Cited by 348Retinal Diseases and TreatmentsComplement system in diseasesOcular Diseases and Behçet’s Syndrome

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Complement Factor H Polymorphism, Complement Activators, and Risk of Age-Related Macular Degeneration

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Despriet, Dominiek D. G., Klaver, Caroline C. W., Witteman, Jacqueline C. M., Bergen, Arthur A. B., Kardys, Isabella, de Maat, Moniek P. M., Boekhoorn, Sharmila S., Vingerling, Johannes R., Hofman, Albert, Oostra, Ben A., Uitterlinden, André G., Stijnen, Theo, van Duijn, Cornelia M., de Jong, Paulus T. V. M.·2006·JAMA

DOI 10.1001/jama.296.3.301

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Abstract

CONTEXT: The evidence that inflammation is an important pathway in age-related macular degeneration (AMD) is growing. Recent case-control studies demonstrated an association between the complement factor H (CFH) gene, a regulator of complement, and AMD. OBJECTIVES: To assess the associations between the CFH gene and AMD in the general population and to investigate the modifying effect of smoking, serum inflammatory markers, and genetic variation of C-reactive protein (CRP). DESIGN, SETTING, AND PARTICIPANTS: Population-based, prospective cohort study of individuals aged 55 years or older (enrollment between March 20, 1990, and July 31, 1993, and 3 follow-up examinations that were performed between September 1, 1993, and December 31, 2004) in Rotterdam, the Netherlands. The CFH Y402H polymorphism was determined in a total of 5681 individuals. Information on smoking, erythrocyte sedimentation rate, CRP serum levels, and haplotypes of the CRP gene were assessed at baseline. MAIN OUTCOME MEASURES: All severity stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD. RESULTS: The frequency of CFH Y402H was 36.2% (4116/11,362 alleles). At baseline, there were 2062 persons (36.3%) with any type of AMD (prevalent cases), including 78 (1.4%) with late AMD (stage 4). During follow-up (mean, 8 years; median, 10 years), 1649 (35.5%) of 4642 participants progressed to a higher stage of AMD (incident cases), including 93 (5.6%) who developed late AMD. The odds ratio (OR) of AMD increased in an allele-dose manner with 2.00 (95% confidence interval [CI], 1.56-2.55) for stage 2 AMD, 4.58 (95% CI, 2.82-7.44) for stage 3 AMD, and 11.02 (95% CI, 6.82-11.81) for stage 4 (late, vision threatening) AMD for homozygous persons. Cumulative risks calculated by Kaplan-Meier analysis of late AMD by age 95 years were 48.3% for homozygotes, 42.6% for heterozygotes, and 21.9% for noncarriers. The population-attributable risk for CFH Y402H was 54.0%. Elevated erythrocyte sedimentation rates further increased the OR to 20.2 (95% CI, 9.5-43.0), elevated serum CRP levels to 27.7 (95% CI, 10.7-72.0), and smoking to 34.0 (95% CI, 13.0-88.6) for homozygotes compared with noncarriers without these determinants. The CRP haplotypes conferring high levels of CRP significantly increased the effect of CFH Y402H (P<.01). CONCLUSIONS: The CFH Y402H polymorphism may account for a substantial proportion of AMD in individuals similar to those in the Rotterdam Study and may confer particular risk in the presence of environmental and genetic stimulators of the complement cascade.

