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Age-related macular degeneration: two genes, Factor H and Factor B, involved

A study, led by researchers at Columbia University Medical Center and published in Nature Genetics, pinpoints the role that two genes, Factor H and Factor B, play in the development of nearly three out of four cases of age-related macular degeneration ( AMD ), a devastating eye disease that affects more than 10 million people in the United States.

Findings indicate that 74 percent of AMD patients carry certain variants in one or both genes that significantly increase their risk of this disease.

The research, is a continuation of work published last year by the same team in the Proceedings of the National Academy of Sciences ( PNAS ).

The PNAS study showed that several variants in the Factor H gene significantly increase the risk of developing age-related macular degeneration.
Factor H encodes a protein that helps shut down an immune response against bacterial or viral infection, once the infection is eliminated.
People with these inherited risk-increasing variations of Factor H are less able to control inflammation caused by infectious triggers, which may spark age-related macular degeneration later in life.

Though the effect of Factor H on age-related macular degeneration is large, variation in this gene alone does not fully explain who gets AMD and who doesn't.
As described in the PNAS paper, about one-third ( 29 percent ) of people with a Factor H risk variant had not been diagnosed with age-related macular degeneration.

The investigators decided to look for additional culprits and focused on genes in the same immune response pathway that contains Factor H.

Their genetic analysis of 1,300 people quickly identified Factor B as the major modifier of the disease.

The discovery makes good biological sense: while Factor H is an inhibitor of the immune response to infection, Factor B is an activator. Because of the complementary roles of the these two genes, a protective Factor B variation can protect against age-related macular degeneration, even if one carries a risk-increasing variant of Factor H, and vice versa.

As described in Nature Genetics, the two genes explained nearly three out of four AMD cases: 74 percent of the subjects with age-related macular degeneration had either the Factor H or Factor B risk variant ( or both ), but no protective variants of either gene.

" I am not aware of any other complex disorder where nearly 75 percent of genetic causality has been identified," said Rando Allikmets, at Columbia University and senior author of the paper.

" These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of age-related macular degeneration. We confirmed this association not just statistically and genetically but, most importantly, pinpointed the biological origin of the disease," added Allikmets. " In just a few short years, we've gone from knowing very little about what causes age-related macular degeneration to knowing quite a lot. We now have clear targets for early therapeutic intervention."

Though the new paper explains much of the genetic risk, the specific triggers that set off the immune response and subsequent inflammation are still unknown. Researchers at Columbia University Medical Center and the University of Iowa are now searching for specific viral and bacterial culprits.

Source: Columbia University Medical Center, 2006