罹患老化型黄斑病变 (age-related macular degeneration;简称 AMD)的患者有福了,因为最新一期出刊的科学(Science) 杂志,连续刊出了两篇论文,指出特定基因的变异,很可能就是幕后造成疾病发生的黑手。
临床上 AMD的发生是因为视网膜里光感细胞(light-sensitive cells) 的异常,导致视力的丧失, 通常来说,这类的疾病又分为干式(dry)和湿式 (wet)两种,这其中的湿式,具有病情快速恶化的特征,罹患这种疾病的人,很快的就会恶化到丧失所有的视力,严重的影响到生活的质量。
这次由耶鲁大学 Josephine Hoh教授所领导的研究团队,接连的在第一号染色体和第十号染色体上,发现称为 CFH(complement factor H )和HTRA1 这两个基因的变异,和湿式老化型黄斑病变的发生,有高度的相关,而且这两个基因的变化,都是属于单一核酸多样型 (single nucleotide polymorphism)的变化,也就是说单一个核酸基因的变化,造成细胞生理活动的改变,导致了疾病的发生 研究人员进一步的分析 确定这两个基因的角色,分别隶属不同的生理活动,但当它们同时出现变异时,几乎逃不掉眼睛黄斑病变的发生。
目前参与的科学家, 也从这两个基因位点下手 ,希望透过基因调控机制的了解 ,找出治辽黄斑病变的新方法。
英文原文:
Gene linked to aggressive 'wet' age-related macular degeneration
A gene variant that increases the risk of developing the aggressive "wet" form of age-related macular degeneration (AMD), the most common cause of blindness in people over age 50, is reported in two recent articles in Science by researchers at Yale School of Medicine.
AMD causes light-sensitive cells in the retina to break down, resulting in progressive loss of central vision. Of the two forms of AMD, the "dry" is more common than the "wet" form. Wet macular degeneration can rapidly lead to blindness, while the dry AMD progresses more slowly.
Last year, Josephine Hoh, associate professor in the Departments of Epidemiology & Public Health and Ophthalmology at Yale and senior author on one of the two new studies, identified a gene for dry AMD and found that both wet and dry AMD are associated with a variant in the complement factor H (CFH) gene on chromosome 1.
Hoh now reports they have found a single nucleotide polymorphism (SNP)梐 one-base change in the sequence梠f the regulatory part of the HTRA1 gene on chromosome 10 that leads to greatly increased risk of developing the wet form of AMD.
According to Hoh, buildup of abnormal blood vessels in Caucasian patients is compounded by development of large waste deposits called drusen. Chinese patients, she said, develop little to no drusen and progress directly to wet AMD. This study demonstrates that these two major genes, CFH and HTRA1, in two different biological pathways, each affect the risk for a distinct component of the AMD phenotype: CFH influences the drusen of dry AMD, whereas HTRA1 influences blood vessel development, the hallmark of the wet disease type. When the two processes are combined, it leads to the composite characteristics that are seen in some cases of AMD.
Hoh, her collaborators in Hong Kong, and her colleagues at Yale including Michael Snyder and Colin Barnstable in the Departments of Molecular, Cellular and Developmental Biology and Molecular Biophysics and Biochemistry, and Ophthalmology, did trans-racial gene mapping by comparing genomes between precisely defined populations to find the incidence of SNP in a Chinese population?6 with AMD and 130 with normal vision.
"We found that patients with the HTRA1 SNP were 10 times more likely to have wet AMD than those without this gene variant," said Hoh. "While this is only preliminary work, it points to possible directions for future treatment of wet AMD."
Hoh also worked on a replication study led by Kang Zhang at the University of Utah School of Medicine that found a link between the same SNP and AMD. Zhang and his team studied 581 Caucasian patients with AMD and 309 with normal vision. These patients had wet AMD as well as a large amount of drusen.
To confirm the association, the Utah team also examined several donor eyes and measured the expression of the gene and the encoded protein. They found that the expressions were elevated in the eyes of patients who carry HTRA1.
"The marker we have identified is very much associated with AMD, but no one has ever pinpointed the clinical features of the gene. We need to conduct further analysis in order to understand the biological mechanisms," said Hoh.