Study shows novel biologic pathway in AMD cascade

Johanna M. Seddon

A study has found a genetic link between a gene related to high-density lipoprotein, or “good” cholesterol, and a risk of age-related macular degeneration.

The study, led by investigators at Tufts Medical Center/Massachusetts General Hospital in Boston identified the role of the hepatic lipase gene in AMD risk. This discovery sheds light on a new mechanism for development of AMD, said the principal investigator and lead author in an interview with Ocular surgery News.

Johanna M. Seddon, MD, ScM, professor of ophthalmology at Tufts University School of Medicine and director of the ophthalmic epidemiology and genetics service at Tufts Medical Center and New England Eye Center, said that the discovery of new genetic pathways offers a way to look at their mechanism of action, target various proteins in the pathways and eventually find a new way to treat the disease or a new way to delay its progression.

The study showed potential new AMD cascades apart from neovascularization, a hallmark of wet AMD, and geographic atrophy, a sign of dry AMD, the authors wrote.

“Intriguingly, our most significant, replicated association is a functional variation in the hepatic lipase gene (LIPC), a gene involved in triglyceride hydrolysis and high-density lipoprotein (HDL) function, thus revealing another candidate pathway for AMD pathogenesis,” they said. “It adds to the knowledge of the genetic architecture of the disease.”

The study was one of the first large genome-wide association studies designed to explore and identify the remaining genetic susceptibility loci for AMD, they wrote.

The data were published in the Proceedings of the National Academy of Sciences in April.

Cases and controls

The genome-wide study used a platform that included more than 900,000 single nucleotide polymorphisms and found an association between AMD and a variant in the LIPC gene.

The analysis included 979 unrelated advanced AMD cases and 1,709 unrelated controls in the discovery cohort.

All study participants were of European descent, and all control samples were genotyped on the same platform to maximize compatibility between participant subsets. The analysis also included seven replication cohorts comprising 5,789 cases and 4,234 unrelated controls from collaborators worldwide.

“This was a great collaborative effort,” Dr. Seddon said, and noted her colleagues’ valuable participation in the project.

Pathway of HDL metabolism

“This is a gene in the high-density lipoprotein or HDL pathway, and it is involved in the metabolism of HDL,” Dr. Seddon said. “The T allele of that particular gene is associated with higher levels of HDL and lower risk of AMD.”

Results showed possible associations with other genetic loci in the HDL pathway as well. However, the results were not all in the same direction as the association between LIPC and AMD, in which the T allele of the LIPC gene reduced risk of AMD. Thus, the LIPC association with AMD may not be due to its effect on serum HDL levels, but may stem from another mechanism, the authors said.

Dr. Seddon and colleagues are exploring additional associations between LIPC, lipids and AMD and presented results at the recent Association for Research in Vision and Ophthalmology meeting.

“It opens up a new avenue for looking at other mechanisms other than the inflammatory pathway,” Dr. Seddon said. – by Matt Hasson

Reference:

• Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci. 2010;107(16):7395-7400.

• Johanna M. Seddon, MD, ScM, can be reached at Department of Ophthalmology, Tufts Medical Center, 800 Washington St. #450, Boston, MA 02111; 617-636-9000; fax: 617-636-1124; e-mail: jseddon@tuftsmedicalcenter.org.