Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics.
Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics.
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DOI：
10.1016/j.mam.2012.04.004
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发表时间：
2012-08
影响因子：
10.6
通讯作者：
Gorin MB
中科院分区：
文献类型：
--
作者：
Gorin MB
老年性黄斑变性(AMD)是老年人群中的一种常见疾病，可导致进行性中心视力丧失，严重影响患者的生活质量。它也是为数不多的几种疾病之一，对其遗传学的研究对其多样性和因果关系产生了丰富的见解，并有望使临床医生能够为个人提供更好的风险评估，以及开发和有选择地部署新的治疗方法，以预防或减缓疾病的发展，减少视力丧失的威胁。AMD的遗传学最初始于对家族聚集性和风险增加的认识，并随着APOE变异与疾病的最初关联而扩大。最初的重大突破来自于对受影响(和不一致)的同胞进行的基于家庭的连锁研究，该研究确定了一些遗传基因座，并导致有针对性地搜索1q31和10q26基因座以寻找相关的变异。关于CFH变异体Y402H的最初四个报告中有三个是基于区域候选搜索的，关于ARMS2/HTRA1基因座变异体的两个初始报告也是如此。病例对照关联研究最初也在发现AMD的主要遗传变异方面发挥了作用，这些早期研究的成功已被用于激发人们对一些疾病的方法学的热情。直到2010年，所有与AMD相关的后续基因变异都来自基于补体因子途径的候选基因测试。2010年，几项大规模的全基因组关联研究(GWAS)发现了以前没有发现的基因。这些历史信息中的大部分都可以在最近的一些评论中找到。对AMD GWAS的大型荟萃分析为这一集合增加了新的基因座和变异。本文将关注目前AMD遗传学面临的持续争议，而不是试图总结这一在过去5年中爆炸性增长的领域。
Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews. Large meta analysis of AMD GWAS has added new loci and variants to this collection. This paper will focus on the ongoing controversies that are confronting AMD genetics at this time, rather than attempting to summarize this field, which has exploded in the past 5 years.
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