Study Finds Potential Biomarkers for Distinguishing Glaucoma Subtypes

Results from a prospective observational study showed aqueous transforming growth factor beta (TGF-β) and autotaxin (ATX) exhibited high diagnostic performance in detecting glaucoma subtypes and could serve as promising biomarkers for glaucoma. Findings were published in Scientific Reports.

Progression of glaucoma depends on the disease’s subtype, the authors explained. Although high intraocular pressure (IOP) is characteristic in some types of glaucoma, it can vary and does not always give an exact diagnosis of subtype. “Therefore, there is an urgent and unmet need for biomarkers that can differentiate glaucoma subtypes and presume disease progression,” they wrote.

Elevations in IOP are thought to be the result of increased aqueous humor (AH) outflow resistance, primarily in the conventional pathway which consists of the trabecular meshwork (TM) and Schlemm’s canal (SC) tissues.

However, “in open-angle glaucoma (OAG), primary open-angle glaucoma (POAG), secondary open-angle glaucoma (SOAG), and exfoliation glaucoma (XFG), an abnormal accumulation of extracellular matrix (ECM) is found along the conventional outflow pathway, leading to the disorganization and degeneration of the TM and SC as well as IOP elevation,” researchers explained.

Previous studies have found that upregulated or downregulated levels of TGF-β and ATX are present in patients with various forms of glaucoma. Based on these findings, the researchers hypothesized that “crosstalk may exist between ATX and TGF-βs, suggesting that concurrent levels of these mediators may be promising diagnostic biomarkers.”

To investigate the correlation between ATX and TGF-βs in different glaucoma subtypes, the investigators collected AH samples from patients with cataracts or glaucoma who were 20 years or older and who underwent surgery for these complications between March 2014 and December 2019. Participants presented at the University of Tokyo Hospital and 3 affiliated eye clinics. Machine learning was used to classify eyes into 3 groups depending on OAG diagnosis: POAG, SOAG, and XFG.

IOP was measured using Goldmann applanation tonometry, and maximum preoperative IOP was evaluated within 3 months prior to AH collection. In addition, the authors wrote, “[l]evels of ATX in the AH were determined via a two-site immunoenzymatic assay with an ATX assay reagent using a Tosoh AIA system. TGF-β levels in the AH were measured using a Bio-Plex Pro TGF-β assay.”

Two hundred and eighty-one eyes from as many patients were included in the study. Eighty-eight eyes were normal (without any ocular complications) while 97 had POAG, 48 had SOAG, and 48 had XFG. Researchers measured areas under the curve (AUC), sensitivity, and specify for 4 glaucoma indicators (ATX, TGF-β1, TGF-β2, and TGF-β3).

Analyses revealed:

• ATX, TGF-β1, and TGF-β3 were positively correlated with IOP.
• ATX was significantly and negatively correlated with the mean deviation.
• From least absolute shrinkage and selection operator regression analysis, the AUC values to distinguish each subgroup (normal, POAG, SOAG, and XFG) ranged between 0.675 (POAG vs normal) and 0.966 (XFG vs normal) when the 4 variables were used.
• High AUC values were obtained with ATX for discriminating XFG from normal eyes and with TGF-β3 for discriminating XFG from normal eyes, POAG, or SOAG.

“Collectively, ATX and TGF-βs can be used as biomarkers to differentiate glaucoma subtypes; specifically, TGF-β3 and ATX have the ability to discriminate XFG from other subtypes or normal eyes…and ATX is effective in presuming severity in glaucoma,” the authors wrote. “If we can measure the levels of ATX and TGF-β1–β3 in the AH, it would provide information in addition to clinical findings to differentiate glaucoma subtypes.”

The lack of baseline IOP data, as most subjects had already been administered glaucoma eyedrops during their first visit to an outpatient facility, marks a limitation to the study. AH samples for SOAG included those from patients with elevated IOP due to various causes, meaning future studies could benefit from more discrimination. In addition, further in vitro or in vivo studies ought to be conducted to confirm the mechanisms underlying the changes in aqueous ATX and TGF-βs induced in glaucoma, the researchers concluded.

Reference

Igarashi N, Honjo M, Asaoka R, et al. Aqueous autotaxin and TGF-βs are promising diagnostic biomarkers for distinguishing open-angle glaucoma subtypes. Sci Rep. Published online January 14, 2021. doi:10.1038/s41598-021-81048-3