ABCA1基因原发性开角型青光眼致病机制研究

Primary open angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of irreversible blindness and visual damage. There are currently no effective methods for prevention or treatment of POAG. Recent studies have shown that approximately 5% of POAG resulted from single gene mutations, while most POAG cases were caused by interaction of both genetic and environmental factors. We have performed a genome-wide association study (GWAS) with 2906 POAG cases and 5974 controls from Han Chinese populations and found that single nucleotide polymorphisms (SNPs) in the ABCA1 gene are significantly associated with POAG. We have also found that ABCA1 is particularly expressed in the retinal ganglion cell layer. In order to identify the disease-causing SNPs in the ABCA1 gene and pathogensis of ABCA1 in POAG, we propose to determine what ABCA1 transports and explore the biological functions of ABCA1 by biochemistry and molecular biology cell biology. We will also investigate the role of ABCA1 in glaucoma using Abca1 gene knockout and transgenic mice models and metabolic analysis of serum samples from POAG patients with different ABCA1 alleles. This study will pinpoint how ABCA1 is involved in the development of POAG and provide clues for the prevention and treatment of POAG.

原发性开角型青光眼（POAG）是最常见的一类青光眼，也是不可逆的致盲和视力损伤眼病，尚无有效早期防治手段。遗传因素在POAG发病中起着重要作用，通过对POAG疾病基因的研究，可阐明其发病机制。大约5％的POAG由单基因突变所致，而大部分POAG则是由多基因和环境因素所致的复杂性疾病。在前期复杂性POAG研究中，我们通过2906例汉族人POAG和5974例对照的全基因组关联分析（GWAS）及验证发现ABCA1基因单核苷酸多态性（SNP）位点与POAG的发生显著关联，且ABCA1在视网膜视神经节层特异性高表达。本研究将在此基础上通过精确定位和功能分析找出ABCA1基因区域导致POAG的功能SNPs，发现ABCA1的转运物质，并结合Abca1基因敲除和转基因小鼠模型以及不同ABCA1基因型患者血清组学分析，阐明ABCA1导致POAG的分子机制，从而为POAG的防治奠定基础。