Analysis of genome reveals clues to macular degeneration

Biomedical research into the genetic basis of disease has progressed at a rapid clip since the sequence of the human genome was announced in 2000, but March 10 saw the scientific equivalent of a triple play.

Three research teams, including one led by Josephine J. Hoh, Ph.D., of Yale’s Department of Epidemiology and Public Health, simultaneously announced that they had identified a gene variant associated with a greatly increased risk of age-related macular degeneration (AMD), a progressive disease leading to blindness that affects more than 10 million elderly Americans (see related story, Drive to Cure Blindness Hits $5 Million).

The human genome can be thought of as a vast string of 3 billion letters in which each letter represents one of the four nucleotides that provide instructions to the body’s protein-building machinery. The genome is 99.8 percent identical among humans, but after every 100- to 300-letter stretch on average are single nucleotide polymorphisms, or SNPs (pronounced “snips”), sites where one letter is substituted for another. Scientists believe that these single-letter variations may help explain why some people are predisposed to certain diseases or respond differently to drug therapies.

Remarkably, all three of the teams who published their findings in March independently zeroed in on precisely the same SNP, a spot on chromosome 1 that is home to a gene that codes for an immune system protein known as complement factor H (CFH).

In its usual form, CFH acts as a brake on the complement system, a component of the body’s innate immune response. According to Hoh, whose group scanned the full genomes of 96 individuals with AMD and those of 50 controls, those who carry two copies of the newly identified variant in the CFH gene are nearly 7.5 times more likely than the rest of the population to develop AMD. “This is only an association,” Hoh emphasizes. “It doesn’t really tell you that this is the cause of the disease.”

But a faulty version of CFH may indeed be a culprit in AMD, which has many features of an autoimmune disease. For example, yellowish deposits at the back of the eye known as drusen, the clinical hallmark of AMD, contain complement proteins.

Hoh, an assistant professor, credits the Raymond and Beverly Sackler Fund for the Arts and Sciences for making the study possible. “This particular kind of study is expensive, not the normal thing a junior faculty member can perform,” she says. “I am extremely grateful for the support from the Sackler family.”

Michael B. Bracken, Ph.D., M.P.H., the Susan Dwight Bliss Professor of Epidemiology and Hoh’s collaborator, adds that the work represents a wholly new way of doing epidemiology. “For the past 100 years, we’ve used a hypothesis-testing approach, where hypotheses were generated from animal studies or small human studies and then we did large epidemiology studies.”

By contrast, whole-genome searches for SNPs are “hypothesis-free”: “The association between a gene and disease is established first, and the biology is done after,” Bracken says. “This takes all that we’ve thought about doing science and turns it on its head, and it’s likely to have major payoffs in the future.”