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Genetic Epidemiology of Age-Related Macular Degeneration (AMD): The Role of the Complement Component 2 (C2) and Complement Factor B (CFB) Genes in Determining AMD Subphenotypes

Longville, Brooke Allison Cattell (2009) Genetic Epidemiology of Age-Related Macular Degeneration (AMD): The Role of the Complement Component 2 (C2) and Complement Factor B (CFB) Genes in Determining AMD Subphenotypes. PhD thesis, Murdoch University.

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Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in people over the age of 50 in the developed world. Inflammation has a central role in the pathobiology of AMD; complement pathway dysfunction is thought to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes. The complement component 2 (C2) and complement factor B (CFB) genes are among several loci implicated though basic biology and genetic association studies in playing a significant role in determining susceptibility to AMD. The precise manner by which these genes affect AMD risk is unclear and largely theoretical. The purpose of this study was to examine the potential role of C2/CFB polymorphic genetic loci in determining the clinical severity of AMD and the manifestation of different AMD subphenotypes. Specifically, it was hypothesised that the C2/CFB genes are associated with AMD severity, independent of known AMD risk factors such as the complement factor H (CFH) Y402H polymorphism, smoking, and other plausible covariates.
This research forms part of, and contributed greatly to, the WA Macular Degeneration Study (WAMDS); a cross-sectional clinic-based case series of 1013 AMD cases comprising 675 choroidal neovascularisation (CNV) patients, 71 geographic atrophy patients, and 267 “early” (Age-Related Eye Disease Study [AREDS] grades 1-3) patients. Case-control analyses of subphenotypes utilised either or both of the geographic atrophy and early AMD subsets as „controls.. All participants were existing patients of the Lions Eye Institute Elsie Gadd Eye Clinic in Nedlands, Western Australia.
DNA samples were genotyped for C2/CFB using a haplotype-tagging set of 19 single nucleotide polymorphisms (SNPs) to capture 78% of the common variation in these genes. Additionally, the DNA samples were also genotyped for the CFH Y402H variant. AMD severity was graded according to the AREDS scale by ophthalmologists upon review of fundus photographs. Smoking and other relevant environmental/medical histories were collected via a comprehensive questionnaire. The multivariate associations of tagging SNPs and AMD phenotypes were tested.
Significant associations between C2/CFB genetic variants and AMD subphenotypes were observed. The rs7746553 (P = 0.04), rs3020644 (P = 0.008) and rs4151657 (P = 0.02) variants were associated with neovascular AMD; rs7746553 was also associated with legal blindness (P = 0.04). The rs2072633 (P = 0.002), rs1048709 (P = 0.005) and rs537160 (P = 0.002) variants were associated with neovascular lesion composition. Models were adjusted for appropriate covariates and CFH Y402H, and all P values were adjusted for multiple testing.
These results support the hypothesis, suggesting that C2/CFB genetic variants are associated with altered/compromised functioning of the alternative complement pathway and with a concomitant increased risk of developing more severe AMD independent of the CFH Y402H variant. Additionally, in establishing this study, I and my collaborators have created a comprehensive and useful resource for current and future AMD research.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary and Biomedical Sciences
Supervisor(s): Greene, Wayne
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