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“58 for stage 3), which were defined according to their increasing prediction of incident late AMD.(25) This suggests that high-risk early AMD is more closely related to the CC genotype than low-risk early AMD and that subjects with early AMD may be heterogeneous, not only with respect to their probability of developin…”
BackgroundResultInfluential
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“…of Klein et al. (2005) and Spencer et al. In fact, the region containing the CFH gene has been repeatedly linked to AMD earlier (Klein et al., 2005; Despriet et al., 2006; Li et al., 2006; Maller et al., 2006; Spencer et al., 2007; Zhang et al., 2008), although this is the first time that a…”
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“Recently, a strong association between the Y402H single-nucleotide polymorphism in the complement factor H (CFH) gene and AMD was found in 3 clinic-based case control studies (59), and in a longitudinal population based study (60).”
Background
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Background
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“This allele causes over-activation of complement and disrupts the transport of oxidative lipids from the RPE layer as well as the regulatory function of CFH (Despriet et al., 2006; Edwards et al., 2005).”
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“…studies have identified a specific CFH gene polymorphism, Y402H, which is a variation has been associated with increased risk for AMD development (Despriet et al. 2006; Edwards et al. 2005; Hageman et al. 2005; Haines et al. 2005; Klein et al. 2005) and is thought to comprise the major…”
Background
Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants
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“These genes account for a substantial proportion of the genetic predisposition associated with the disease.(10,12,19,21) Of the genes thus far identified, a majority play roles in the immune/inflammatory system.”
Background
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C-Reactive Protein and Age-Related Macular Degeneration and Cataract: The Singapore Malay Eye Study
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Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large
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The Association of Statin Use with Age-Related Macular Degeneration Progression
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Pharmacogenetics of Complement Factor H Y402H Polymorphism and Treatment of Neovascular AMD with Anti-VEGF Agents: A Meta-Analysis
Chen, G., Tzekov, R., Li, W., Jiang, F., Mao, S., & Tong, Y. (2015) · Scientific Reports · doi:10.1038/srep14517 · Cited by 31
The association between complement factor H rs1061170 polymorphism and age‐related macular degeneration: a comprehensive meta‐analysis stratified by stage of disease and ethnicity
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The Association of Lipoprotein Parameters and C-Reactive Protein in Patients with Age-Related Macular Degeneration
Čolak, E., Kosanović-Jaković, N., Zoric, L. D., Radosavljević, A., Stankovic, S. D., & Majkić‐Singh, N. (2011) · Ophthalmic Research · doi:10.1159/000323815 · Cited by 30
Activation of Rap1 inhibits NADPH oxidase‐dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization
Wang, H., Jiang, Y., Shi, D., Quilliam, L. A., Chrzanowska‐Wodnicka, M., Wittchen, E. S., Li, D. Y., & Hartnett, M. E. (2013) · The FASEB Journal · doi:10.1096/fj.13-240028 · Cited by 30
Can innate and autoimmune reactivity forecast early and advance stages of age-related macular degeneration?
Adamus, G. (2017) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.01.005 · Cited by 28
“Mutations in CFH, CFB, and C3 genes cause defects in the encoded proteins [78, 79].”
Background
PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation
Coco, R. M., Sánchez-Tocino, H., Desco, C., Usategui‐Martín, R., & Orriols, J. J. T. (2020) · Genes · doi:10.3390/genes11070773 · Cited by 31
An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism
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“2007 Netherlands European 5066 AMD-Rotterdam Despriet et al.(44) 2006 Netherlands European 3619 AMD 2392 Droz et al.”
Background
Association of Smoking andCFHandARMS2Risk Variants With Younger Age at Onset of Neovascular Age-Related Macular Degeneration
Lechanteur, Y. T. E., van de Camp, P., Smailhodzic, D., van de Ven, J. P. H., Buitendijk, G. H. S., Klaver, C. C. W., Groenewoud, J. M. M., den Hollander, A. I., Hoyng, C. B., & Klevering, B. J. (2015) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2015.18 · Cited by 28
Self-citation
The ERCC6 Gene and Age-Related Macular Degeneration
Baas, D. C., Despriet, D. D. G., Gorgels, T. G. M. F., Sawitzke, J., Uitterlinden, A. G., Albert Hofman, D., van Duijn, C. M., Merriam, J. E., Smith, R. T., Barile, G. R., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013786 · Cited by 28
“Statistical significance for biological interaction was determined by calculating the synergy index (SI), which measures deviation from additivity of two risk factors [49,50].”
MethodSelf-citation
