- In this study, associations were measured between 4,795 single nucleotide polymorphisms (SNPs) previously associated with age-related macular degeneration (AMD) and 544 metabolites in 388 patients with AMD and 98 control subjects
- Of the 28 highly significant SNP–metabolite associations, 25 were with SNPs in the LIPC gene
- All LIPC polymorphisms were significantly associated with levels of phosphatidylethanolamines, which are glycerophospholipids and belong to the same metabolomic pathway influenced by LIPC
- These observations were reinforced by associations between metabolites and genetic risk scores
- LIPC and glycerophospholipid metabolism appear to be important in AMD pathogenesis and may represent novel treatment targets
Age-related macular degeneration (AMD) is well established to have a genetic component, and genome-wide association studies have linked more than 7,000 single nucleotide polymorphisms (SNPs) to AMD risk. However, such studies cannot determine the biologic consequences of those genetic variants.
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Metabolites are downstream of the genetic transcription process, so they are closely related to disease phenotypes. Researchers at Mass Eye and Ear previously observed a distinctive plasma metabolomic profile in patients with AMD compared with controls, and as reported in Ophthalmology, this profile changed with disease severity.
As the next step in this research, Deeba Husain, MD, a clinician-scientist at the Mass Eye and Ear/Massachusetts General Hospital Department of Ophthalmology and associate professor of Ophthalmology at Harvard Medical School, and colleagues analyzed genomic–metabolomic associations in patients with and without AMD. In Ophthalmology Science, they report further evidence that glycerophospholipid metabolism has an important pathogenic role in AMD.
The participants in this cross-sectional study included 388 patients with AMD and 98 control participants, age 50 or older. They were recruited between January 2015 and July 2016 from the University of Coimbra, Portugal (n=293) and Mass Eye and Ear/Mass General (n=193). All provided two blood samples: one for metabolomic profiling by mass spectroscopy, which led to analysis of 544 endogenous metabolites, and one for genotyping, which led to analysis of 4,795 AMD risk SNPs.
Meta-analysis of the two cohorts (U.S. and Portugal) showed 28 highly significant SNP–metabolite associations that corresponded to two genes: LIPC and ASPM.
Twenty-five of the SNP–metabolite associations were with SNPs in the LIPC gene. All LIPC polymorphisms were significantly associated with levels of phosphatidylethanolamines, which are glycerophospholipids and belong to the same metabolomic pathway influenced by LIPC.
ASPM encodes the abnormal spindle-like microcephaly-associated protein, which modulates early neural development and helps regulate the division and proliferation of adult cells. SNPs in ASPM were linked with a branched-chain essential amino acid that modulates energy metabolism, as well as protein synthesis and degradation.
These observations were reinforced by associations between metabolites and genetic risk scores the researchers generated, which explain a larger fraction of AMD variance than any individual SNP alone. Taken together, the findings suggest that LIPC and the glycerophospholipid metabolites pathway are important in AMD pathogenesis and may point to much needed treatment targets.
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