May 4, 2005

Variant of gene TLR4 doubles the risk of developing AMD
Discovery suggests that AMD is an inflammatory disease

Ann Arbor, MI—University of Michigan scientists have identified a variant of a gene that doubles the risk of developing age-related macular degeneration (AMD), a blinding disease for which there is as yet no cure. The study also sheds light on AMD’s connection to the immune system. The same gene plays a pivotal role in fighting infection, suggesting that AMD can best be understood as an inflammatory disease.

A given gene may have many different forms, in which even a single nucleotide of DNA is altered, resulting in a different function. When scientists examined the gene toll-like receptor 4 (TLR4), they discovered that a single amino acid change (TLR4-D299G variant) increases an individual’s susceptibility to AMD by a factor of 2.6. The risk increases fourfold when the variant is in the presence of two other previously identified gene variants. These two variants (APOE-ε2/3 and ABCA1-R219K) are considered to have an additive effect.

The findings were published in the April 13 Advance Access issue of Human Molecular Genetics by a research team led by Anand Swaroop, Ph.D., Harold F. Falls Professor of Ophthalmology, from the University of Michigan Kellogg Eye Center. The study involved 667 patients with AMD and 439 unrelated controls, with an average age of 75 -79 years.

These findings come on the heels of three recent studies (and one by Drs. Sepideh Zareparsi, Goncalo Abecasis and Swaroop, to be published in an upcoming issue of the American Journal of Human Genetics) that identified a gene variant in Complement Factor H (CFH), another component of the immune system. This gene variant accounts for over 40 per cent of AMD susceptibility among older adults.

“It appears that the genetic changes in both CFH and TLR4 have an additive effect on susceptibility to AMD,” says Dr. Swaroop. “If an individual inherits both alleles, the risk of getting AMD goes up to almost eight-fold.”

According to the Kellogg scientist, “The newest study, which offers evidence of a link between AMD and the immune system, suggests that an inflammatory event could be a trigger for the disease.” He adds, “The event may not necessarily cause AMD, but could occur at some critical stage, accelerating the progression of the disease.”

The findings may prompt scientists to reassess their assumptions about the characterization of the disease. “Some say AMD is caused by oxidative stress, others say it is caused by a defect in a particular layer of the retina,” says Dr. Swaroop. “Our study suggests that there may be a link between these apparently distinct pathways and inflammation.”

Dr. Swaroop explains that AMD is an extremely complex disease, and that finding its cause is not simply a matter of identifying a single gene. The disease most likely occurs as a result of a combination of many genetic variants, together with environmental factors, such as smoking and diet.

According to Dr. Swaroop, treatments for AMD will be possible as soon as we understand the multiple cellular pathways involved in the disease. “Once we know the major players—the pathways and how they relate to each other—we will be able to direct treatments to the correct biological site,” he says. “The gene TLR4 helps us connect the dots among the various pathways involved in the disease.”

AMD and Atherosclerosis
The genes examined in this study also play a role in heart disease; however, the effect of the gene variants appears to be the opposite of that shown in AMD. While the three gene variants increase the risk of AMD, they reduce the risk of atherosclerosis, the clogging or narrowing of the arteries.

The observation is of interest because the two diseases—AMD and atherosclerosis—share common pathogenic disease mechanisms. Both are characterized by thickening of connective tissue and by lipid deposits. In AMD, these deposits take the form of drusen; in atherosclerosis, the deposits emerge as plaque in arteries. Other studies have shown that cardiovascular disease and hypertension are risk factors for AMD. Dr. Swaroop says that further studies are needed to learn more about the relationship between the two diseases.

For the moment, Dr. Swaroop says, the challenge is to determine exactly how the known cellular pathways exacerbate or enhance the development of AMD. “We need to learn more about the biochemical mechanisms underlying this complex disease process. Once we fill in the blanks, we can begin to devise strategies for treatment."

Contact: Betsy Nisbet 734 647-5586, bsnisbet@umich.edu