Complement C3 variant and the risk of age-related macular degeneration.
BACKGROUND
Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.


METHODS
We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.


RESULTS
The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.


CONCLUSIONS
Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.
Yates
John R W
JR
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. jrwy1@cam.ac.uk
Sepp
Tiina
T
Matharu
Baljinder K
BK
Khan
Jane C
JC
Thurlby
Deborah A
DA
Shahid
Humma
H
Clayton
David G
DG
Hayward
Caroline
C
Morgan
Joanne
J
Wright
Alan F
AF
Armbrecht
Ana Maria
AM
Dhillon
Baljean
B
Deary
Ian J
IJ
Redmond
Elizabeth
E
Bird
Alan C
AC
Moore
Anthony T
AT
D000368:Aged; D016022:Case-Control Studies; D003176:Complement C3 / Q000737:chemistry / Q000235:genetics*; D003182:Complement C5 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D020836:Protein Structure, Quaternary
D003176:Complement C3; D003182:Complement C5