 |
|
Complement Factor H Polymorphism, Complement Activators, and Risk of Age-Related Macular Degeneration
Dominiek D. G. Despriet, MD;
Caroline C. W. Klaver, MD, PhD;
Jacqueline C. M. Witteman, PhD;
Arthur A. B. Bergen, PhD;
Isabella Kardys, MD;
Moniek P. M. de Maat, PhD;
Sharmila S. Boekhoorn, MD;
Johannes R. Vingerling, MD, PhD;
Albert Hofman, MD, PhD;
Ben A. Oostra, PhD;
André G. Uitterlinden, PhD;
Theo Stijnen, PhD;
Cornelia M. van Duijn, PhD;
Paulus T. V. M. de Jong, MD, PhD
JAMA. 2006;296:301-309.
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.
Author Affiliations: Departments of Epidemiology and Biostatistics (Drs Despriet, Klaver, Witteman, Kardys, Boekhoorn, Vingerling, Hofman, Uitterlinden, Stijnen, Van Duijn, and De Jong), Ophthalmology (Drs Despriet, Klaver, and Vingerling), Hematology (Dr De Maat), Clinical Genetics (Dr Oostra), and Internal Medicine (Dr Uitterlinden), Erasmus Medical Center, Rotterdam, the Netherlands; and the Department of Molecular and Clinical Ophthalmogenetics, the Netherlands Institute for Neuroscience, Amsterdam, the Netherlands (Drs Despriet, Klaver, Bergen, and De Jong); and the Departments of Clinical Genetics (Dr Bergen) and Ophthalmology (Dr De Jong), Academic Medical Centre, Amsterdam, the Netherlands.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Prevalence and Associated Risk Factors of Age-Related Macular Degeneration in an Elderly Chinese Population in Taiwan: The Shihpai Eye Study
Chen et al.
IOVS 2008;49:3126-3133.
ABSTRACT
| FULL TEXT
Association Analysis of CFH, C2, BF, and HTRA1 Gene Polymorphisms in Chinese Patients with Polypoidal Choroidal Vasculopathy
Lee et al.
IOVS 2008;49:2613-2619.
ABSTRACT
| FULL TEXT
Dietary {omega}-3 Fatty Acid and Fish Intake in the Primary Prevention of Age-Related Macular Degeneration: A Systematic Review and Meta-analysis
Chong et al.
Arch Ophthalmol 2008;126:826-833.
ABSTRACT
| FULL TEXT
Pulmonary Disease and Age-Related Macular Degeneration: The Beaver Dam Eye Study
Klein et al.
Arch Ophthalmol 2008;126:840-846.
ABSTRACT
| FULL TEXT
Functional and Structural Implications of the Complement Factor H Y402H Polymorphism Associated with Age-Related Macular Degeneration
Ormsby et al.
IOVS 2008;49:1763-1770.
ABSTRACT
| FULL TEXT
Toll-like Receptor Polymorphisms and Age-Related Macular Degeneration
Edwards et al.
IOVS 2008;49:1652-1659.
ABSTRACT
| FULL TEXT
CKD Increases the Risk of Age-Related Macular Degeneration
Liew et al.
J. Am. Soc. Nephrol. 2008;19:806-811.
ABSTRACT
| FULL TEXT
Genotype-phenotype correlation of age-related macular degeneration: influence of complement factor H polymorphism
Droz et al.
Br. J. Ophthalmol. 2008;92:513-517.
ABSTRACT
| FULL TEXT
Assessment of cumulative evidence on genetic associations: interim guidelines
Ioannidis et al.
Int J Epidemiol 2008;37:120-132.
ABSTRACT
| FULL TEXT
Comprehensive Analysis of the Candidate Genes CCL2, CCR2, and TLR4 in Age-Related Macular Degeneration
Despriet et al.
IOVS 2008;49:364-371.
ABSTRACT
| FULL TEXT
Coding and Noncoding Variants in the CFH Gene and Cigarette Smoking Influence the Risk of Age-Related Macular Degeneration in a Japanese Population
Mori et al.
IOVS 2007;48:5315-5319.
ABSTRACT
| FULL TEXT
C-reactive Protein Level and Risk of Aging Macula Disorder: The Rotterdam Study
Boekhoorn et al.
Arch Ophthalmol 2007;125:1396-1401.
ABSTRACT
| FULL TEXT
Exposure to Chlamydia pneumoniae Infection and Age-Related Macular Degeneration: The Blue Mountains Eye Study
Robman et al.
IOVS 2007;48:4007-4011.
ABSTRACT
| FULL TEXT
Macular Degeneration: Risk Factors for Progression
Wiggs
Arch Ophthalmol 2007;125:1264-1265.
FULL TEXT
Predictive Value of Multiple Genetic Testing for Age-Related Macular Degeneration
Despriet et al.
Arch Ophthalmol 2007;125:1270-1271.
FULL TEXT
Ethnic Differences in Macular Pigment Density and Distribution
Wolf-Schnurrbusch et al.
IOVS 2007;48:3783-3787.
ABSTRACT
| FULL TEXT
Complement Factor H Polymorphism, Inflammatory Mediators, and Retinal Vessel Diameters: The Rotterdam Study
de Jong et al.
IOVS 2007;48:3014-3018.
ABSTRACT
| FULL TEXT
Association Between Vitamin D and Age-Related Macular Degeneration in the Third National Health and Nutrition Examination Survey, 1988 Through 1994
Parekh et al.
Arch Ophthalmol 2007;125:661-669.
ABSTRACT
| FULL TEXT
Y402H Polymorphism of Complement Factor H Affects Binding Affinity to C-Reactive Protein
Laine et al.
J. Immunol. 2007;178:3831-3836.
ABSTRACT
| FULL TEXT
High-Sensitivity C-Reactive Protein, Other Markers of Inflammation, and the Incidence of Macular Degeneration in Women
Schaumberg et al.
Arch Ophthalmol 2007;125:300-305.
ABSTRACT
| FULL TEXT
A Clinician's View of the Molecular Genetics of Age-Related Maculopathy
Gorin
Arch Ophthalmol 2007;125:21-29.
ABSTRACT
| FULL TEXT
A Prospective Study of 2 Major Age-Related Macular Degeneration Susceptibility Alleles and Interactions With Modifiable Risk Factors
Schaumberg et al.
Arch Ophthalmol 2007;125:55-62.
ABSTRACT
| FULL TEXT
Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid
Johnson et al.
Proc. Natl. Acad. Sci. USA 2006;103:17456-17461.
ABSTRACT
| FULL TEXT
Age-Related Macular Degeneration
de Jong
NEJM 2006;355:1474-1485.
FULL TEXT
Systematic review and meta-analysis of the association between complementary factor H Y402H polymorphisms and age-related macular degeneration
Thakkinstian et al.
Hum Mol Genet 2006;15:2784-2790.
ABSTRACT
| FULL TEXT
What's new in the other general journals
Tonks
BMJ 2006;333:249-250.
FULL TEXT
|
