Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.
Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.
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DOI：
10.1016/j.ajhg.2021.06.002
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发表时间：
2021-08-05
影响因子：
9.8
通讯作者：
den Hollander AI
中科院分区：
文献类型：
--
作者：
Lorés-Motta L;van Beek AE;Willems E;Zandstra J;van Mierlo G;Einhaus A;Mary JL;Stucki C;Bakker B;Hoyng CB;Fauser S;Clark SJ;de Jonge MI;Nogoceke E;Koertvely E;Jongerius I;Kuijpers TW;den Hollander AI
视网膜相关性黄斑变性（AMD）是老年人群失明的主要原因。据报道，CFH基因座的遗传变异对AMD风险有很强的影响，包括补体因子H（CFH）和补体因子H相关（CFHR）基因，但其潜在机制尚未完全了解。我们的目的是在202名对照组和216名AMD患者的队列中分析因子H（FH）和FH相关（FHR）蛋白在AMD中的作用。我们检测到AMD患者FHR-1（p = 1.84 × 10−6）、FHR-2（p = 1.47 × 10−4）、FHR-3（p = 1.05 × 10−5）和FHR-4A（p = 1.22 × 10−2）的全身水平升高，而FH浓度保持不变。CFH基因座的常见AMD遗传变异和单倍型与FHR蛋白浓度强烈相关（例如，FH p.Tyr402His和FHR-2浓度，p = 3.68 × 10−17），而与FH浓度的相关性有限。此外，在一个由17，596名对照和15，894名AMD患者组成的国际AMD基因组学联盟队列中，我们发现低频和罕见的蛋白质改变CFHR 2和CFHR 5变异与AMD相关，独立于所有先前报道的全基因组关联研究（GWAS）信号（p = 5.03 × 10−3和p = 2.81 × 10−6，分别）。CFHR 2和CFHR 5中的低频变体导致FHR-2和FHR-5浓度降低或缺失（例如，CFHR 2和FHR-2中的p.Cys72Tyr，p = 2.46 × 10−16）。最后，我们发现FHR-2和FHR-5在脉络膜毛细血管和玻璃疣中的定位。我们的研究确定FHR蛋白是AMD疾病机制中的关键蛋白。因此，调节FHR蛋白的疗法可能有效治疗或预防AMD的进展。这种疗法可以根据CFH基因座的基因型靶向特定的AMD个体。
Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10−6), FHR-2 (p = 1.47 × 10−4), FHR-3 (p = 1.05 × 10−5) and FHR-4A (p = 1.22 × 10−2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10−17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10−3 and p = 2.81 × 10−6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10−16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
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影响因子：
3.5
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
通讯作者：
Wright AF
影响因子：
3.6
作者：
García-Layana A;Cabrera-López F;García-Arumí J;Arias-Barquet L;Ruiz-Moreno JM
通讯作者：
Ruiz-Moreno JM
影响因子：
4.1
作者：
FONTAINE, M;DEMARES, MJ;RIPOCHE, J
通讯作者：
RIPOCHE, J
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：
8.1
作者：
Geerlings, Maartje J.;Kremlitzka, Mariann;den Hollander, Anneke I.
通讯作者：
den Hollander, Anneke I.