Clues to the Complex Pathogenesis of Glaucoma

Researchers have found the causation of primary open-angle glaucoma (POAG) is a puzzle of many factors, not just one or two. But Oana A. Zeleznik, Ph.D., a researcher at Brigham and Women’s Hospital in Boston, and her colleagues have found that higher levels of diglycerides and triglycerides in the blood are adversely associated with glaucoma, suggesting that they play an important role in the pathogenesis.

Genome-wide association studies have identified more than 120 genetic loci for POAG, the researchers note, and the finding of multiple genes in various pathways suggests a “complex metabolic network that affects optic nerve health.”

Their study, published in Nature Communications, used data from almost 1,200 participants in the Nurses’ Health Studies and Health Professionals’ Follow-Up Study. It is the first, the researchers say, to evaluate the relation between pre-diagnostic plasma metabolites and POAG. Their investigation is part of the research into the “metabolome,” the set of metabolites that are critical for the growth and maintenance of cells and tissues and represent the end-products of environmental factors and gene expression

When Zeleznik and colleagues measured plasma metabolites, 369 from 18 metabolite classes passed quality control analyses. In multivariable-adjusted analyses of individual metabolites, 6 triglyceride metabolites were nominally associated with higher glaucoma risk (p < 0.05). Tyrosine, glucose, glutamine, and one triglyceride metabolite were also significantly associated with higher risk.

“Notably,” the researchers say, data on glucose, acetate, 3-hydroxybutyrate, citrate, pyruvate, and lactate were not available in the three study cohorts; however, there were null associations between tyrosine, valine, glutamine, and phenylalanine with POAG.

To confirm their findings, the researchers also performed a cross-sectional analysis in the UK Biobank, measuring 168 metabolites in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using nuclear magnetic resonance spectroscopy.

According to that analysis, amino acids and triglycerides were positively associated with glaucoma while ketone bodies were inversely associated. Glycolysis-related metabolites were inversely associated with glaucoma.

The replication of adverse associations between selected lipid species with glaucoma is “remarkable,” the researchers note, because the assay systems were fundamentally different: liquid chromatography with tandem mass spectrometry in the cohorts versus NMR spectroscopy in UK Biobank.

Their study is unique and the findings, credible, say Zeleznik and her co-authors, for several reasons: The sample size was large, it did not depend on a convenience control sample (e.g., those with cataract or other non-glaucoma eye conditions) and the pre-diagnostic plasma was collected an average of 10.3 years before the POAG diagnosis. The findings, they argue, indicate that lipid dysregulation and mitochondrial function play an important role in causing glaucoma and might lead to new targets for prevention or treatment.