Polypoidal choroidal vasculopathy (PCV) is a choroidal vascular disease of first described in the early 1980s as polypoidal subretinal vascular lesions associated with serous or hemorrhagic detachment of the retinal pigment epithelium (RPE) [
Many studies have indicated lipid deposition in Bruch’s membrane and soft drusen, and the amount of lipid was lower in the peripheral area than in the macula of human eyes [
Thus far, some studies have studied the impact of lipid metabolism-related and systemic lipoprotein genes in PCV. Here, in order to give the comprehensive analysis of effects and solve the controversies, we conduct meta-analysis and report a systematic review by summing up all published articles of genetic associations in the HDLMP of PCV. This study (1) conducted an investigation of which genetic variants of the HDLMP are meaningfully associated with PCV and their effect sizes and (2) analyzed whether there were differences between genetic risks of the HDLMP in PCV and AMD.
We searched EMBASE, PubMed, and Web of Science using the following MeSH terms and free words: (polypoidal choroidal vasculopathy or polypoidal choroidal vascular disease or polypoidal choroidal vascular diseases or PCV) and (cholesteryl ester transfer protein or CETP or hepatic lipase or LIPC or lipoprotein lipase or LPL or ATP-binding cassette transporter A1 or ABCA1 or ATP-binding cassette transporter G1 or ABCG1). All searched articles were published before September 30, 2017, without language restriction. We also screened the reference lists of all eligible studies, reviews, and meta-analyses to ensure that any relevant studies were not omitted. We also searched all reported genome-wide association studies of PCV including the supplementary materials to maximize the usable data. The detail of search strategy is revealed in Table
We included those studies that satisfied the following criteria in the meta-analysis: (1) case-control studies, cohort studies, or population-based studies that evaluated the association of gene variants of CETP/LIPC/LPL/ABCA1/ABCG1 with PCV or its subtypes and (2) allele or genotype counts and/or frequencies being presented or able to be calculated from the data in the study. Case reports, conference reports, reviews, animal studies, and reports with insufficient information were excluded (Table
Two reviewers (Y. M. z. and Y. J. y.) independently reviewed and extracted data from studies on the association between CETP/LIPC/LPL/ABCA1/ABCG1 SNPs and PCV. If there were any differences between them, another two reviewers would help to resolve it (Z. C. x. and H. R. a.) after thorough discussion. The following information was extracted from each article: the name of first author, publication year, ethnicity of the study population, study design, genotyping method, sample size, demographics, allele and genotype distribution (Table
Characteristics of the included studies in the meta-analysis.
First author and reference | Year | Ethnicity | Study design | Genotyping method | HWE reported | PCV | AMD | Control | Gene/loci investigated | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Male ratio | Mean age ± SD (yrs) |
|
Male ratio | Mean age ± SD (yrs) |
|
Male ratio | Mean age ± SD (yrs) | |||||||
Nakata et al. [ |
2013 | Japanese | 1 | TaqMan and Beadchip | Yes | 581 | 0.73 | 72.59 ± 8.13 | — | — | — | 793 | 0.41 | 65.99 ± 4.33 | CETP, LIPC, LPL |
Zhang et al. [ |
2013 | Chinese | 1 | PCR | Yes | 250 | 0.66 | 65 ± 8.6 | 157 | 0.64 | 67 ± 9.21 | 204 | 0.61 | 69 ± 9 | LIPC, ABCA1, CETP, LPL, |
Li et al. [ |
2014 | Chinese | 1 | PCR | Yes | 298 | 0.62 | 66.8 ± 9.7 | 300 | 0.63 | 69.4 ± 8.9 | 296 | 0.48 | 65.1 ± 9.5 | ABCA1 |
Liu et al. [ |
2014 | Chinese | 1 | PCR | Yes | 233 | 0.7 | 68.5 ± 5.9 | 200 | 0.55 | 75.3 ± 7.7 | 275 | 0.44 | 74.3 ± 7.6 | ABCA1, LIPC, CETP, ABCG1 |
Meng et al. [ |
2015 | Chinese | 1 | PCR | Yes | 291 | 0.79 | 66.6 ± 9.6 | 230 | 0.63 | 69.3 ± 8.8 | 221 | 0.48 | 67.2 ± 9.6 | CETP, LIPC, LPL |
Li et al. [ |
2016 | Chinese (Hong Kong) | 1 | TaqMan and PCR | Yes | 236 | 0.69 | 68.5 ± 9 | 235 | 0.55 | 75.3 ± 7.6 | 365 | 0.42 | 74.4 ± 7.7 | ABCG1 |
2016 | Chinese (Shantou) | 1 | TaqMan and PCR | Yes | 187 | 0.72 | 63.1 ± 10.5 | 189 | 0.69 | 67.3 ± 10.1 | 670 | 0.43 | 73.8 ± 6.8 | ABCG1 | |
2016 | Japanese (Osaka) | 1 | TaqMan and PCR | Yes | 204 | 0.77 | 72.2 ± 8.0 | 192 | 0.67 | 74.3 ± 7.3 | 157 | 0.33 | 47.9 ± 15.1 | ABCG1 | |
Qiao et al. [ |
2017 | Chinese (Hong Kong) | 1 | Beadchip | Yes | 156 | — | — | 310 | — | — | 1006 | — | — | CETP |
The characteristics of the eligible studies are shown. PCV: polypoidal choroidal vasculopathy; AMD: age-related macular degeneration; HWE: Hardy–Weinberg equilibrium.
