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A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration
Open accessAbstract
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, χ 2 = 26.1 and P = 3.2 × 10 -7 and Y402H, χ 2 = 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.
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In the citing paper
“A major AMD-associated SNP is the Y402H (tyrosine to histidine substitution at amino acid 402) variant of complement factor H (CFH) (Edwards et al., 2005; Hageman et al., 2005; Haines et al., 2005; Klein et al., 2005).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Hageman et al., 2005
In the citing paper
“These SNPs have been reported to be major genetic factors for developing AMD in Caucasians (Edwards et al., 2005; Hageman et al., 2005; Haines et al., 2005; Klein et al., 2005; Tuo et al., 2006).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Hageman et al., 2005
In the citing paper
“These findings are consistent with findings in drusen of humans with AMD (Hageman et al., 2005), as well as the critical role in AMD of complement overactivity, which has been discussed above.”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Hageman et al., 2005
In the citing paper
“Complement activation playing a major role in AMD pathogenesis is yet another source of inflammation [107-110].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [107]
In the citing paper
“Polymorphisms in human complement regulatory factor H (CFH) predispose individuals to AMD [35, 46, 59]”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [46]
In the citing paper
“Genes in the complement pathway4–11 and a region of chromosome 10 12,13 have now been implicated as the major genetic contributors to disease.”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [10]
In the citing paper
“This analysis resulted in the identification of the previously well documented independently associated variants near CFH and C2/CFB8,10,31,32 and of additional independent signals near C3, CETP, LIPC, FRK/COL10A1, IER3/DDR1, RAD51B (Supplementary Table 6).”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [10]
In the citing paper
“Initial reports of association included candidate gene approach, fine mapping of candidate loci, and the first successful whole-genome association study in humans (40, 63, 65, 95) and were immediately replicated (175).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [63]
In the citing paper
“More recently, several studies have found an association between advanced age-related macular degeneration and complement factor H, an integral component of the alternative pathway of complement activation.54–65”
From Age-related macular degeneration (2008) · cites this paper as [57]
In the citing paper
“Biochemical analysis of drusen have indeed resulted in identification of complement components and inflammatory modulators [2–8].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [3]
In the citing paper
“CFH protein has been detected in choriocapillaris and within soft drusen [3].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [3]
In the citing paper
“The addition of markers within the linkage peak led to recent reports by five groups that there is an association between a common missense variant (Y402H) in CFH and AMD in the United States [3,16–19].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [3]
In the citing paper
“The Y402H allele was present in at least 60% of AMD patients with risk ratios of between 2.0 and 3.5 for one risk allele, and with risk ratios of between 3.3 and 7.4 for carriers of two risk alleles.”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [3]
In the citing paper
“However, the question of how the Y402H allele contributes to the different subtypes of AMD has not been properly addressed, owing either to insufficient clinical information or to sample size, as neovascular AMD dominates the patient cohorts in most previously reported studies [3,16–19].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [3]
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Citations
Cites
Inflammation and Alzheimer’s disease
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Self-citationHageman, G. (2001) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(01)00010-6 · Cited by 1,265
Self-citationDrusen proteome analysis: an approach to the etiology of age-related macular degeneration
Crabb, J. W., Miyagi, M., Gu, X., Shadrach, K., West, K. A., Sakaguchi, H., Kamei, M., Hasan, A., Yan, L., Rayborn, M. E., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222551899 · Cited by 1,208
