| In this thesis, we report on our evaluations in a cohort of 708 unrelated Han Chinese individuals, including 200 neovascular age-related macular degeneration (AMD), 233 polypoidal choroidal vasculopathy (PCV) and 275 controls, their associations with genes in the complement pathways (the C2-CFB-RDBP-SKIV2L locus, SERPING1, C3, C5 and C7) and the HDL metabolism pathway (ABCA1, LIPC, CETP, LCAT, PLTP and ABCG1). We also attempted a GWAS to discover genes for PCV on a hypothesis-free approach.;In the complement pathway, we found SKIV2L, but not C2/CFB, responsible for the global association of the C2-CFB-RDBP-SKIV2L locus with neovascular AMD. After adjusting for CFH rs800292 and HTRA1 rs11200638, the association of SKIV2L rs429608 remained significant with AMD. Neither individual SNP nor haplotypes in this locus were associated with PCV. As for C3, a male-specific association with PCV was revealed for rs17030 and haplotype AG defined by rs17030 and rs344555. Meanwhile, a significant interaction existed between C5 and C3 in both neovascular AMD and PCV, although both C5 and C7 are not associated with AMD or PCV. No SERPING1 SNPs are associated with PCV and AMD in our Chinese cohort, but a meta-analysis revealed association of rs2511989 with AMD in Caucasians.;In the HDL metabolism pathway, CETP rs3764261 conferred a 1.89-fold risk on AMD and 1.80-fold risk on PCV. A gene-gene interaction was identified between CETP and CFH. The CFH rs800292 G allele increases risk of AMD and PCV in individuals carrying the CETP rs3764261 risk allele T. Therefore, CETP could be a modifier gene of CFH in the development of the diseases and CFH may affect HDL cholesterol metabolism. SNP rs57137919 in ABCG1 in the HDL pathway was associated with PCV. Four other genes in the lipid metabolism pathway, ABCA1, LIPC, LCAT, and PLTP, are not associated with both diseases. Therefore, neovascular AMD and PCV in our Chinese cohort have consistently significant or insignificant associations with CETP, SERPING1, C5, C7, ABCA1, LIPC, LCAT and PLTP, but different association patterns on the C2-CFB-RDBP-SKIV2L locus, C3 and ABCG1. It is likely that they shared similar molecular mechanisms, whilst additional genes may have existed to affect their developments.;In a GWAS for PCV, 106 PCV patients and 747 controls were included in the discovery phase. In the replication phase, another 127 PCV patients, 227 AMD patients and 722 controls were investigated. Eight novel SNPs had associations reaching a P value of 10-4. They are located in or near the KCNJ4, SERPINE2 and CSPG5 genes, and the 2p25.1, 11q24, 14q21.2, 16q23.1 and 21q21.1 chromosomal regions. Significant difference between PCV and neovascular AMD was observed at CSPG5. The novel genes identified suggested the implication of potassium regulation ( KCNJ4) and angiogenesis (SERPINE2) in the development of PCV. KCNJ4 encodes a type of inward rectifier potassium channels, dysfunction of which may disturb the potassium balance and lead to abnormal vasodilation of small vessels. Therefore, disruption of potassium homeostasis may be involved in the pathogenesis of PCV. This is the first time that potassium regulation is indicated in the development of PCV, further replication and functional studies are needed to confirm its role in PCV. Validation and biological assays of these gene findings from the GWAS are in progress. (Abstract shortened by UMI.). |
