PuSH - Publication Server of Helmholtz Zentrum München

Fritsche, L.G.* ; Freitag-Wolf, S.* ; Bettecken, T.* ; Meitinger, T. ; Keilhauer, C.N.* ; Krawczak, M.* ; Weber, B.H.F.*

Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.

Hum. Mutat. 30, 1048-1053 (2009)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
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
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Journal Human Mutation
Quellenangaben Volume: 30, Issue: 7, Pages: 1048-1053 Article Number: , Supplement: ,
Publisher Wiley
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)