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Michael A. Williams, Gareth McKay, David Craig, Peter Passmore, Giuliana Silvestri; Age-related Macular Degeneration Genes In Alzheimer’s Disease. Invest. Ophthalmol. Vis. Sci. 2011;52(14):106.
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Age-related macular degeneration (AMD) has provided a paradigm for the study of the genetic basis of complex diseases. AMD has several similarities with Alzheimer’s disease (AD). For example retinal drusen and cerebral plaques, the extracellular deposits that characterise each condition, share constituents including complement components. Inflammation, including overactivity of the complement cascade is implicated in both AMD and AD. The proportion of an individual’s risk of developing AD that is hereditable is estimated to be 60 to 80% and yet the only gene consistently shown to influence the risk of age-related AD is APOE. The aim of this study was to investigate whether polymorphisms in 'AMD genes' segregated with higher frequency in AD patients than in an age-matched cognitively normal cohort.
A case-control association study was performed, opportunistically sampling the populations of AD patients for cases and cognitively intact individuals over 65 years for controls. Ethical committee approval was granted and a power calculation made. Genes for study were selected on the basis of their association with AMD, and genotyping performed using i-plex Sequenome reagents and protocols. Chi-squared tests were used to compare frequencies of single nucleotide polymorphisms (SNPs) in cases and controls, and Haploview used to compare haplotype frequencies for two genes, CFH and APOE.
Six hundred and three subjects agreed to participate, and data was collected on 580; 322 controls and 258 cases. The presence of the APOE ε4 allele was significantly associated with AD. There was no significant association of Y402H, of other CFH SNPs or of CFH haplotypes with AD. SNPs in CFI, VEGFR1 and TOMM40 were statistically significantly associated with AD. There was no association of SNPs in C3, SERPING1, TLR1 or TLR3 with AD, though SNPs in ARMS2 and C2/CFB approached statistical significance. Only the association with TOMM40 SNPs survived correction for multiple testing using a multiple permutation test.
The lack of association of the 'AMD genes' studied with AD has several possible explanations, including methodological reasons, the choice of genetic markers or the nature of the genetic basis of AD. Although abundant evidence implicates complement overactivity in AD, complement has complex and potentially contradictory effects. Knowledge gained of the genetic basis of AMD can inform the study of AD, and vise versa; such shared understanding may prove useful in the development of therapies for each.
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