Meta-Analysis of Dyslipidemia and Blood Lipid Parameters on the Risk of Primary Open-Angle Glaucoma

Objective We aimed to explore the effect of blood lipid parameters on the risk of primary open-angle glaucoma (POAG) by meta-analysis. Methods The databases of PubMed, Scopus, CNKI, and Wanfang were systematically searched from inception to April 2022, and the relevant research literature was obtained, screened, and analyzed. Results A total of 15 studies were included in this meta-analysis, including 11 reporting dyslipidemia and risk of POAG and 5 reporting specific lipid level and risk of POAG. Dyslipidemia increased the risk of POAG with an odd ratio (OR) of 1.25 (95% CI: 1.23, 1.26). Total triglyceride and total cholesterol were not related to the prevalence of POAG, but high-density lipoprotein cholesterol was significantly negatively correlated with the risk of POAG with an OR of 0.96 (95% CI: 0.94, 0.99). Conclusion Dyslipidemia is a risk factor for POAG. Given the small sample size and significant interstudy heterogeneity, additional studies are needed to establish this conclusion.


Introduction
Glaucoma is a group of ocular conditions characterized by progressive optic nerve damage with corresponding visual field defect. Pathologically, glaucoma is characterized by the loss of retinal ganglion cells, the thinning of the retinal nerve fiber layer and the morphological change of the optic disc. Primary open-angle glaucoma (POAG) is a type of glaucoma with an open, normal-appearing anterior chamber angle and raised intraocular pressure, in the absence of other underlying diseases [1]. According to prior reports, the number of patients with glaucoma worldwide is 76 million with an incidence of 3.54% in people aged 40-80, which is expected to be increased to 112 million by 2040. The exact pathogenesis of POAG remains unclear. The risk factors identified include elevated intraocular pressure [2], advanced age [3], race [4], and a family history of glaucoma [5]. The study by Jonas et al. that first evaluated the relationship between blood lipid levels and POAG found no significant correlations [6]. A recent metastudy showed that the total triglyceride level in POAG was significantly higher than that of the control group [7]. This finding is echoed by a recent meta-analysis [8]. Nonetheless, the associations between specific blood lipid parameters and the risk of POAG remain scarcely investigated. The purpose of this study is to explore the relationship between dyslipidemia, specific blood lipid parameters, and the prevalence or risk of POAG through a meta-analysis.

Inclusion and Exclusion Criteria. Inclusion criteria: (i)
The study purpose was to explore the effect of blood lipid level (or abnormal lipid metabolism) on the risk of POAG; (ii) Study design was cross-sectional, case-control, or cohort study; (iii) Publication language limited to Chinese or English; (iv) Study population is not limited by age, race, and gender.
Literature exclusion criteria: (i) The literature content is inconsistent or weakly relevant; (ii) Animal experiments, in vitro tests, letters, reviews, case reports, abstracts, or incomplete reports; (iii) No data available in terms of study exposure (no blood lipid level) or relevant outcomes; (iv) No original text.

Data Sorting.
Yan completed the content extraction from eligible publications, while Huang and Wang checked independently. The contents extracted included study author name, year of publication, study type, inclusion criteria of patients, number of patients, main observation indicators, and other information.

Literature Quality
Evaluation. The quality of the included publications was evaluated by the scale reported by Viswanathan et al. [9,10]. The quality assessment method included 15 items involving the design, criteria for observational studies, and data analysis evaluation. It evaluated the methods of research objects selection, results and exposure measurement, and the methods of controlling confounders, potential conflicts of interest and the risk of deviation related to different designs. A score of 0 or 1 would be assigned to each item assessed, and the total score would be 15 points.

Statistical
Analysis. All data in this study were analyzed by Stata v16.0 software. Two-sided P < 0:05 denoted statistically significance. The binary enumeration data was expressed as odds ratio (OR) with 95% confidence interval (95% CI). If the OR was not provided, it was calculated according to the number of events in the diseased and non-diseased population. The specific calculation equation is OR = ðnumber of exposed persons in the diseased group/ number of nonexposed persons in the diseased groupÞ/ð number of exposed persons in the nondiseased group/ number of nonexposed persons in the nondiseased groupÞ. The heterogeneity test between different studies was described by the I 2 statistic with the following equation I 2 = ðQ − df Þ/Q, in which Q represents the χ2 statistic and df denotes its degrees of freedom). I 2 corrected by degrees of freedom ≥50% or <50% was deemed to indicate high or low inter-study heterogeneity, respectively. All studies were pooled using the fixed-effect models. The association between hyperlipidemia and glaucoma was evaluated according to the study design, and subgroup analysis was performed. Publication bias was assessed using Begg's funnel plot, along with Begg's test. The Begg's test is a rank correlation funnel plot asymmetry test method, and when P > 0:05, it can be considered that the funnel plot has no obvious asymmetry. When the data is less than 10 points, the funnel plot and asymmetric test methods cannot judge whether there is publication bias due to the low-test power. In this study, we do not report funnel plots with fewer than 10 points, but still report the results of Begg's test.

Literature Search.
The screening process of this study is shown in Figure 1. A total of 591 articles were retrieved, including 585 relevant Chinese and English documents and 6 ambiguous documents. After removing 406 duplicate documents, 158 documents were screened and excluded by reading the title and abstract. The full-texts of the remaining 27 documents were read, and 11 publications were excluded for absence of original text (n = 1) and data unavailability (n = 10). Of the 15 included literature, 11 reported abnormal lipid metabolism and risk of POAG, and 5 reported the relationship between blood lipid level and POAG.

