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首页> 外文期刊>Experimental Eye Research >Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration
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Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration

机译：与年龄相关性黄斑变性相关的CFH变体中视网膜mtDNA损伤增加

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Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE. (C) 2016 Elsevier Ltd. All rights reserved.
机译：与年龄有关的黄斑变性（AMD）是发达国家老年人失明的主要原因。 AMD的遗传分析已确定了34个与AMD相关的高风险基因座。这些高风险基因座的基因属于多种生物学途径，提示导致AMD发病的机制不同。因此，针对所有AMD患者的单一途径的治疗可能不会普遍有效。最近的证据表明，视网膜色素上皮（RPE）的线粒体（mt）缺陷可能是某些AMD患者的关键致病事件。这项研究的目的是确定具有特定遗传背景的个体是否对线粒体DNA损伤的倾向更大。我们使用来自76个供体的AMD和42个年龄匹配的对照的人眼库组织来确定RPE的mtDNA损伤程度，该RPE是使用长延伸聚合酶链反应测定从黄斑中收获的。对十个常见的AMD相关的核风险等位基因（ARMS2，TNFRSF10A，CFH，C2，C3，APOE，CETP，LIPC，VEGF和COL10A1）和mtDNA单倍型进行了基因型分析。有足够的样品可用于与TNFRSF10A，CFH，CETP，VEGFA和COL10A1的mtDNA损伤相关的基因型。我们的结果表明，与具有野生型遗传特征的供体相比，带有CFH（C）高风险等位基因的AMD供体具有更多的mtDNA损伤。 CFH等位基因的另外39个供体（12个对照和27个AMD）基因型的数据进一步支持了这些发现。综上所述，这些研究揭示了CFH高风险等位基因与mtDNA加速损伤之间的显着相关性，从而为治疗AMD的更具个性化的方法提供了理论依据。具有这种遗传危险因素的患者可能会受益于稳定和保护RPE中mt的疗法。 （C）2016 Elsevier Ltd.保留所有权利。

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