10q26 – The enigma in age-related macular degeneration

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY Progress in Retinal and Eye Research Pub Date : 2023-09-01 DOI:10.1016/j.preteyeres.2022.101154
David A. Merle , Merve Sen , Angela Armento , Chloe M. Stanton , Eric F. Thee , Magda A. Meester-Smoor , Markus Kaiser , Simon J. Clark , Caroline C.W. Klaver , Pearse A. Keane , Alan F. Wright , Michael Ehrmann , Marius Ueffing
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引用次数: 1

Abstract

Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.

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10q26-年龄相关性黄斑变性的谜。
尽管在过去的几十年里进行了全面的研究,但年龄相关性黄斑变性(AMD)的发病机制仍远未被理解。大规模全基因组关联研究(GWAS)能够提供一组明确的导致疾病风险的遗传畸变,其中最强的贡献者分布在1号和10号染色体上的不同区域。虽然1号染色体基因座包括具有众所周知功能的补体系统因子,但10q26基因座在AMD病理生理学中的作用仍然是个谜。10q26包含一个由三个功能基因组成的簇,即PLEKHA1、ARMS2和HTRA1,大多数AMD相关的遗传变异定位于后两个基因。长期以来,ARMS2和HTRA1之间的高度连锁不平衡使关联研究无法可靠地确定致病基因,直到最近,遗传风险区域才缩小到ARMS2,这表明这是该基因座上真正的AMD基因。然而,仅凭基因关联不足以证明因果关系,该单倍型上的14个SNP中的一个或多个可能参与基因表达的长期控制,使HTRA1和PLEKHA1仍然被怀疑是致病途径。ARMS2和HTRA1都与细胞外基质稳态有关,但它们的确切分子功能及其在AMD发病机制中的作用仍有待揭示。10q26基因座的转录调控增加了额外的复杂性,因为基因调控和表观遗传学改变可能影响患病个体10q26的表达水平。在这里,我们对10q26基因座及其三种不同生物复杂性水平的基因产物进行了全面概述,并讨论了当前和未来的研究策略,以揭示AMD领域中剩下的一个神秘点。
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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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