Methodological quality of the review: Low confidence

Author: Rongfeng L, Minjie Y, Xiping X

Geographical coverage: United Kingdom (UK), United States of America (USA), China, Japan, Saudi Arabia, Germany, Tasmania

Sector: Glaucoma

Sub-sector: Primary angle glaucoma, Alzheimer’s

Equity focus: None specified

Review type: Meta-analysis

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background: The second most common cause of blindness in the world, glaucoma is grouped within the family of degenerative diseases. Disease manifestation involves visual field loss and optic nerve degeneration. Primary open-angle glaucoma (POAG) is a leading type of primary glaucoma and is characteristically expressed by an open anterior chamber angle and elevated intraocular pressure (IOP), without other co-morbidities.

Disease progression in POAG is slow, the symptoms develop gradually and are concealed. Diagnosis is consequently late until irreversible damage has been sustained. Because of this delayed diagnosis, the pathogenesis of POAG is not fully understood. Previous studies have identified multiple genes and epigenetic factors of POAG, of which only three genes (GLC1A [myocilin, MYOC, OMIM 601652], GLC1E [optineurin, OPTN; OMIM 602432] and GLC1G [WD repeat domain 36, WDR36; OMIM 609669]) have had their involvement confirmed.

The relationship between Alzheimer’s disease (AD) and POAG has recently gained traction, with research confirming a strong association. This relationship is enhanced by the retinal ganglion cells and optic nerve degeneration occurring in patients with AD. One of the major genetic risk factors in AD is apolipoprotein E (APOE; OMIM 107741). This protein is vital to the transportation of cholesterol and triglyceride. The identification of these risk factors has led to investigations focusing on associations between POAG and AD by centering on the APOE gene and its variants.

To date, the mechanism of the relationship between the APOE gene and POAG has no real consensus, with conflicting findings from different authors. To clarify, the authors conducted a systematic meta-analysis to ascertain the associations between APOE polymorphisms and the risk of POAG.

Objectives: To study the association of apolipoprotein E (APOE) polymorphisms and primary open-angle glaucoma (POAG).

Main findings: Twelve studies were included in this meta-analysis, which used a range of measures that were clinically relevant. The thematic focus of this study was to determine if the APOE gene had a role to play in POAG. The studies included multiple ethnic populations. Review findings suggest a relationship between genotype ε4/ε4 and the risk of POAG, although this is a claim based on ethnic grounds – the authors express that this discrepancy between Asian and Caucasian populations may be due to differences in lifestyle, environmental factors, nutrition and genetic factors. Overall, the meta-analysis indicated that the ε4/ε4 genotype is associated with increased risk of POAG in Asian people.

Authors note that the population size of the meta-analysis was reduced due to a lack of representation of the different genotypes between the studies. In turn, the need for larger, more comparative population sizes was raised.

Methodology: The data was obtained from PubMed, Web of Science, EMBASE and China National Knowledge Infrastructure (CNKI). The following index terms were used in the search strategy to include all possible studies: APOE OR apolipoprotein E and primary open-angle glaucoma or POAG or high-tension glaucoma or HTG or normal tension glaucoma or NTG.

The selected articles were included based on the following criteria: case-control studies, reports on the association between APOE polymorphisms and POAG, studies with full-text articles, and the number of APOE genotypes/alleles in the case and control groups that were calculated. The reference group in the study was the genotype ε3/ε3. Seven genetic models were analysed (ε2/ε2 versus ε3/ε3, ε2/ε3 versus ε3/ε3, ε2/ε4 versus ε3/ε3, ε3/ε4 versus ε3/ε3, ε4/ε4 versus ε3/ε3, allele ε2 versus allele ε3, and allele ε4 versus allele ε3). Two independent investigators reviewed the articles, and extracted and evaluated the quality of the data.

Statistical analysis was carried out by Stata 11.0 (StataCorp, College Station, TX). The odds ratio (OR) and 95% confidence interval (CI) were expressed as a means of association between APOE polymorphisms and risk of POAG. The I2 statistic was used to measure the effects of heterogeneity. The fixed-effects model (the Mantel-Haenszel method) or the random-effects model (the DerSimonian-Laird method) were used to calculate the odds ratio according to the heterogeneity. Sub-group analyses were performed based on ethnicity and POAG sub-type. A chi-square test was applied to assess if the genotype distributions of the control group reported conformed to Hardy-Weinberg equilibrium (HWE; p≤0.05 was representative of statistical significance). Funnel plots and Egger’s regression test were used to evaluate publication bias visually.

Applicability/external validity: The authors of the review advised taking into consideration the limitations of this study. Due to these limitations, further studies need to be carried out before any applicability or validity can be taken into account.

Geographic focus: The review included studies from different geographical locations, some of them being low/middle-income countries.

Summary of quality assessment: Low confidence was attributed in the conclusions about the effects of this study as important limitations were identified. The review didn’t avoid certain biases, but acknowledged them. There was no mention of a search timeframe. The authors did not conduct a comprehensive search through the reference list of the included studies. The quality assessment and risk of bias were not carried out, which questions the reliability of the evidence used in the included studies.