Systematic Review and Meta-Analysis of the Association
between Complement Factor H I62V Polymorphism and
Risk of Polypoidal Choroidal Vasculopathy in Asian
Zhao-Yang Wang1,2., Keke Zhao2., Jingwei Zheng3, Brian Rossmiller2, Cristhian Ildefonso2,
Manas Biswal2, Pei-quan Zhao1*
1Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, 2Departments of Molecular Genetics, University of
Florida, Gainesville, Florida, United States of America, 3Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Purpose: To investigate whether the polymorphism rs800292 (184G.A, I62V) in the complement factor H gene is
associated with polypoidal choroidal vasculopathy (PCV) and the genetic difference between PCV and neovascular age-
related macular degeneration (nAMD), in Asian populations.
Methods: A comprehensive literature search was performed in PubMed, Medline, Web of Science, and reference lists. A
system review and meta-analysis of the association between I62V and PCV and/or nAMD were performed from 8 studies
involving 5,062 subjects. The following data from individual studies were extracted and analyzed: 1) comparison of I62V
polymorphisms between PCV and controls; 2) comparison of I62V polymorphisms between PCV and nAMD. Summary odds
ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effects models. The Q-statistic test was used to
assess heterogeneity, and Egger’s test was used to evaluate publication bias. Sensitivity analysis and cumulative meta-
analysis were also performed.
Results: The I62V polymorphism showed a significant summary OR1for genotype GA+GG versus homozygous genotype AA
was 3.18 (95% CI, 2.51–4.04, P,0.00001), the OR2of heterozygous genotype GA versus AA was 2.29 (95% CI: 1.79–2.94, P,
0.00001), the OR3of homozygous genotype GG versus AA was 4.42 (95% CI: 3.45–5.67, P,0.00001), and the OR4of allele G
versus A was 2.04 (95% CI: 1.85–2.26, P,0.00001). Sensitivity analysis indicated the robustness of our findings, and evidence
of publication bias was not observed in our meta-analysis. Cumulative meta-analysis revealed that the summary ORs were
stable. There was no significant difference in every genetic model between PCV and nAMD (n=5, OR1=0.92, OR2=0.96,
Conclusions: Our analysis provides evidence that the I62V polymorphism is associated with an increased risk of PCV. The
variant of I62V could be a promising genetic biomarker of PCV in Asian populations.
Citation: Wang Z-Y, Zhao K, Zheng J, Rossmiller B, Ildefonso C, et al. (2014) Systematic Review and Meta-Analysis of the Association between Complement Factor
H I62V Polymorphism and Risk of Polypoidal Choroidal Vasculopathy in Asian Populations. PLoS ONE 9(2): e88324. doi:10.1371/journal.pone.0088324
Editor: Michael G. Anderson, University of Iowa, United States of America
Received September 6, 2013; Accepted January 6, 2014; Published February 10, 2014
Copyright: ? 2014 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by Project of the National Natural Science Funds of China (No. 81371040, 81070760 and No. 81100677), and Shanghai Rising-
Star Program (No. 12QA1402200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
. These authors contributed equally to this work.
Polypoidal choroidal vasculopathy (PCV) is a hemorrhagic and
exudative macular disorder that is characterized by inner
branching choroidal networks with surrounding polypoidal
dilatation of the choroidal vessels, which can be clearly demon-
strated by indocyanine green angiography .
PCV can occur in any gender or race, but it is more commonly
seen in Asians than in Caucasians, accounting for 24.5% of
patients with findings suggestive of neovascular age-related
macular degeneration (nAMD) in the Chinese population ,
for 24.6% in the Korean population , for 54.7% in the Japanese
population , but for only about 4–9.8% in Caucasians. .
PCV is categorized by some experts as a subtype of nAMD,
[4,5] but others consider it as a different disease entirely. [3,6–8]
Clinically, PCV shares several common manifestations with
nAMD, such as subretinal exudation and hemorrhage involving
the macular region. However, important differences have been
noted that patients with PCV are younger and more likely Asians.
Their eyes are lack of drusen, often occurrence with serosanguin-
ous maculopathy or hemorrhagic pigment epithelial detachment.
They show different responses to photodynamic therapy and
PLOS ONE | www.plosone.org1 February 2014 | Volume 9 | Issue 2 | e88324
therapy involving anti-vascular endothelial growth factor (VEGF)
There are also significant differences in angiographic and
optical coherence tomography features between PCV and nAMD.