A role for local inflammation in the formation of drusen in the aging eye
Anderson, D. H., Mullins, R. F., Hageman, G. S., & Johnson, L. V. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(02)01624-0 · Cited by 1,087
Self-citationMullins, R. F., Russell, S. R., Anderson, D. H., & Hageman, G. S. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.7.835 · Cited by 937
Self-citationThe epidemiology of age-related macular degeneration
Klein, R., Peto, T., Bird, A., & Vannewkirk, M. R. (2004) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2003.11.069 · Cited by 932
Mutation of the Stargardt Disease Gene ( ABCR ) in Age-Related Macular Degeneration
Allikmets, R. L., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A. P., Zabriskie, N. A., Li, Y., Hutchinson, A. A., et al. (1997) · Science · doi:10.1126/science.277.5333.1805 · Cited by 879
Self-citationSystematic Identification and Analysis of Exonic Splicing Silencers
Wang, Z., Rolish, M. E., Yeo, G. W.-M., Tung, V., Mawson, M., & Burge, C. B. (2004) · Cell · doi:10.1016/j.cell.2004.11.010 · Cited by 678
Johnson, L. V., Leitner, W. P., Staples, M. K., & Anderson, D. H. (2001) · Experimental Eye Research · doi:10.1006/exer.2001.1094 · Cited by 621
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- Klaver, C. C., Assink, J. J., van Leeuwen, R., Wolfs, R. C., Vingerling, J. R., Stijnen, T., Hofman, A. & de Jong, P. T. (2001) Invest. Ophthalmol. Visual Sci. 42, 2237-2241.11527936
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Cited by
Sorted by citations
Complement: a key system for immune surveillance and homeostasis
Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D. (2010) · Nature Immunology · doi:10.1038/ni.1923 · Cited by 3,654
Complement System Part I – Molecular Mechanisms of Activation and Regulation
Merle, N. S., Church, S. E., Fremeaux-Bacchi, V., & Roumenina, L. T. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00262 · Cited by 1,620
Age-related macular degeneration
Jager, R. D., Mieler, W. F., & Miller, J. W. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0801537 · Cited by 1,379
Replicating genotype–phenotype associations
NCI-NHGRI Working Group on Replication in Association Studies, Chanock, S. J., Manolio, T., Boehnke, M., Boerwinkle, E., Hunter, D. J., Thomas, G., Hirschhorn, J. N., Abecasis, G., Altshuler, D., et al. (2007) · Nature · doi:10.1038/447655a · Cited by 1,352
The AMD Genetics Clinical Study Group, Gold, B., Merriam, J. E., Zernant, J., Hancox, L. S., Taiber, A. J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., et al. (2006) · Nature Genetics · doi:10.1038/ng1750 · Cited by 1,075
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Metadata
- Authors
- Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., Smith, R. J. H., Silvestri, G., Russell, S. R., Klaver, C. C. W., Barbazetto, I., Chang, S., Yannuzzi, L. A., Barile, G. R., Merriam, J. C., Smith, R. T., Olsh, A. K., Bergeron, J., Zernant, J., Merriam, J. E., Gold, B., Dean, M., & Allikmets, R.
- Affiliations
- Queen's University Belfast (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-05-03
- Volume
- 102
- Issue
- 20
- Pages
- 7227-7232
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1088171
- OpenAlex
- W2125236492
- Cited by
- 1,961
- References
- 58
- Citations by year
- 2026: 22 · 2025: 45 · 2024: 43 · 2023: 37 · 2022: 75 · 2021: 78 · 2020: 67 · 2019: 50 · 2018: 59 · 2017: 60 · 2016: 78 · 2015: 105 · 2014: 111 · 2013: 117 · 2012: 116
- FWCI
- 146.43
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- Research to Prevent Blindness
- Retina Research Foundation
- Queen's University
- National Institutes of Health (n01co12400-79-0-22, NO1-CO12400)
- National Eye Institute (EY11515, R01EY013435, EY-13435, R01EY011521, EY 11-521, R01EY011527, R01EY011515, EY11527)
- National Cancer Institute (N01CO12400, N01-CO-012400)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, complement factor H, complement regulatory proteins, alternative complement pathway, drusen, retinal pigment epithelium, haplotype association, single nucleotide polymorphisms, genetic susceptibility, missense mutations, complement activation
- MeSH terms
- Aged, Aged, 80 and over, DNA Mutational Analysis, Genotype, Haplotypes, Humans, Immunohistochemistry, Macular Degeneration, Middle Aged, Pigment Epithelium of Eye, Risk Factors, Genetic Variation, Odds Ratio, Complement Factor H, Mutation, Missense, Polymorphism, Single Nucleotide, Gene Components, White People
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