Noncoding Variant in the Complement Factor H Gene and Risk of Exudative Age-Related Macular Degeneration in a Chinese Population
Cui, L., Zhou, H., Yu, J., Sun, E., Zhang, Y., Jia, W., Jiao, Y., Snellingen, T., Liu, X., Lim, A., et al. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-4265 · Cited by 27
“The frequency of bilateral exudative AMD has also been reported to be significantly higher than that of unilateral AMD in those with the homozygous CFH Y402H variant and HTRA1 polymorphisms.(45,46) It has long been known that the prevalence and phenotypic spectrum of AMD vary among different ethnic groups.”
Background
Pharmacologic treatment of atrophic age-related macular degeneration
Mata, N. L., & Vogel, R. (2010) · Current Opinion in Ophthalmology · doi:10.1097/icu.0b013e32833866c8 · Cited by 26
Altered activation state of circulating neutrophils in patients with neovascular age-related macular degeneration
Nielsen, M. K., Hector, S. M., Allen, K., Subhi, Y., & Sørensen, T. L. (2017) · Immunity & Ageing · doi:10.1186/s12979-017-0100-9 · Cited by 28
“in the complement system [58, 59] in light of our findings on CD66b.”
Background
Age-related Macular Degeneration (AMD): A Review on its Epidemiology and Risk Factors
Salimiaghdam, N., Riazi-Esfahani, M., Fukuhara, P. S., Schneider, K., & Kenney, M. C. (2019) · The Open Ophthalmology Journal · doi:10.2174/1874364101913010090 · Cited by 30
Complement inhibitors for age-related macular degeneration
Williams, M. A., McKay, G. J., & Chakravarthy, U. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009300.pub2 · Cited by 25
CFB/C2Gene Polymorphisms and Risk of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis
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Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome
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“Mutations in complement-associated genes, and particularly in the CFH gene, have been shown to be associated with age-related macular degeneration (AMD), one of the leading causes of blindness worldwide [60].”
Background
Epidemiology of Age-Related Macular Degeneration
Seddon, J. M., & Chen, C. A. (2006) · Elsevier eBooks · doi:10.1016/b978-0-323-02598-0.50064-1 · Cited by 26
Chlamydia pneumoniae and age‐related macular degeneration: a role in pathogenesis or merely a chance association?
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Complement factor H Y402H polymorphism and characteristics of exudative age‐related macular degeneration lesions
Seitsonen, S., Järvelä, I. E., Meri, S., Tommila, P. V., Ranta, P., & Immonen, I. J. R. (2007) · Acta Ophthalmologica · doi:10.1111/j.1600-0420.2007.01050.x · Cited by 25
“Later studies, however, found higher prevalences of the CFH Y402H polymorphism in late lesions (ORs 11.02, 12.43, respectively) compared with those with predisposing lesions (ORs 2.00, 6.52, respectively) (Despriet et al. 2006; Baird et al. 2006).”
ResultInfluential
Systemic inflammation and eye diseases. The Beijing Eye Study
Jonas, J. B., Wei, W. B., Xu, L., & Wang, Y. X. (2018) · PLoS ONE · doi:10.1371/journal.pone.0204263 · Cited by 26
Age-Related Macular Degeneration
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The Effects of Brazilian Green Propolis against Excessive Light-Induced Cell Damage in Retina and Fibroblast Cells
Murase, H., Shimazawa, M., Kakino, M., Ichihara, K., Tsuruma, K., & Hara, H. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/238279 · Cited by 23
“Brazilian green propolis may become amajor therapeutic candidate for the treatment of AMD and skin damage induced by UV irradiation.”
BackgroundInfluential
Impairment of the Ubiquitin-Proteasome Pathway in RPE Alters the Expression of Inflammation Related Genes
Liu, Z., Qin, T., Zhou, J., Taylor, A., Sparrow, J. R., & Shang, F. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3209-8_31 · Cited by 22
Association between Decreased Renal Function and Reticular Macular Disease in Age-Related Macular Degeneration
Leisy, H. B., Ahmad, M. T., Marmor, M. F., & Smith, R. T. (2016) · Ophthalmology Retina · doi:10.1016/j.oret.2016.08.011 · Cited by 22
Direct-to-Consumer Personal Genome Testing for Age-Related Macular Degeneration
Buitendijk, G. H. S., Amin, N., Albert Hofman, D., van Duijn, C. M., Vingerling, J. R., & Klaver, C. C. W. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15142 · Cited by 21
Self-citation
Epidemiology of Age-related Macular Degeneration
Seddon, J. M., & Sobrin, L. (2008) · Elsevier eBooks · doi:10.1016/b978-1-4160-0016-7.50041-2 · Cited by 22
Complement factor H and related proteins in age-related macular degeneration
Calippe, B., Guillonneau, X., & Sennlaub, F. (2014) · Comptes Rendus. Biologies · doi:10.1016/j.crvi.2013.12.003 · Cited by 18
“Furthermore, the Y402H polymorphism of CFH is associated with the progression of Drusen size [41] and progression from ARM to AMD [40– 42].”
Background
Gene therapy for age-related macular degeneration: a promising frontier in vision preservation
Hushmandi, K., Lam, H. Y., Wong, W., Tan, W., Daryabari, S., Reiter, R. J., Farahani, N., & Kumar, A. P. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02246-4 · Cited by 25
“These lysosomes merge with the membrane, sealing off forming MAC pores and blocking calcium entry [28].”
