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Open Access Green as soon as Postprint is submitted to ZB.
Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.
Hum. Mutat. 30, 1048-1053 (2009)
Age-related macular degeneration (AMD) is a frequent, multifactorial disease of the central retina and a major cause of irreversible vision loss in industrialized countries. Apolipoprotein E (APOE) has been consistently associated with AMD, particularly ist two functional isoforms E2 (predisposing) and E4 (protective). The biological correlate of this association, however, is still unclear. In this study, we have defined an extended haplotype block encompassing the entire APOE gene locus, including known coding as well as cis-regulatory promoter variants. Of the five extended APOE haplotypes common in the general population, two were found to be significantly associated with AMD, namely G-G-G-G-epsilon 2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon 4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon 3/T-G-A-G-epsilon 4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon 3-haplotype, G-G-G-A-epsilon 3 to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49-0.87). Since single nucleotide polymorphism (SNT) rs405509:G > T is a constituent of the extended epsilon-haplotype block and is known to significantly influence APOE promoter activity, we hypothesize that both the relative rate of APOE isoform. Expression in conjunction with established functional differences of the respective isoforms may be crucial in mediating AMD pathology. This would also imply that genotyping of the core epsilon-haplotypes alone is not sufficient to estimate AMD risk, but that determination of extended haplotype combinations, including the functional promoter SNP rs405509, is required instead.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
age-related macular degeneration; AMD; apolipoprotein E; APOE; epsilon isoforms; promoter variants; case-control association study; complement factor-h; developing alzheimers-disease; apoe gene; regulatory region; linkage disequilibrium; epsilon-4 allele; e polymorphisms; factor-b; risk; association
Language
english
Publication Year
2009
HGF-reported in Year
2009
ISSN (print) / ISBN
1059-7794
e-ISSN
1098-1004
Journal
Human Mutation
Quellenangaben
Volume: 30,
Issue: 7,
Pages: 1048-1053
Publisher
Wiley
Reviewing status
Peer reviewed
Institute(s)
Institute of Human Genetics (IHG)
POF-Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-500700-001
PubMed ID
19384966
Scopus ID
67649670138
Erfassungsdatum
2009-09-03