Elsevier

Ophthalmology

Volume 123, Issue 6, June 2016, Pages 1211-1221
Ophthalmology

Original article
Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-analysis

https://doi.org/10.1016/j.ophtha.2015.12.027Get rights and content

Topic

Systematic review and meta-analysis of the genetic associations of primary angle-closure disease (PACD).

Clinical Relevance

To confirm the genetic biomarkers for PACD, including primary angle-closure glaucoma (PACG) and related phenotypes.

Methods

We searched in the MEDLINE and EMBASE databases for genetic studies of PACG or other PACD published from the start dates of the databases to May 11, 2015. We estimated the summary odds ratios (ORs) and 95% confidence intervals (CIs) for each polymorphism in PACG, primary angle-closure suspect (PACS), and primary angle-closure (PAC) using fixed- or random-effect models. We also performed sensitivity analysis to test the robustness of the results.

Results

Our literature search yielded 6463 reports. Among them, we identified 24 studies that fulfilled the eligibility criteria for meta-analysis, involving 28 polymorphisms in 11 genes/loci. We affirmed the association of PACG and combined PACS/PAC/PACG with 10 polymorphisms in 8 genes/loci, including COL11A1 (rs3753841-G, OR, 1.22; P = 0.00046), HGF (rs17427817-C, OR, 2.02; P = 6.9E-07; rs5745718-A, OR, 2.11; P = 9.9E-07), HSP70 (rs1043618, GG+GC, OR, 0.52; P = 0.0010), MFRP (rs2510143-C, OR, 0.66; P = 0.012; rs3814762-G, OR, 1.40; P = 0.0090), MMP9 (rs3918249-C, OR, 1.35; P = 0.034), NOS3 (rs7830-A, OR, 0.80; P = 0.036), PLEKHA7 (rs11024102-G, OR, 1.24; P = 8.3E-05), and PCMTD1-ST18 (rs1015213-A, OR, 1.59; P = 0.00013). Sensitivity analysis indicated that the results were robust.

Conclusions

In this study, we confirmed multiple polymorphisms in 8 genes/loci as genetic biomarkers for PACD, among which 3 were identified in a genome-wide association study (COL11A1, PLEKHA7, and PCMTD1-ST18), and 5 were identified in candidate gene studies (HGF, HSP70, MFRP, MMP9, and NOS3).

Section snippets

Search Methods for Identifying Studies

We conducted the literature search in the EMBASE and MEDLINE databases via the Ovid platform. We adopted sensitive search strategies using the Boolean logic and search terms with controlled vocabularies (i.e., Medical Subject Heading terms): (“polymorphism(s)” OR “mutation” OR “genotype(s)” OR “genetic(s)” OR “gene(s)” OR “allele(s)” OR “DNA”) AND (“glaucoma” OR “angle closure”) (Table 1, available at www.aaojournal.org). In addition, we manually screened the references of the research

Inclusion of Studies

We identified a total of 8459 records published between 194831 and May 4, 2015,32, 33 from MEDLINE and EMBASE. After removing 1996 duplicates, we evaluated 6463 citations and selected 55 articles for full-text assessment. Among them, 41 were genetic studies (Fig 1), including 34 candidate gene association studies involving 49 genes, 5 re-sequencing studies of 10 nuclear genes,34, 35, 36, 37 and the mitochondrial sequence.38 The remaining 2 were GWAS that identified 4 genetic loci.14, 15 The 2

Discussion

This is the first systematic review and meta-analysis of all reported genetic associations of PACD, including PACG and relevant phenotypes. We confirmed the associations of the 3 GWAS loci (PLEKHA7, COL11A1 and PCMTD1-ST18)14 with PACG, and PCMTD1-ST18 with combined PACS and PAC. Moreover, we affirmed 5 genes, which were identified by candidate gene studies, to be associated with PACD. Among them, 4 genes (HGF, MFRP, MMP9, and NOS3) were associated with PACG, and 1 gene (HSP70) was associated

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      Notably, two of the loci (PLEKHA7 and FERMT2) are also associated with risk of increased IOP (Khawaja et al., 2018b; MacGregor et al., 2018), underlining the key contribution of IOP to PACG disease as well as possible shared mechanisms with POAG. These loci have been replicated in many follow-up studies that dissect the association of these loci to PACG disease severity (Awadalla et al., 2013; Duvesh et al., 2013; Nongpiur et al., 2018; Rong et al., 2016; Shi et al., 2013; Wan et al., 2019). The results largely support the association of these loci with PACG risk, despite heterogeneity in the clinical presentation, ethnic make-up, and sample sizes of cohorts.

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      Heterogeneity was assessed by I2 (Higgins and Thompson, 2002). A I2 value greater than 25% indicates a moderate to high inter-study heterogeneity (Higgins and Thompson, 2002; Higgins et al., 2003; Rong et al., 2016b). To obtain more conservative results we calculated the summary OR and 95% CI only using the random-effect model (Rong et al., 2017), in which the weighted effect of a SNP was estimated by inverse variance (IV) and τ2 from the DerSimonian-Laird estimator (Dersimonian and Laird, 1986).

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    Supplemental material is available at www.aaojournal.org.

    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    Author Contributions:

    Conception and design: Rong, Chen

    Data collection: Rong, FY Tang, Ma, Yam, SM Tang, Li, Gu, Chen

    Analysis and interpretation: Rong, FY Tang, Chu, SM Tang, Li, Gu, Young, Tham, Pang, Chen

    Obtained funding: Not applicable

    Overall responsibility: Rong, Chu, Ma, Yam, Young, Tham, Pang, Chen

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