Complement component C3 and risk of age-related macular degeneration.
OBJECTIVE
To explore the association between polymorphisms in the complement component 3 (C3) gene and age-related macular degeneration (AMD), and to investigate the modifying effect of complement factor H (CFH) Y402H, LOC387715 A69S and smoking.


METHODS
Pooled data from the prospective, population-based Rotterdam Study (enrolment between 1990 and 1993, and 3 follow-up examinations between September 1, 1993, and December 31, 2004) and an independent case-control study from the Netherlands.


METHODS
The Rotterdam Study comprised a total of 6418 persons aged >or=55 years who had gradable fundus photographs. The case-control study consisted of 357 unrelated AMD patients and 173 control individuals aged >or=55 years.


METHODS
The variants R102G and P314L of the C3 gene, CFH Y402H and LOC387715 A69S, were genotyped in all study participants. Information on cigarette smoking was obtained by interview at baseline.


METHODS
Early and late stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD.


RESULTS
We found a population frequency of 0.217 for R102G and 0.211 for P314L in the Rotterdam Study. Both alleles significantly increased the risk of early AMD and all subtypes of late AMD, and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, and smoking. Detailed analysis showed that the haplotype carrying both alleles had the highest frequency difference between cases and controls (P=0.006). We estimated a total population-attributable risk of 14.6%. A meta-analysis of all currently available data yielded a pooled odds ratio (OR) of 1.61 (95% confidence interval [CI], 1.46-1.78) for the R102G allele, and an OR of 1.50 (95% CI, 1.31-1.71) for the P314L allele.


CONCLUSIONS
Our study showed a significant association between variants in the C3 gene and AMD and further highlights the crucial role of the complement pathway in the etiology of AMD.
Despriet
Dominiek D G
DD
Department of Epidemiology and Biostatistics, Rotterdam, Erasmus Medical Centre, the Netherlands.
van Duijn
Cornelia M
CM
Oostra
Ben A
BA
Uitterlinden
Andre G
AG
Hofman
Albert
A
Wright
Alan F
AF
ten Brink
Jacoline B
JB
Bakker
Arne
A
de Jong
Paulus T V M
PT
Vingerling
Johannes R
JR
Bergen
Arthur A B
AA
Klaver
Caroline C W
CC
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D003176:Complement C3 / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000235:genetics
C514392:ARMS2 protein, human; C493495:CFH protein, human; D003176:Complement C3; D011506:Proteins; D017242:Complement Factor H