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Complement C3 gene variant key to AMD pathogenesis, study finds
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Researchers have identified a gene important to the pathogenesis of age-related macular degeneration — complement C3. Specifically, the C3F variant shows a strong association with AMD and likely has a causal role in the disorder, the study authors said.
John R.W. Yates, FRCP, and colleagues tested 13 single-nucleotide polymorphisms across the complement gene C3 and C5 in several groups. Group 1 was composed of 446 case subjects who had end-stage AMD and 267 control subjects who were their spouses. Group 2 had 157 case subjects with end-stage AMD and 83 controls, made up of both spouses and friends of indexed patients. Those patients were mainly based out of Moorfields Eye Hospital in London and the southeastern area of England.
A set of cases and controls was also genotyped in Scotland to test the significance of the findings in England. The Scottish cohort included 505 patients with AMD in various stages and 351 control subjects, according to the study.
Dr. Yates and colleagues found that the C3 gene could have a causal role in AMD, causing an estimated 22% risk in the white population. The common functional polymorphism rs2230199 in the C3 gene, with variants C3S (slow) and C3F (fast), was detected in 603 cases and 350 controls in the English group and in 244 cases and 351 controls in the Scottish group.
"Our study shows a strong association between the C3F variant and age-related macular degeneration, and there is evidence of functional differences between C3 S/F allotypes," Dr. Yates and colleagues said.
"These findings add to our growing understanding of the genetics of age-related macular degeneration and provide conclusive evidence that the complement pathway has a key role in the pathogenesis of this common and debilitating condition," they said.
The C3F allele is found in about 20% of white populations and is less common in other ethnic groups, the authors said.
The gene is the most "abundant" complement component and is synthesized mostly in the liver, but is also present in other cells and tissues. C3 messenger RNA can be found in the neural retina, choroid, retinal pigment epithelium and cultured retinal pigment epithelium cells, according to the study, published in The New England Journal of Medicine.