Histopathological studies suggest differences in the anatomical
details of the associated vascular abnormalities in the retina and
choroids and the relative role of VEGF. These similarities and
differences have been a subject of much interest and debate
regarding whether the vascular abnormality in PCV represents
neovascularization or a phenotype distinct from choroidal
neovascularization (CNV). .
The etiology of PCV remains largely unknown. It is known as a
multifactorial disease due to multiple environmental risk factors
and genetic factors or to the interactions between these. The
phenotypic similarities between PCV and nAMD lead to the
hypothesis that genes involved in AMD may also play a role in
Figure 1. The literature search process. Flow diagram depicts the screening process of retrieved articles, including the reason for and number of
exclusions. CFH=complement factor H; PCV=polypoidal choroidal vasculopathy.
Table 1. Main Characteristics of the Studies Included in the Meta-Analysis.
Totlal (N) Average Age(yrs) Gender Ratio(M/F)
PCVnAMD ControlPCV nAMDControlPCV nAMD Control
2013Japanese 175NA 15074.267.5
NA72.165.6147/28 NA116/34 Case
2013Chinese250157 204 6568.6 6769.2 6969.0166/84101/56124/80Cohort
2013 Japanese 87* 97* NA71.568.4 74.868.3 NA 70/1776/21NA Case
2012Thai97 NA 102 62.968.9 NA62.267.648/49 NA 50/52Case
2011Japanese 381 253 27722.214.171.124.767.572.968.7 271/110 188/65 111/166Case
2010 Japanese518*408* 1351*75.168.5 77.768.451.2616.3 381/137 293/115722/629Case
2009 Japanese100*100*190* 72.768.374.668.8 72.268.5 81/1973/27 86/104Case
72NA 93 63.867.6NA 67.264.646/26NA 40/53Case
NA=not available; nAMD=neovascular age-related macular degeneration; PCV=polypoidal choroidal vasculopathy.
*The number of cases or controls was changed in the next meta-analysis, but the reason was not given.
CFH I62V Polymorphism and Risk of PCV
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Table 2. Allele and Genotype Distribution of the I62V Polymorphism.
HWE=HardyeWeinberg equilibrium; NA=not available; nAMD=neovascular age-related macular degeneration; PCV=polypoidal choroidal vasculopathy.
CFH I62V Polymorphism and Risk of PCV
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PCV.  Therefore, investigators have now focused on comparing
these two entities to discover if these two different phenotypes can
be attributed to genetic differences that may reveal different
underlying pathogenic mechanisms. Several candidate genes such
as complement factor H (CFH), high temperature required factor
A1 (HTRA1), and age-related maculopathy susceptibility 2
(ARMS2) have been reported to increase the risk of AMD and
PCV development. [10–12] The CFH I62V coding variant
(rs800292) on chromosome 1q32 has been extensively studied
via genetic and molecular approaches, which provide strong
statistical evidence for disease association and a plausible biologic
context supporting this variant as an attractive candidate for a
causal polymorphism leading to the development of AMD and
PCV. [13–15] However, the population heterogeneity and
relatively small sizes studies warrant confirmation of the associ-
ation of I62V with PCV across different studies in different
populations. Here we conducted a meta-analysis of previous
studies representing an assessment of the association between the
Figure 2. Forest plots of meta-analysis of the association between I62V polymorphism and PCV. Odds ratios (black squares) and 95%
confidence intervals (bars) are given for each study. Also shown are the diamonds of the summary ORs based on the Mantel–Haenszel fixed-effects
model (M-H Overall). CI=confidence interval; OR=odds ratio. A: OR1(GG+GA vs AA); B: OR2(GA vs AA); C: OR3(GG vs AA); D: OR4(G vs A).
Table 3. Meta-analysis compared the allelic frequencies of I62V between PCV and nAMD.
Sample Size Test of Association Test of Heterogeneity
PolymorphismStudies(N) PCV nAMD Statistical MethodOR (95% CI)P ValueI2%
(GA+GG) vs AA5 1317 993Odds Ratio (M-H, Fixed, 95% CI) 0.92 [0.65, 1.30] 0.480
GA vs AA5 588 423 Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.67, 1.38] 0.2722
GG vs AA5 813 629Odds Ratio (M-H, Fixed, 95% CI) 0.90 [0.63, 1.27]0.690
G vs A5 2634 1986Odds Ratio (M-H, Fixed, 95% CI) 0.94 [0.82, 1.07]10
CI=confidence interval; M-H=Mantel–Haenszel model; nAMD=neovascular age-related macular degeneration; OR=odds ratio; PCV=polypoidal choroidal
CFH I62V Polymorphism and Risk of PCV
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CFH I62V variant and PCV and/or nAMD, comprising a total of
5,062 subjects, to more reliably compare the genetic effect of CFH
I62V between PCV and nAMD.
