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A study conducted by ophthalmology researchers has surprisingly found that a mere two genes – both involved in inflammation – account for 74 percent of the genetic risk in developing age-related macular degeneration (AMD), the most common cause of vision loss in older people.

The discovery of the two genes – Factor H and Factor B – identifies inflammation as the primary cause of AMD. Both genes work together as regulators of a pathway that controls inflammation. Factor H turns the pathway down after inflammatory response to triggers, such as infection, while Factor B turns the pathway up to intensify the response. Previously inflammation was only considered a secondary complicating factor in AMD.

The study, published in the March issue of Nature Genetics, compared genes from 900 AMD
Rando Allikmets
Rando Allikmets
patients with genes from 400 healthy people of the same age and ethnicity. Seventy-four percent of the AMD patients had risk-increasing variants of one or both genes, while having none of the protective variants.

“I don’t know of any other complex disorder in which two genes explain so much,” says senior author Rando Allikmets, Ph.D., the William and Donna Acquavella Associate Professor of Ophthalmology and director of research at Harkness Eye Institute. “AMD looks like it’s not as complex as we once thought.”

Age-related macular degeneration is an eye disease in which the macula, the central part of the retina, deteriorates. Destruction of the macula impairs “straight-ahead” vision, which can make reading or driving impossible. In its mild and severe forms, the disease affects about 30 percent of people age 70 and over – about 10 million people in the United States. Of these, 2 million will experience severe vision loss and may become legally blind, although most will retain their peripheral vision.

Since arriving at Columbia in 1999, Dr. Allikmets has led a large program funded by the National Eye Institute to find genes for AMD, a complex disease with genetic and environmental components. Thousands of patients and people without the disease have enrolled in his studies.

The first breakthrough came last year when Dr. Allikmets and Gregory Hageman, Ph.D., of the University of Iowa discovered the first AMD gene – Factor H – at the same time as three other independent research groups. All four studies found one common variant of Factor H raises the risk of AMD two-to-sevenfold. The study led by Drs. Allikmets and Hageman also found at least two protective variants of Factor H that lower AMD risk.

Factor H alone, however, did not fully explain who gets AMD and who doesn’t. About 30 percent of people with a high-risk variant of Factor H showed no signs of AMD.

In his search for additional AMD genes, Dr. Allikmets limited the scope to a few likely suspects. The findings of that search, published in the current paper, implicated one of the suspects, Factor B. “Because of the complementary roles of these two genes, a protective Factor B can counteract a risky Factor H, and vice versa,” Dr. Allikmets says. Factor H seems to account for about half the risk; Factor B for another quarter.

Environmental factors such as viral and bacterial infections can also affect macular degeneration. This area is being researched by Ian Lipkin, M.D., the Jerome L. and Dawn Greene Professor of Epidemiology and Professor of Neurology and Pathology and other researchers at the Mailman School.

Columbia researchers who contributed to the genetic research include Stanley Chang, M.D., chairman of ophthalmology and the Edward S. Harkness and K. Tse and Ku Teh Ying Professor of Ophthalmology; Joanna Merriam, M.D., Ph.D., associate research scientist; Jana Zernant, MS, staff associate; R. Theodore Smith, M.D., Ph.D., associate clinical professor of ophthalmology; Gaetano Barile, M.D., Irving Assistant Professor of Ophthalmology; John Merriam, M.D., clinical professor of ophthalmology; and Lawrence Yannuzzi, M.D., professor of clinical ophthalmology.

—Susan Conova

The research was supported by the NEI and the NCI, NIH, New York Community Trust, Wallach Foundation, Elyachar Foundation, Kaplen Foundation, Widgeon Point Charitable Foundation, Macula Foundation, and Research to Prevent Blindness, Inc.