛋白浓度，我们知之甚少。我们使用了一种定制的靶向质谱分析法来测量所有七种补体调节剂的循环浓度，并证明了352例晚期AMD患者中所有FHR蛋白的浓度升高（FHR-1，p = 2.4 × 10−10; FHR-2，p = 6.0 × 10−10; FHR-3，p = 1.5 × 10−5; FHR-4，p = 1.3 × 10−3; FHR-5，p = 1.9 × 10−4）和FHL-1（p = 4.9 × 10−4），而FH无差异（p = 0.94）。对照组的全基因组关联分析揭示了所有五种FHR蛋白在CFH基因座的全基因组显著信号，单变量孟德尔随机化分析强烈支持FHR-1、FHR-2、FHR-4和FHR-5与AMD易感性的关联。这些发现为循环FHR蛋白的遗传驱动改变如何成为AMD的主要驱动因素提供了强有力的生化解释，并强调了研究FHR蛋白调节作为AMD可行治疗途径的必要性。
Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10−10; FHR-2, p = 6.0 × 10−10; FHR-3, p = 1.5 × 10−5; FHR-4, p = 1.3 × 10−3; FHR-5, p = 1.9 × 10−4) and FHL-1 (p = 4.9 × 10−4) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.
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影响因子：
9
作者：
Clark SJ;Bishop PN
通讯作者：
Bishop PN
影响因子：
4.4
作者：
Hoffman, Joshua D.;Bailey, Jessica N. Cooke;Haines, Jonathan L.
通讯作者：
Haines, Jonathan L.
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
3.9
作者：
Clark SJ;Bishop PN
通讯作者：
Bishop PN
影响因子：
3.5
作者：
Cipriani, Valentina;Leung, Hin-Tak;Yates, John R. W.
通讯作者：
Yates, John R. W.