Influential
Pulmonary Disease and Age-Related Macular Degeneration
Klein, R. (2008) · Archives of Ophthalmology · doi:10.1001/archopht.126.6.840 · Cited by 20
Complement Factor H Y402H polymorphism is associated with an increased risk of mortality after intracerebral hemorrhage
Appelboom, G., Piazza, M. A., Hwang, B. Y., Bruce, S. S., Smith, S., Bratt, A., Bagiella, E., Badjatia, N., Mayer, S. A., & Connolly, E. S. (2011) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2011.04.001 · Cited by 20
Association between polymorphism rs11200638 in the HTRA1 gene and the response to anti-VEGF treatment of exudative AMD: a meta-analysis
Zhou, Y., Chen, C., Wang, Y.-X., Tong, Y., Fang, X., Li, L., & Wang, Z. (2017) · BMC Ophthalmology · doi:10.1186/s12886-017-0487-2 · Cited by 20
“In recent years, multiple studies have confirmed that genetic factors also play a substantial role in the etiology of AMD [5–7], such as single nucleotide polymorphisms (SNPs) in the complement factor H (CFH) [8, 9], age-related maculopathy susceptibility 2 (ARMS2) [10, 11], and high temperature requirement factor A1…”
BackgroundInfluential
Age-Related Macular Degeneration: Pathogenesis, Genetic Background, and the Role of Nutritional Supplements
Moschos, M. M., Nitoda, E., Chatziralli, I., & Demopoulos, C. A. (2014) · Journal of Chemistry · doi:10.1155/2014/317536 · Cited by 19
Age-Related Macular Degeneration–Associated Genes in Alzheimer Disease
Williams, M. A., McKay, G. J., Carson, R., Craig, D., Silvestri, G., & Passmore, P. (2015) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2015.06.005 · Cited by 19
“In 2005 the results of four studies were published which each identified an association between AMD and a single nucleotide polymorphism (SNP) (Y402H) of the gene for a key regulator of the complement cascade, complement factor H (CFH) (3-6).”
BackgroundInfluential
The Frequency of the H402 Allele of CFH and Its Involvement with Age-Related Maculopathy in an Aged Black African Xhosa Population
Ziskind, A., Bardien, S., van der Merwe, L., & Webster, A. R. (2008) · Ophthalmic Genetics · doi:10.1080/13816810802216472 · Cited by 17
Machine learning to determine relative contribution of modifiable and non-modifiable risk factors of major eye diseases
Nusinovici, S., Zhang, L., Chai, X., Zhou, L., Tham, Y. C., Vasseneix, C., Majithia, S., Sabanayagam, C., Wong, T. Y., & Cheng, C. (2020) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2020-317454 · Cited by 17
Genetic Variants Affecting Anti-VEGF Drug Response in Polypoidal Choroidal Vasculopathy Patients: A Systematic Review and Meta-Analysis
Díaz-Villamarín, X., Blánquez-Martínez, D., Pozo-Agundo, A., Pérez-Gutiérrez, A. M., Muñoz‐Ávila, J. I., Antúnez-Rodríguez, A., Fernández-Gómez, A. E., García-Navas, P., Martínez-González, L. J., & Dávila-Fajardo, C. L. (2020) · Genes · doi:10.3390/genes11111335 · Cited by 17
“Therefore, changes in the coding DNA region of CFH may result in a malfunctioning CFH, rendering it unable to inhibit the complement cascade [46] and, especially, its affinity to C-reactive protein (CRP), enhancing CRP levels in the choroid, which means an enhanced local inflammatory response.”
Background
LOC387715, Smoking and Their Prognostic Impact on Visual Functional Status in Age-Related Macular Degeneration—The Muenster Aging and Retina Study (MARS) Cohort
Neuner, B., Wellmann, J., Dasch, B., Dietzel, M., Farwick, A., Stoll, M., Pauleikhoff, D., & Hense, H. (2008) · Ophthalmic Epidemiology · doi:10.1080/09286580802105830 · Cited by 17
Ocular Involvement in Primary Immunodeficiency Diseases
Hosseinverdi, S., Hashemi, H., Aghamohammadi, A., Ochs, H. D., & Rezaei, N. (2013) · Journal of Clinical Immunology · doi:10.1007/s10875-013-9974-2 · Cited by 17
“Furthermore, age-related macular degeneration (AMD) has been seen in 2 patients with partial CHF deficiency and MPGN2 [204], associated with a CHF polymorphism [Y402H] [205].”
Background
An association of neovascular age‐related macular degeneration with polymorphisms of CFH, ARMS2, HTRA1 and C3 genes in Czech population
Matušková, V., Zeman, T., Ewerlingová, L., Hlinomazová, Z., Souček, J., Vlková, E., Goswami, N., Balcar, V. J., & Šerý, O. (2020) · Acta Ophthalmologica · doi:10.1111/aos.14357 · Cited by 19
The Contribution of Genetic Architecture to the 10-Year Incidence of Age-Related Macular Degeneration in the Fellow Eye
Miyake, M., Yamashiro, K., Tamura, H., Kumagai, K., Saito, M., Sugahara-Kuroda, M., Yoshikawa, M., Oishi, M., Akagi-Kurashige, Y., Nakata, I., et al. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16020 · Cited by 17
Association of Single Nucleotide Polymorphisms inCFH, ARMS2andHTRA1Genes with Risk of Age-related Macular Degeneration in Egyptian Patients
Abbas, R. O., & Azzazy, H. M. E.-S. (2013) · Ophthalmic Genetics · doi:10.3109/13816810.2012.762934 · Cited by 17
Relationship Between Age-Related Macular Degeneration-Associated Variants of Complement Factor H and LOC387715 With Coronary Artery Disease
Pulido, J. S., McConnell, J. P., Peterson, L. M., Highsmith, W. E., Lennon, R. J., Bryant, S. C., Berger, P. B., & Somers, V. K. (2007) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(11)61026-4 · Cited by 16

