Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

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

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals... 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 ≈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, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Proceedings of the National Academy of Sciences PNAS

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

Proceedings of the National Academy of Sciences , Volume 102 (20): 7227 – May 17, 2005

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 ≈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, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 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.

Loading next page...
 
/lp/pnas/a-common-haplotype-in-the-complement-regulatory-gene-factor-h-hf1-cfh-aHegKb5kka

References

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher
PNAS
Copyright
Copyright ©2009 by the National Academy of Sciences
ISSN
0027-8424
eISSN
1091-6490
Publisher site
See Article on Publisher Site

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 ≈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, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 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.

Journal

Proceedings of the National Academy of SciencesPNAS

Published: May 17, 2005

There are no references for this article.