Study Identifies Crucial Pathway of AMD Pathogenesis

Age-related macular degeneration (AMD) loci are associated with levels of specific lipid and amino acid plasma metabolites, according to a study presented at the American Academy of Ophthalmology (AAO) 2020 Virtual meeting.

“AMD is a multifactorial disease combining environmental and genetic risk factors,” said study presenter Ines Lains, MD, PhD, an ophthalmology resident at Massachusetts Eye and Ear, Harvard Medical School. “In particular, more than 7,000 single nucleotide polymorphisms (SNPs) have been linked with risk of AMD. However, the truth is that for most of them, we still don’t know their biological meaning and functional consequences.”

Dr. Lains and colleagues hypothesized that studying metabolites could be an appropriate approach to address this challenge and to better understand the functional goal of AMD risk genes.

To do this, Dr. Lains and colleagues evaluated fasting blood samples from 191 U.S. patients with AMD and 295 patients with AMD from Portugal. Samples were evaluated for metabolomics using mass spectrometry and underwent genetic profiling.

The researchers obtained data on 544 plasma metabolites and gained information on 4,795 AMD SNPs. They built linear regression models adjusted for age, sex, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. They also accounted for false discovery rate. Each cohort was analyzed separately and then in a meta-analysis.

They identified 28 associations or metabolomic quantitative trait loci. Three of them were seen between SNPs in the ASPM gene and an amino acid metabolite. The majority (n=25) were seen between SNPs in the LIPC gene and four metabolites that were lipids.

“This means that the LIPC gene and the glycerophospholipids pathway are likely crucial in AMD pathogenesis and may represent potential targets for treatment of this blinding disease,” Dr. Lains said. “In this work, we confirm that AMD risk SNPs have an impact on the plasma metabolome and that by looking at genetic metabolomic associations we can get unique insights into the pathogenesis of AMD.

This study was designated a “Best Poster” by AAO 2020 Virtual meeting organizers.