A recent large-scale cohort study has illuminated the potential role of metabolic profiling in enhancing glaucoma risk predictions, particularly among individuals with a high genetic predisposition to the disease. The study highlights that incorporating metabolite data from a Nuclear Magnetic Resonance (NMR) platform only marginally improved the efficiency of existing glaucoma prediction algorithms. However, an intriguing finding emerged: high levels of lactate, pyruvate, and citrate were associated with a 29% reduced risk of developing glaucoma in individuals who fall within the top quartile of genetic risk estimates.

The researchers conducted a comprehensive analysis using a human-relevant genetic mouse model, demonstrating that pyruvate supplementation significantly lowered the incidence of glaucoma. A synergistic relationship was discovered between the polygenic risk score (PRS) for glaucoma and a metabolic risk score (MRS), based on 168 metabolites. This interaction provided critical insights into the glaucoma risk profile, enabling the identification of individuals who, despite a high genetic risk, may possess favorable metabolic characteristics that could lower their chances of developing glaucoma. Conversely, the findings also highlighted those at heightened risk who may require earlier monitoring and intervention.

Historically, studies have focused predominantly on genetic factors associated with glaucoma. Earlier research indicated modest predictive capabilities of glaucoma PRS (Mabuchi et al., 2017; Tham et al., 2015). However, more recent genome-wide association studies have showcased improved risk prediction capabilities (Craig et al., 2020; Han et al., 2019). Despite the advancements, there has been a notable gap in research regarding the integration of metabolite data into glaucoma risk assessments. The current study emphasizes the necessity to explore how non-genetic variablessuch as air pollution, psychological stress, physical activity, and dietary habitscould interact with metabolic profiles and further alter glaucoma risk.

Research into metabolomics has previously unearthed potential biomarkers for open-angle glaucoma (OAG). A thorough systematic review analyzing 13 different studies identified a total of 144 metabolites, with 12 being directly linked to OAG. Notably, four key metabolic pathwayssphingolipid metabolism, arginine and proline metabolism, and beta-alanine metabolismwere found to be significantly enriched among subjects using plasma samples. Additionally, a recent study encompassing three US cohorts and the UK Biobank revealed that elevated levels of plasma diglycerides and triglycerides were linked to an increased risk of glaucoma. This aligns with the present study's findings that indicated lower triglyceride levels could contribute to resilience against glaucoma, even though this association was less pronounced when compared to the glycolysis-related metabolites.

The biological underpinnings suggest that hypertriglyceridemia could lead to heightened blood viscosity and increased intraocular pressure (IOP)two critical risk factors for glaucoma. In fact, a meta-analysis found that individuals diagnosed with glaucoma exhibited an average triglyceride level 14.2 mg/dl higher than their non-glaucomatous counterparts.

While numerous studies have successfully pinpointed biomarkers associated with glaucoma, this research uniquely identifies markers indicative of resilience against a high genetic risk for the disease. Elevated levels of lactate, pyruvate, and citrate were observed in individuals at high genetic risk who did not develop glaucoma. These metabolites are critical energy sources for retinal ganglion cells (RGCs), which are integral to ocular health. RGCs utilize energy derived from glycolysis and oxidative phosphorylation, and they express monocarboxylate transporters that facilitate the uptake of extracellular pyruvate and lactate, which are crucial for maintaining cellular energy and survival.

Pyruvate, a key metabolite, plays a pivotal role in energy metabolism by linking glycolysis to the tricarboxylic acid (TCA) cycle, which is essential for ATP production. Beyond its metabolic function, it exhibits antioxidant properties, scavenging reactive oxygen species (ROS) and activating the antioxidant response gene Nrf2. Recent studies have substantiated pyruvate's neuroprotective effects on RGCs in both cell culture models and induced glaucoma in rats. Notably, a randomized phase II clinical trial testing pyruvate and nicotinamide demonstrated improved visual function in glaucoma patients as compared to a placebo group, underscoring the therapeutic potential of pyruvate.

Citrate, another important metabolite identified in the study, serves as a significant intermediate in the TCA cycle, contributing to aerobic energy production. Elevated citrate levels may indicate enhanced energy supply and antioxidative capabilities in ocular tissues, thereby protecting RGCs from oxidative damage. Several studies have reported decreased citrate levels in both adult and pediatric glaucoma patients, suggesting a potential biomarker for the disease.

The research also identified various lipoproteins associated with resilience against glaucoma, most notably cholesteryl esters in small and medium-sized high-density lipoproteins (HDL). Although these findings did not meet the stringent statistical thresholds to be considered definitive, they align with previous studies that documented the neuroprotective effects of HDL within glaucoma pathophysiology. Lipoproteins transport essential lipids in the bloodstream, and HDL's antioxidant properties may contribute to protecting RGCs through cholesterol efflux.

This study boasts several strengths, including the utilization of the UK Biobanka large cohort with detailed demographic and clinical dataand the integration of a PRS derived from extensive genome-wide association studies. Furthermore, the research was bolstered by functional tests in a mouse model, which demonstrated pyruvate's protective effects against IOP elevation and glaucomatous nerve damage.

Despite these strengths, the study is not without limitations. A predominant focus on a European population raises concerns about the generalizability of the findings to other ethnic groups, including African, Asian, and mixed American ancestries. Moreover, the reliance on self-reported diagnoses for glaucoma within the UK Biobank may have implications for the accuracy of the data, although the prevalence of glaucoma within the study sample mirrors established estimates in similar populations. Additionally, the limited metabolites analyzed and the study's cross-sectional design complicate the interpretation of the temporal relationships between metabolic changes and glaucoma onset.

In conclusion, this research highlights the role of plasma metabolites in enhancing the predictive power of glaucoma risk assessments and their potential for identifying individuals who may be resilient to glaucoma despite a high genetic predisposition. The findings suggest that therapeutic strategies targeting metabolites such as pyruvate could offer new avenues for managing glaucoma risk in genetically susceptible individuals.