Materials and Methods
Identification and Eligibility of Relevant Studies
This meta-analysis was conducted according to the PRISMA
guidelines.  We searched PubMed, Medline and Web of
Science using the following search terms: (‘‘polypoidal choroidal
vasculopathy’’ OR ‘‘PCV’’) and (‘‘CFH’’ OR ‘‘complement factor
H’’), and other alternative names (I62V, Val62Ile,184G.A,
rs800292). All related articles should have been published before
Aug 31, 2013 and without any language limitation.
Studies were included only if they fulfill all of the following five
criteria: (1) All patients had a complete ophthalmic examination,
including fundus photography, and fluorescent or indocyanine
green angiography (ICG). The diagnostic criteria of PCV was
based on these clinical features and ICG showing a branching
vascular network terminating in polypoidal swelling. The diag-
nostic criteria of nAMD based on the clinical features and grading
were classified using a standard grid suggested by the International
Age-related Maculopathy Epidemiologic Study Group for age-
related maculopathy. (2) Study design was limited to case-control
study, cohort study, or population-based epidemiologic survey, not
a review, case report, or editorial comment. (3) The major study
objective was to evaluate the association between CFH I62V
polymorphism and PCV and/or nAMD. (4) Raw data of allele or
genotype frequencies or counts available. Allele was A/G, and the
genotypes covered AA, AG, and GG. (5) For studies published by
the same group on the same gene and markers, only the most
recent report or the report with the largest sample size was
included for analysis.
Two reviewers (Z.Y.W. and K.K.Z.) independently extracted
the data and evaluated the quality. The following variables were
extracted from each study: the name of the first author, year of
publication, ethnicity, phenotype of cases evaluated, sample size,
mean age and sex ratio of study participants, and allele and
genotype distributions in cases and controls. If publications listed
allele and genotype counts stratified according to the PCV sub-
phenotype, they were combined into one case group.
Independent review and resolution by a third reviewer (P.Q.Z.)
was sought if the two reviewers disagreed.
Figure 3. Results of Leave-One-Out Sensitivity Analysis. The horizontal axis shows the omitted study. The horizontal axis represents the odds
ratio. Every circle indicates the pooled OR when the left study is omitted in this meta-analysis. The two ends of every broken line represent the
respective 95% confidence interval. A: OR1(GG+GA vs AA); B: OR2(GA vs AA); C: OR3(GG vs AA); D: OR4(G vs A).
CFH I62V Polymorphism and Risk of PCV
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Hardy-Weinberg Equilibrium (HWE) was tested by the exact
test to compare the observed genotype frequencies with the
expected genotype frequencies within the control subjects.  To
investigate the associations of I62V polymorphism with PCV, the
allele and genotype frequencies of the SNPs between PCV and
controls were compared. To determine whether PCV and nAMD
have different genetic risks, the allele frequencies of the SNPs were
compared between patients with PCV and nAMD in the studies
that included both disorders. The following four odds ratios (ORs)
and their 95% confidence intervals (95% CIs) were calculated in
each study: OR1for (GG+GA) versus AA, OR2for GA versus AA,
OR3for GG versus AA, and OR4for allele G versus A.
Between-study heterogeneity was assessed by the Q-statistic test
and I2statistic. [18,19] A P value ,0.1 was considered statistically
significant for the Q-statistic test.  I2ranges between 0% and
100% (where a value of 0% represents no heterogeneity) and
larger values represent increasing heterogeneity. The fixed-effects
estimates were described in the text for originally homogenous or
post hoc homogenized datasets. If there was evidence of between-
study heterogeneity, random-effects estimates were described.
