A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration

Heather A Stockman; James D Borchardt; Karen M Gehrs; Richard J H Smith; Giuliana Silvestri; Stephen R Russell; Caroline C W Klaver; Irene Barbazetto; Stanley Chang; Lawrence A Yannuzzi; Gaetano R Barile; John C Merriam; R Theodore Smith; Adam K Olsh; Gregory S Hageman; Julie Bergeron; Don H Anderson; Jana Zernant; Lincoln V Johnson; Joanna E Merriam; Lisa S Hancox; Bert Gold; Andrew J Taiber; Michael Dean; Lisa I Hardisty; Rando Allikmets; Jill L Hageman

doi:10.1073/pnas.0501536102

Back

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration

Journal article

Open access

Peer reviewed

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration

Heather A Stockman, James D Borchardt, Karen M Gehrs, Richard J H Smith, Giuliana Silvestri, Stephen R Russell, Caroline C W Klaver, Irene Barbazetto, Stanley Chang, Lawrence A Yannuzzi, …

Proceedings of the National Academy of Sciences - PNAS, Vol.102(20), pp.7227-7232

05/17/2005

DOI: 10.1073/pnas.0501536102

PMCID: PMC1088171

PMID: 15870199

Files and links (1)

url

https://doi.org/10.1073/pnas.0501536102View

Published (Version of record) Open Access

Abstract

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of approximately 900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, chi2 = 26.1 and P = 3.2 x 10(-7) and Y402H, chi2 = 54.4 and P = 1.6 x 10(-13)). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.

Immunohistochemistry

Humans

Middle Aged

Risk Factors

European Continental Ancestry Group

Genotype

Mutation, Missense - genetics

Genetic Variation

Haplotypes - genetics

Macular Degeneration - genetics

DNA Mutational Analysis

Aged, 80 and over

Pigment Epithelium of Eye - pathology

Aged

Polymorphism, Single Nucleotide

Gene Components

Complement Factor H - genetics

Odds Ratio

Macular Degeneration - pathology

Details

Title: Subtitle: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration
Creators: Heather A Stockman
James D Borchardt
Karen M Gehrs
Richard J H Smith
Giuliana Silvestri
Stephen R Russell
Caroline C W Klaver
Irene Barbazetto
Stanley Chang
Lawrence A Yannuzzi
Gaetano R Barile
John C Merriam
R Theodore Smith - Columbia University
Adam K Olsh
Gregory S Hageman - Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, University of Iowa, Iowa City, IA 52240, USA. gregory-hageman@uiowa.edu
Julie Bergeron
Don H Anderson - University of California, Santa Barbara
Jana Zernant
Lincoln V Johnson
Joanna E Merriam
Lisa S Hancox
Bert Gold
Andrew J Taiber
Michael Dean
Lisa I Hardisty
Rando Allikmets
Jill L Hageman
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.102(20), pp.7227-7232
DOI: 10.1073/pnas.0501536102
PMID: 15870199
PMCID: PMC1088171
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: United States
Grant note: R01 EY011521 / NEI NIH HHS EY11527 / NEI NIH HHS EY11515 / NEI NIH HHS R01 EY011515 / NEI NIH HHS N01CO12400 / NCI NIH HHS N01-CO-12400 / NCI NIH HHS EY13435 / NEI NIH HHS R01 EY011527 / NEI NIH HHS R01 EY013435 / NEI NIH HHS EY11521 / NEI NIH HHS
Language: English
Date published: 05/17/2005
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Ophthalmology and Visual Sciences
Record Identifier: 9983980076402771

Metrics

50 Record Views

1689 Times Cited - Web of Science