Immune Gene Variant May Cause Macular Degeneration

CAMBRIDGE, England, July 18 -- A new picture of age-related macular degeneration has emerged from studies here that found a gene for part of the immune system is significantly associated with the disease.

The gene that codes for part of the innate immune system, John R.W. Yates, MBBS, of the University of Cambridge, and colleagues, reported online in the New England Journal of Medicine. A variant in the C3 complement gene "is likely to have a causal role in the disorder," they said.

Their study was released early in conjunction with two other reports of genetic links to disease, both of which used the new technique of genome-wide association scanning.

Dr. Yates and colleagues, on the other hand, used similar microarray methods in sequential case-control studies, but focused more sharply on variations in the complement genes C3 and C5, rather than the whole genome.

For their first study, the researchers evaluated 446 volunteers with end-stage age-related macular degeneration (either geographic atrophy or choroidal neovascularization) and 267 controls, who were spouses of the index patients.

They compared the frequencies of 12 single nucleotide polymorphisms (SNPs) that span the two immune system genes and found no suggestion of an association with the C5 gene.

But a polymorphism dubbed rs2230199 in the C3 gene - which changes the electrophoretic character of the gene from "slow" to "fast" -- showed significant evidence of an association with the disease (P<0.001).

The "slow" form of the gene has been associated with better graft survival in kidney transplants, while the "fast" form has several associations with disease, the researchers said.

When the "fast" allele was tested in another group - of 157 cases and 83 controls - the association was even stronger, at P=5.9X10^-5, Dr. Yates and colleagues said.

Finally, the association was tested in a Scottish cohort of 244 people with late-stage age-related macular degeneration, 261 with age-related maculopathy (an early form of the disease), and 351 controls.

That analysis also found the "fast" allele was significantly associated with disease, at P=5.9X10^-5, the researchers said, although it was not associated with age-related maculopathy.

When all the test groups were combined:

• Having one copy of the "fast" allele increased the risk of disease by 70%, compared with people with two copies of the "slow" allele. The odds ratio was 1.7, with a 95% confidence interval from 1.3 to 2.1.
• Having two copies of the allele nearly tripled the risk. The odds ratio was 2.6, with a 95% confidence interval from 1.6 to 4.1.

The population attributable risk associated with the "fast" allele - the risk that would be eliminated if the alleles did not exist -- is 22%, the researchers said.

The findings "provide conclusive evidence" that the complement system plays a central role in the development of age-related macular degeneration, the researchers concluded.