We conducted meta-analysis for each polymorphism which had been reported in ≥2 studies or cohorts. The association was evaluated by different genetic models, including allelic, heterozygous, and homozygous models. For each study, the odds ratio (OR) with 95% confidence interval (95% CI) was calculated to evaluate the strength of association between the each SNP and PCV risk. Moreover, we used the
Figure
Flow diagram and results of literature review. The flow diagram describes the filtering process of related articles, including the number and reason of exclusion. PCV: polypoidal choroidal vasculopathy; AMD: age-related macular degeneration.
As shown in Table
Totally 17 SNPs had been studied in PCV in the literature (Figure
Forest plot of 7 SNPs in PCV in allelic model. The figure shows specific odds ratios (ORs) for study. The size of the box is proportional to the weight of the study. Horizontal lines represent 95% confidence intervals (CIs). A diamond is on behalf of the summary OR with its corresponding 95% CI. (a) CETP rs3764261 (T); (b) LIPC rs493258 (G); (c) LIPC rs10468017 (T); (d) CETP rs2303790 (G); (e) ABVA1 rs1883025 (T); (f) LPL rs12678919 (G); (g) ABCG1 rs57137919 (A).
Meta-analysis of CETP/LIPC/LPL/ABCA1/ABCG1 polymorphisms in PCV.
Region | Gene | Polymorphism | Ethnicity | Associated versus reference allele | Number of cohorts | Sample size (case/control) | OR (95% CI) |
|
|
|
|
|
---|---|---|---|---|---|---|---|---|---|---|---|---|
16q21 |
|
rs3764261 | Asia | T versus G | 4 | 1355/1493 | 1.46 (1.28–1.665) | 5.64 | 0 | 0 | 0.308 | 0.415 |
Chinese | T versus G | 3 | 774/700 | 1.528 (1.268–1.841) | 4.46 | 0 | 0 | >0.999 | 0.071 | |||
9q31 |
|
rs1883025 | Chinese | T versus C | 3 | 781/775 | 0.968 (0.828–1.131) | 0.41 | 0.679 | 78.2 | >0.999 | 0.745 |
9q31 |
|
rs493258 | Asia | G versus A | 3 | 1064/1272 | 1.041 (0.907–1.195) | 0.57 | 0.565 | 0 | >0.999 | 0.867 |
15q22 |
|
rs10468017 | Chinese | T versus C | 3 | 774/700 | 0.849 (0.7–1.028) | 1.68 | 0.094 | 0 | >0.999 | 0.465 |
15q22 |
|
rs12678919 | Asia | G versus A | 3 | 1122/1218 | 0.972 (0.814–1.161) | 0.32 | 0.751 | 0 | >0.999 | 0.799 |
21q22 |
|
rs57137919 | Asia | A versus G | 4 | 860/1467 | 1.168 (1.016–1.343) | 2.18 | 0.029 | 61.5 | >0.999 | 0.808 |
16q21 | CETP | rs2303790 | Asia | G versus A | 5 | 1312/5479 | 1.57 (1.258–1.96) | 3.99 | 0 | 0 | >0.999 | 0.527 |
Summary of the allelic associations of CETP/LIPC/LPL/ABCA1/ABCG1 polymorphisms in PCV. PCV: polypoidal choroidal vasculopathy; AMD: age-related macular degeneration; OR: odds ratio; CI: confidence intervals.
CETP rs3764261 is the most widely investigated SNP in PCV, with a number of 1355 cases and 1493 controls studied for the meta-analysis [
We identified 6 studies in which both PCV and AMD were assessed for associations with a total of 7 SNPs in 5 genes (i.e., CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919) (Table
Meta-analysis of CETP/LIPC/LPL/ABCA1/ABCG1 polymorphisms compared between PCV and AMD.
