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

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. +6 more·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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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
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
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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