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NIH Research Matters

April 19, 2010

Cholesterol Genes Tied to Age-Related Macular Degeneration

A large genetic study has identified 3 new genes associated with the blinding eye disease age-related macular degeneration (AMD). Two of the genes are involved in the cholesterol pathway—a formerly unknown biological pathway for AMD disease development. The finding suggests new treatment and prevention approaches.

Illustration of an eye with AMD deposits.

In AMD, small yellowish deposits made partly of cholesterol form under the retina, blurring the sharp central area of vision. Image courtesy of NEI.

AMD gradually destroys sharp, central vision as a person ages. It is a leading cause of visual impairment and blindness in older Americans. Genome-wide association studies (GWAS) have previously uncovered genes linked to AMD risk. In these studies, researchers scan the entire human genome looking for genetic variations between people with AMD and matched controls.

The larger the GWAS, the greater its ability to uncover more genes. For the new study, Drs. Anand Swaroop of NIH's National Eye Institute (NEI) and Goncalo Abecasis at the University of Michigan, Ann Arbor, led a team that analyzed the genomes of more than 18,000 people. NEI provided partial support for the research.

The team reported in the online early edition of Proceedings of the National Academy of Sciences on April 12, 2010, that the strongest genetic association was in a region on chromosome 22, near a gene called metalloproteinase inhibitor 3 (TIMP3). The TIMP3 gene was previously tied to Sorsby's fundus dystrophy, a rare inherited early-onset form of macular degeneration. Although further research is needed, the researchers suspect that the region in question influences the gene's expression.

The study also uncovered 2 genes associated with AMD risk in the high-density lipoprotein (HDL) cholesterol pathway: human hepatic lipase (LIPC) and cholesterol ester transfer protein (CETP). Two more genes in the cholesterol pathway—lipoprotein lipase (LPL) and ATP binding cassette transporter 1 (ABCA1)—showed some association with AMD, but more research will be needed to confirm the finding.

In the same edition of Proceedings of the National Academy of Sciences, another research team reported finding a link between AMD and LIPC in a separate GWAS effort funded in part by NEI. That team—led by Johanna M. Seddon at Tufts University Medical School and Mark Daly at Massachusetts General Hospital and the Broad Institute—also found weak associations with other HDL genes. The team was able to visualize the LIPC protein within monkey retinas as well.

HDLs are among a family of lipoproteins that transport essential fats, such as cholesterol, through the bloodstream. They are known to play a role in heart disease. One hallmark of AMD is the appearance of drusen—deposits of protein, cholesterol and other lipids—under the retinal pigment epithelium, a layer of cells at the back of the eye. However, the relationship between HDL cholesterol levels in the blood and AMD is still unclear.

"We suspect that these genetic variations found in the cholesterol pathway impact the retina differently from the circulatory system, so cholesterol levels in the blood may not provide meaningful information about AMD risk," Swaroop says. "Nonetheless, we have uncovered a major biochemical pathway that may be a target for future AMD treatments."

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

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This page last reviewed on December 3, 2012

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