Tags

Type your tag names separated by a space and hit enter

Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.
Hum Mutat. 2009 Jul; 30(7):1048-53.HM

Abstract

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-epsilon2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon3/T-G-A-G-epsilon4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon3-haplotype, G-G-G-A-epsilon3, 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 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.

Authors+Show Affiliations

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19384966

Citation

Fritsche, Lars G., et al. "Age-related Macular Degeneration and Functional Promoter and Coding Variants of the Apolipoprotein E Gene." Human Mutation, vol. 30, no. 7, 2009, pp. 1048-53.
Fritsche LG, Freitag-Wolf S, Bettecken T, et al. Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. Hum Mutat. 2009;30(7):1048-53.
Fritsche, L. G., Freitag-Wolf, S., Bettecken, T., Meitinger, T., Keilhauer, C. N., Krawczak, M., & Weber, B. H. (2009). Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. Human Mutation, 30(7), 1048-53. https://doi.org/10.1002/humu.20957
Fritsche LG, et al. Age-related Macular Degeneration and Functional Promoter and Coding Variants of the Apolipoprotein E Gene. Hum Mutat. 2009;30(7):1048-53. PubMed PMID: 19384966.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. AU - Fritsche,Lars G, AU - Freitag-Wolf,Sandra, AU - Bettecken,Thomas, AU - Meitinger,Thomas, AU - Keilhauer,Claudia N, AU - Krawczak,Michael, AU - Weber,Bernhard H F, PY - 2009/4/23/entrez PY - 2009/4/23/pubmed PY - 2009/9/24/medline SP - 1048 EP - 53 JF - Human mutation JO - Hum Mutat VL - 30 IS - 7 N2 - 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-epsilon2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon3/T-G-A-G-epsilon4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon3-haplotype, G-G-G-A-epsilon3, 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 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/19384966/Age_related_macular_degeneration_and_functional_promoter_and_coding_variants_of_the_apolipoprotein_E_gene_ L2 - https://doi.org/10.1002/humu.20957 DB - PRIME DP - Unbound Medicine ER -