Region | Gene | Polymorphism | Ethnicity | Associated versus reference allele | Number of cohorts | Sample size (PCV/AMD) | OR (95% CI) |
|
|
|
|
|
---|---|---|---|---|---|---|---|---|---|---|---|---|
16q21 |
|
rs3764261 | Chinese | T versus G | 3 | 774/587 | 1.17 (0.971–1.409) | 1.65 | 0.178 | 33.6 | >0.999 | 0.572 |
9q31 |
|
rs1883025 | Chinese | T versus C | 3 | 781/775 | 1.025 (0.869–1.208) | 0.29 | 0.77 | 0 | >0.999 | 0.832 |
9q31 |
|
rs493258 | Chinese | G versus A | 2 | 483/357 | 1.123 (0.897–1.407) | 1.01 | 0.312 | 0 | >0.999 | — |
15q22 |
|
rs10468017 | Chinese | T versus C | 3 | 774/587 | 1.101 (0.892–1.359) | 0.89 | 0.371 | 0 | 0.296 | 0.483 |
15q22 |
|
rs12678919 | Asia | G versus A | 2 | 541/387 | 1.163 (0.861–1.572) | 0.98 | 0.325 | 0 | >0.999 | — |
21q22 |
|
rs57137919 | Asia | A versus G | 4 | 860/816 | 1.208 (1.035–1.411) | 2.39 | 0.017 | 0 | 0.734 | 0.156 |
16q21 | CETP | rs2303790 | Asia | G versus A | 5 | 1312/1314 | 1.067 (0.825–1.378) | 0.49 | 0.622 | 0 | 0.462 | 0.299 |
Summary of the genetic difference in CETP/LIPC/LPL/ABCA1/ABCG1 polymorphisms between PCV and AMD is shown. PCV: polypoidal choroidal vasculopathy; AMD: age-related macular degeneration; OR: odds ratio; CI: confidence interval.
Forest plot of SNPs compared between PCV and AMD in allelic model. The figure shows specific odds ratios (ORs) for study. The size of the box is proportional to the weight of the study. Horizontal lines represent 95% confidence intervals (CIs). A diamond is on behalf of the summary OR with its corresponding 95% CI. (a) ABCG1 rs57137919 (A); (b) CETP rs2303790 (G); (c) CETP rs3764261 (T); (d) ABCA1 rs1883025 (T); (e) LIPC rs493258 (G); (f) LIPC rs10468017 (T); (g) LPL rs12678919 (G).
In theory, due to the limited number of available studies, it is not suitable for publication bias analysis. But in order to make this meta-analysis more powerful and more creditable, we used funnel plots and Begg’s/Egger’s test to detect publication bias. Begg’s test and Egger’s test suggested an absence of publication bias in the all SNPs (
In the systematic review and meta-analysis, we have summarized the association profiles of genes in the HDLMP in PCV and assessed the genetic difference in the HDLMP between PCV and AMD for the first time (i.e., CETP, LIPC, LPL, ABCA1, and ABCG1). We found significant association between reported CETP rs2303790/rs3764261, ABCG1 rs57137919, and PCV. Also, we identified ABCG1 rs57137919 showing significant differences between PCV and AMD. In contrast, LIPC rs10468017/rs493258, LPL rs12678919, and ABCA1 rs1883025 were not statistically significant in PCV and reported SNPs in 4 genes in the HDLMP (i.e., CETP, LIPC, LPL, and ABCA1) showed no significant differences between PCV and AMD.
CETP can make oxidized lipids transfer from the outer segments of the photoreceptors or other membranes to HDL-like lipoprotein particles. The particles are internalized by RPE and excreted back into the circulation via ABCG1 transporters through Bruch’s membrane [
In the studies (including 3 in Chinese [
From the studies [
From our meta-analysis, we found other 4 SNPs (LIPC rs10468017/rs493258, LPL rs12678919, and ABCA1 rs1883025) were not statistically significant in PCV and AMD. Besides, the associations of eleven SNPs in CETP/LIPC/ABCA1/ABCG1 were reported in only 1 study [
Another recent study reported that LIPC rs1532085 conferred an increased risk for PCV (A allele;
In conclusion, our systematic review and meta-analysis has provided an overview of the association profiles of genes in the HDLMP in PCV for the first time and assessed the genetic difference in the HDLMP between PCV and AMD. The results suggest that CETP (rs3764261/rs2303790) and ABCG1 (rs57137919) are the major susceptibility genes for PCV in the Asian population, and ABCG1 (rs57137919) has different effects in PCV and AMD in the Asian population. However, due to the small pooled sample size for PCV and AMD, further studies of these genes in larger samples are warranted to confirm the association of gene variations in the HDLMP with PCV in other populations such as Caucasian and Australian. Moreover, further studies should focus on the genotype-phenotype correlations and the relevance of genotype to therapy in PCV, which may provide us the clues about the pathogenesis of PCV.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Table S1: the search strategy applied in all databases. Table S2: lists of included/excluded studies with reasons. Table S3: Hardy–Weinberg equilibrium of polymorphisms in control subjects. Table S4: quality assessment of each study based on the Newcastle–Ottawa Scale. Table S5: the number of studies for CETP/LIPC/LPL/ABCA1/ABCG1 polymorphisms in PCV. Figure S1: funnel plot of 7 SNPs in PCV in the allelic model. Figure S2: funnel plot of 7 SNPs compared between PCV and AMD in the allelic model.