Basic Information
Included in the Study. The 11 literature that reported the prevalence or risk of dyslipidemia in POAG are shown in Table 1. A total of 2879714 patients, including 155928 POAG, were involved in 4 cross-sectional studies, 4 case-control studies, and 3 cohort studies. Eight studies were conducted in Asian populations (3 in Taiwan and 5 in South Korea), and 3 in European and American populations (all conducted in the United States). The five literature that reported the risk of blood lipid level are shown in Table 2. A total of 23296 patients, including 1315 POAG, were studied in 2 cross-sectional studies and 3 case-control studies in Asian populations (3 in China and 2 in South Korea). The quality of the literature was evaluated, and the results are shown in Table 3.

Reports of included studies (n = 15)
Records excluded a er reading abstract (n = 158) Full text unavailable (n = 1) Reports excluded: No data available (n = 11)   Figure 2. Subgroup analysis found that both cross-sectional and case-control studies      Note: Quality criteria and evaluation of design and data analysis for observational studies criteria (1) Was the research question or objective in this paper clearly stated? (2) Was the study population clearly specified and defined? (3) Was the study population representative of the general population? (4) Was the participation rate of eligible persons at least 50%? (5) Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? (6) Were sample size justification, power description, or variance and effect estimates provided? (7) For the analyses in this paper, were the exposures of interest measured prior to the outcomes being measured? (8) Was the time frame sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? (9) Were the exposure measures (independent variables) clearly defined, objective, valid, reliable, and implemented consistently across all study participants? (10) Were the exposures assessed more than once over time? (11) Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? (12) Were the outcome assessors blinded to the exposure status of participants? (13) Was the statistical analysis appropriate? (14) Was loss to follow-up after baseline 20% or less? (15) Were the key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposures and outcomes? (1: yes; 0: no or not applicable).     Figure S1, supplementary data) showed that the points were distributed on both sides, showing an inverted funnel shape, and P = 0:755 by Begg's test. Still, some studies were not within the confidence interval due to significant heterogeneity.

Blood Lipid Level and Risk of POAG.
Meta-analysis conducted on the 5 literature reporting associations between blood lipid levels and risk of POAG showed the OR for POAG by triglyceride (TG) was 1.00 (95% CI: 1.00, 1.00). There was great heterogeneity among the studies (I 2 = 82:6%, P < 0:001), as shown in Figure 3. Subgroup analysis showed significant positive correlation between TG and risk of POAG (OR = 1:73, 95% CI: 1.70, 1.76) in casecontrol studies but not in cross-sectional studies. No publication bias was found by Begg's test (P = 0:086).   Figure 5: Forest map reporting the study on the association between HDLC and POAG risk.

Discussion
Abundant prior studies have reported the relationship between abnormal lipid level and risk of POAG with no consistent conclusions. Abnormal lipid metabolism usually refers to the increase of TC or TG, which may be accompanied by the decrease of HDLC [27]. Lipid metabolism is an important risk factor for cardiovascular disease [270]. Previous studies have suggested that abnormal lipid metabolism may increase POAG risk by reducing blood flow velocity and changing lipid components in the aqueous humour [24,25]. Apolipoprotein B and apolipoprotein E in the aqueous humour of POAG patients were significantly increased, which may then change cholesterol transport. On the other hand, genetic factors may also modulate the the association between lipid metabolism and risk of POAG. It has been shown that several genes involved in lipid metabolism were significantly related to POAG risk, such as ATP binding cassette subfamily A member 1gene and caveolin 1 gene [28,29].
The aim of this study is to assess the correlation between lipid abnormalities or specific blood lipid levels and the risk of POAG. The results showed that dyslipidemia increased the risk of POAG in cross-sectional and case-control studies, but not in cohort studies. This disparity might be related to the effect of confounding factors. For instance, patients with diagnosed hyperlipidemia were more likely to receive treatment. In a large cohort study by Newman-Casey et al., significant negative correlation between hyperlipidemia and POAG (hazard ratio 0.95, 95% CI 0.91, 0.98) was noted even after correcting for a series of covariates. In previous studies, statins have been shown to reduce the adverse effect of hyperlipidemia on POAG by decreasing intraocular pressure while reducing cholesterol [30]. It is currently unclear whether hyperlipidemia and the use of lipid-lowering medications are independent risk factors for POAG, which should be further clarified in future studies.
For a specific blood lipid parameter, this study did not find that TC and TG were related to an increased risk of POAG. A recent cross-sectional study in Singapore found that high levels of HDL-3 cholesterol were associated with a reduced risk of POAG (OR, 0.91; 95% CI, 0.84-0.99, P = 0:021), but no association was found between conventional lipids (e.g., TC, HDLC, and low-density lipoprotein cholesterol) and POAG [31]. Although we noted a negative corre-lation between HDLC and POAG, it is limited by small sample size and needs further confirmation.
This study suffers from several limitations. First, significant interstudy heterogeneity was noted, which might be related to the diversity of study designs and subject population. However, further subgroup analysis or meta-regression to clarify the source of heterogeneity was difficult due to quantitative limitations. Second, part of the results of this study included less than 10 studies. The funnel plot and asymmetry test methods cannot judge whether the funnel is symmetrical or not due to the low-test performance. More original research is needed in the future to clarify our preliminary conclusions. Third, most of the studies included were cross-sectional or case-control in design, and the number of cohort studies was small, so the causal relationship between dyslipidemia and POAG risk could not be inferred. Fourth, this study failed to clarify the impact of other identified risk factors for POAG. In addition, the OR values reported in some studies were not corrected by covariates, especially intraocular pressure. Finally, this study analyzed the correlations between specific lipid and risk of POAG, providing evidence to clarify the impact of individual lipid on the risk of POAG. However, given the small number of studies included, additional studies are needed in the future to firmly establish this conclusion.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
The authors have no conflicts of interest to declare.