Authors: Despriet, D. D. G., Klaver, C. C. W., Witteman, J. C. M., Bergen, A. A. B., Kardys, I., de Maat, M. P. M., Boekhoorn, S. S., Vingerling, J. R., Hofman, A., Oostra, B. A., Uitterlinden, A. G., Stijnen, T., van Duijn, C. M., & de Jong, P. T. V. M.
Affiliations: Erasmus MC (NL)
Netherlands Institute for Neuroscience (NL)
Amsterdam Neuroscience (NL)
ORCID: Klaver, Caroline C. W.
Bergen, Arthur A. B.
Kardys, Isabella
Vingerling, Johannes R.
Uitterlinden, André G.
Stijnen, Theo
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2006-07-19
Volume: 296
Issue: 3
Pages: 301
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.296.3.301
OpenAlex: W2107143742
Cited by: 348
References: 44
Citations by year: 2026: 4 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 2 · 2021: 8 · 2020: 10 · 2019: 11 · 2018: 8 · 2017: 8 · 2016: 7 · 2015: 21 · 2014: 17 · 2013: 28 · 2012: 24
FWCI: 36.22
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: other-oa
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
Pure Amsterdam UMC (submittedVersion)
Funders: Erasmus Medisch Centrum
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, CFH Y402H polymorphism, complement system, genetic susceptibility, smoking, C-reactive protein, serum inflammatory markers, erythrocyte sedimentation rate, inflammation, AMD progression, late AMD, genetic risk factors, Rotterdam Study, older adults, gene-environment interaction
MeSH terms: Aged, Aged, 80 and over, Blood Sedimentation, C-Reactive Protein, Complement Pathway, Alternative, Female, Haplotypes, Humans, Leukocyte Count, Macular Degeneration, Male, Middle Aged, Polymorphism, Genetic, Prospective Studies, Risk Factors, Smoking, Cohort Studies, Complement Factor H, Inflammation Mediators

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Complement Factor H Polymorphism, Complement Activators, and Risk of Age-Related Macular Degeneration

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