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Age‐related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene
Author(s) -
Fritsche Lars G.,
FreitagWolf Sandra,
Bettecken Thomas,
Meitinger Thomas,
Keilhauer Claudia N.,
Krawczak Michael,
Weber Bernhard H.F.
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20957
Subject(s) - biology , macular degeneration , genetics , gene , apolipoprotein b , coding region , endocrinology , ophthalmology , cholesterol , medicine
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 its 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‐ε2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19–2.12) and T‐G‐A‐G‐ε4 (OR, 0.76; 95% CI, 0.58–0.99). When analyzing common extended haplotype combinations, T‐C‐G‐G‐ε3/T‐G‐A‐G‐ε4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20–0.51). Intriguingly, we also found one extended ε3‐haplotype, G‐G‐G‐A‐ε3, to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49–0.87). Since single nucleotide polymorphism (SNP) rs405509:G>T is a constituent of the extended ε‐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 ε‐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. Hum Mutat 0:1–6, 2009. © 2009 Wiley‐Liss, Inc.