年龄相关性白内障(ARC)是全球最常见的致盲眼病,其发病率趋于年轻化。然而,遗传因素与机制之间的关系尚不完全清楚。该研究的目的是进一步阐明东亚人群中ARC与遗传机制之间的关系,并阐明其发病机理。
这项研究收集了来自中国东部省份的191名散发性白内障患者和208名健康人,平均年龄约60岁。对所有参与者进行全面的眼科临床检查,收集外周血样本并提取其基因组DNA。在792个候选基因中筛选突变,以通过靶向捕获和高通量测序增强对疾病的理解。
我们发现了新的候选易感基因,这可能是导致年龄相关性白内障发病率增加的潜在易感性因素。三个新基因座与年龄相关性白内障相关:DBH中的rs129882(p=5.27E-07,比值比=3.9),DMD中的rs1800280(p=2.85E-06,比值比=1.4)和ATP13A2中的rs2871776(p=4.18E-05,比值比=0.04)。基因-基因相互作用分析表明,基因之间最重要的相互作用包括DBH和TUB之间的相互作用(TUB中的rs17847537,rs129882在DBH,p值=2.12E-14),以及DBH和DMD之间的相互作用(DMD中的rs1800280,rs129882在DBH,p值=2.12E-14)。通路分析表明,最显著的过程集中在响应光刺激(调整后的p值=5.56E-03),对辐射的响应(调整后的P值=5.56E-03),非生物刺激(调整后的p值=5.56E-03)。eQTL分析表明,DBHrs129882可以调节包括视网膜在内的各种组织中DBHmRNA的表达。
我们的研究表明rs129882和rs1800280位点与年龄相关性白内障有关。扩大了年龄相关性白内障的基因图谱。
Age-related cataracts (ARC) is the most common blinding eye disease worldwide, and its incidence tend to become younger. However, the relationship between genetic factors and mechanisms is not fully understood. The aim of the study was to further clarify the relationship between ARC and genetic mechanisms in East Asian populations and to elucidate the pathogenesis.
The study collected 191 sporadic cataracts and 208 healthy people from the eastern provinces of
China, with an average age of about 60 years. All participants were subjected to a comprehensive ophthalmic clinical examination and peripheral blood samples were collected and their genomic DNA was extracted. Mutations were screened among 792 candidate genes to enhance understanding of the disease through targeted capture and high-throughput sequencing.
We identified novel candidate susceptibility gene, which may serve as a potential susceptibility factor leading to an increase in the incidence of age-related cataracts. Three novel loci are associated with age-related cataracts significant significance: rs129882 in DBH (p = 5.27E-07, odds ratio = 3.9), rs1800280 in DMD (p = 2.85E-06, odds ratio = 1.4) and rs2871776 in ATP13A2 (p = 4.18E-05, odds ratio = 0.04). Gene-gene interaction analysis revealed that the most significant interactions between genes include the interaction between DBH and TUB (rs17847537 in TUB, rs129882 in DBH, p-value = 2.12E-14), and the interaction between DBH and DMD (rs1800280 in DMD, rs129882 in DBH, p-value = 2.12E-14). Pathway analysis shows that the most significant processes are concentrated in response to light stimulation (adjusted p-Value = 5.56E-03), response to radiation (adjusted P-Value = 5.56E-03), abiotic stimulus (adjusted p-Value = 5.56E-03). eQTL analysis shows that DBH rs129882 could regulate the expression of DBH mRNA in various tissues including retina.
Our study indicates rs129882 and rs1800280 loci are associated with age-related cataracts, which enlarge the gene map of age-related cataracts.