Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration.
BACKGROUND
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.


OBJECTIVE
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).


METHODS
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.


METHODS
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.
Despriet
Dominiek D G
DD
Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
Klaver
Caroline C W
CC
Witteman
Jacqueline C M
JC
Bergen
Arthur A B
AA
Kardys
Isabella
I
de Maat
Moniek P M
MP
Boekhoorn
Sharmila S
SS
Vingerling
Johannes R
JR
Hofman
Albert
A
Oostra
Ben A
BA
Uitterlinden
André G
AG
Stijnen
Theo
T
van Duijn
Cornelia M
CM
de Jong
Paulus T V M
PT
D000368:Aged; D000369:Aged, 80 and over; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics*; D003170:Complement Pathway, Alternative; D005260:Female; D006239:Haplotypes; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007958:Leukocyte Count; D008268:Macular Degeneration / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking
D018836:Inflammation Mediators; D017242:Complement Factor H; D002097:C-Reactive Protein