To assess the publication bias and small-study bias, a funnel plot
of the data was applied. In addition, Egger’s test was used to detect
publication bias.  A leave-one-out sensitivity analysis was
performed by iteratively removing 1 study at a time to confirm
that our findings were not driven by any single study. Cumulative
meta-analysis was performed to evaluate the accumulation of
evidence on the association between CFH I62V and PCV. The
results of individual studies were pooled using the software Review
Manager (version 5.2, the Cochrane Collaboration, Oxford,
England; available at: http://ims.cochrane.org/revman. Accessed
June 30, 2013). All other statistical analysises were performed
using Stata software (version 11.0; Stata Corporation, College
Station, TX). All tests were 2-tailed. A P value ,0.05 was
considered statistically significant except for the test of between-
Eligibility of Studies
A total of 113 relevant studies were identified by our initial
search, of which 8 studies were eligible for inclusion in the review.
[21–28] Two of these studies did not have genotype information,
but authors kindly provided supplementary information. [22,23]
Figure 1 shows the flow chart of the selection process used to
identify the studies concerned. Table 1 lists the studies included in
the meta-analysis together with summary characteristics of study
subjects. The combined sample size for this meta-analysis was
5,062, which included 1,680 PCV patients, 1,015 nAMD patients
and 2,367 controls. The average ages ranged from 63.8 to 75.7
years in PCV groups, 67.0 to 77.7 years in nAMD groups and 51.2
to 72.2 years in control groups. Gender ratios (male/female) in the
3 groups varied from 0.98 (48/49) to 5.28 (147/28) in PCV
groups, 1.80 (101/56) to 3.62 (76/21) in nAMD groups, and from
0.67 (111/166 ) to 3.41 (116/34) in control groups. All studies,
except 1 study  was cohort design, were case–control designs
with subjects of Asian ancestry, 5 studies were conducted in Japan,
1 study was conducted in China, 1 study was conducted in
Singapore, 1 study was conducted in Thailand (Table 1).
Allele and genotype distributions for the I62V polymorphism
from individual studies are shown in Table 2. Except one study not
observing HWE , and one study without a control group ,
all other studies observed HWE and were included in pooling
Figure 4. Cumulative meta-analysis of the association between I62V polymorphism and PCV. Every circle represents the pooled OR
when studies accumulated over time, and the horizontal line represents the 95% confidence interval of pooled OR. A: OR1(GG+GA vs AA); B: OR2(GA
vs AA); C: OR3(GG vs AA); D: OR4(G vs A).
CFH I62V Polymorphism and Risk of PCV
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We initially performed a meta-analysis based on different
genetic models between PCV and Control groups. In the fixed-
effects model, the pooled OR1for the risk allele (GA+GG) versus
AA was 3.18 (95% CI, 2.51–4.04, P,0.00001), pooled OR2for
GA versus AA was 2.29 (95% CI: 1.79–2.94, P,0.00001), pooled
OR3 for GG versus AA was 4.42 (95% CI: 3.45–5.67, P,
0.00001), and pooled OR4for the risk allele G versus A was 2.04
(95% CI: 1.85–2.26, P,0.00001) (Figure 2). The heterogeneity
tests of these 4 comparisons are also shown in Figure 2.
We also calculated four summary ORs between PCV group and
nAMD group. No significant difference between PCV and nAMD
(n=5, OR1=0.92, OR2=0.96, OR3=0.90, OR4=0.94) was
found in each genetic model (Table 3).
Sensitivity Analysis and Cumulative Meta-Analysis
To evaluate the robustness of the association results, we
performed a leave-one-out sensitivity analysis by iteratively
removing one study at a time and recalculating the summary
OR. The summary ORs remained stable (Figure 3), indicating
that our results were not driven by any single study and that
similar results could be obtained after excluding the two study not
observing the HWE.
The cumulative meta-analysis revealed that the summary ORs
were very high in the first two studies but did not vary much after
the third study (Figure 4).
We assessed publication bias using Egger’s test. No statistically
significant evidence of publication bias was detected for the OR1
(P=0.12), OR2(P=0.10), OR3(P=0.11) and OR4(P=0.82).
The reliable assessment of the association between CFH I62V
and PCV has been hindered in low frequency of variant alleles and
small sample sizes in studies. To overcome these barriers, we
performed a systematic meta-analysis to summarize the evidence
to date regarding the association between CFH I62V and PCV,
representing a pooled total of 6 case-control and 1 cohort studies
between PCV and Control, 5 case-control studies between PCV
and nAMD, involving 5,062 subjects.
Our meta-analysis focused on the association between the CFH
I62V polymorphism and PCV risk specifically. The results indicate
a strong association between CFH I62V and PCV with no
evidence of publication bias. The ORs of all comparisons
supported the view that I62V is a risk factor for PCV in Asian
populations, and these results also showed that the G allele might
be a PCV-causing locus and that the GG homozygote genotype
(4.4-fold) had a stronger effect than the GA heterozygote genotype
(2.3-fold) with a significant dose response correlation. In individ-
uals carrying at least one copy of the risk allele, disease risk was
increased by 3.2-fold.
In addition, sensitivity analyses by iteratively removing one
study at a time including one study not observing HWE  and
one study without control group  with the leave-one-out
sensitivity analysis showed similar and consistent result, thus
indicating the robustness of our findings.
CFH is a critical negative regulator of the alternative pathway of
the complement system. It binds to C3b, promotes the decay of C3
convertase, and serves as a cofactor for the factor I–mediated
proteolytic inactivation of C3b, resulting in the inhibition of the
complement cascade.  The CFH gene is found on the 1q32
region. Although the pathogenetic mechanism of CFH leading to
PCV is still unclear, the I62V coding variant (rs800292) in CFH
has been extensively studied via genetic and molecular approach-
es, which provide strong statistical evidence for disease association
and a plausible biologic context supporting this variant as an
attractive candidate for a causal polymorphism leading to the
development of AMD and PCV. [13–15] Recently, one meta-
analysis, reported by Yuan et al , demonstrated that the I62V
polymorphism is significantly associated with AMD in Asian
populations but there is no link in Caucasian populations. In the
current study, we provide evidence that the I62V polymorphism is
associated with an increased risk of PCV. There was no significant
difference in every genetic model between PCV and nAMD (n=5,
OR1=0.92, OR2=0.96, OR3=0.90, OR4=0.94) in our study.
Our meta-analysis did not found any heterogeneity in each of
the OR. To minimize the bias of our research, we did not use the
option of language limitation on PubMed, Medline, or Web of
Science, and all previous studies that met our criteria were
included. The study must be published in peer-reviewed journals;
second, we collected the nAMD data in our studies, excluding the
data of dry AMD and other type of wet AMD, such as Retinal
angiomatous proliferation; third, all studies which fulfill the
inclusion criteria were conducted with subjects of Asian ancestry,
5 studies were conducted in Japan, 1 study was conducted in
China, 1 study was conducted in Singapore, 1 study was
conducted in Thailand. We didn’t find any evidence or study
about CFH I62V and PCV with subjects of Caucasian, Africa and
other populations based upon our search strategy. Chen et al 
also reported that the polymorphisms at CFH, LOC387715,
HTRA1, and C2 were found to be significantly associated with
PCV, which was similar to our conclusions. But in their research
the number of included studies was 5, which were all included in
Several limitations of this meta-analysis should be acknowl-
edged. First, there were a limited number of original studies, and
all reports were on Eastern Asians. There were no reports on
research involving Caucasian, Africa or other populations. These
conclusions remain to be confirmed by further research. Second,
because the allele and genotype data were not available in several
studies, [13,32,33] our meta-analysis may have not included all the
studies that have been published. Third, by studying CFH I62V
polymorphism and other CFH polymorphisms (e.g., Y402H, C3
and CFB) in this population, it may be useful to understand the
effect of these variations on the onset and progression of PCV.
In conclusion, our analysis provides evidence that the CFH
I62V polymorphism is associated with an increased risk of PCV in
the Asian population. We found that Asian patients with the CFH
I62V variant might have a higher risk of developing PCV
compared with controls. Our results expand the number of
confirmed PCV susceptibility loci for Asian populations and
provide a better understanding of the genetic architecture
underlying disease susceptibility. The potential for preclinical
prediction in future genetic testing may advance by combined
evaluation of inherited susceptibility with previously established
loci. Further investigations are necessary to confirm the roles of the
CFH I62V polymorphism reported in a limited number of original
studies. Genetic analysis might provide timely preclinical predic-
tion, prevention, and treatment for PCV.
Flow Diagram S1
PRISMA Flow Diagram.
CFH I62V Polymorphism and Risk of PCV
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Conceived and designed the experiments: ZYW PQZ KKZ. Performed the
experiments: KKZ ZYW. Analyzed the data: JZ ZYW KKZ. Contributed
reagents/materials/analysis tools: BR CI MB. Wrote the paper: ZYW BR
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CFH I62V Polymorphism and Risk of PCV
PLOS ONE | www.plosone.org8 February 2014 | Volume 9 | Issue 2 | e88324