
ASSOCIATION BETWEEN OSTEOPROTEGERIN GENE
POLYMORPHISMS AND RISK OF CORONARY ARTERY
DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS Jia P, Wu N, Jia D*, Sun Y* *Corresponding Author: Professor Dalin Jia and/or Professor Yingxian Sun, Department of Cardiology, The First Affiliated
Hospital of China Medical University, 155th North Nanjing Street, Heping District, Shenyang 110001, Liaoning Province,
People’s Republic of China. Tel: +86-242-326-9477. Fax: +86-242-326-9477. Email: jdl2001@126.com and/or
yxsun@mail.cmu.edu.cn page: 27
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MATERIALS AND METHODS
Search Strategy. A systematic search assembling the
following terms: genetic polymorphism, single nucleotide
polymorphism, gene mutation, genetic variants, coronary
atherosclerosis, myocardial ischemia, acute coronary syndrome,
coronary artery disease, myocardial infarction,
ischemic heart disease, TNFRSF11B, osteoprotegerin, was
conducted in PubMed, Web of Science, Cochrane Library,
Chinese National Knowledge Infrastructure (CNKI) and
Chinese Wan Fang databases up to May 1 2017 to identify
all potentially relevant studies. Hand-searching was carried
out to determine other potential eligible studies through
scanning the references cited in the retrieved articles.
The full-text articles were further reviewed to determine
whether they were included in the final analysis strictly
based on eligibility criteria. If two reviewers disagreed,
all the authors critically evaluated the studies to judge of
the inclusion or exclusion of a certain study.
Eligibility Criteria. All the eligible articles were
supposed to meet the following major inclusion criteria:
i) assessment of the association between OPG gene polymorphisms
and CAD; ii) case-control or cohort studies; iii)
data provided by articles about allele frequency should be
sufficient for calculating genotypic odds ratio (OR) with
corresponding to 95% confidence interval (95% CI) in cases
and controls. Moreover, only when a single nucleotide polymorphism
(SNP) in the OPG gene was reported by at least
two articles would it be analyzed by meta-analysis. Studies
were excluded when they were i) duplicated data; ii) case
report, review articles and editorial comment. The diagnosis
of the CAD case was based on the WHO criteria for CAD
as previously described (stenosis ≥50.0% of the diameter
in at least one major coronary artery based on computerassisted
assessments) [17]. All healthy control subjects were
identified according to patient history, serum biochemistry
examination and electrocardiogram (ECG) test.
Data Extraction. Data extraction was performed
independently by two authors using a standardized data
extraction form including following elements: 1) author’s
name, year of publication; 2) patient characteristics of
each group; 3) number of participants in case and control
groups; 4) study type; 5) genotyping method; 6) p value of
Hardy-Weinberg equilibrium (HWE) test in the control; 7)
OR and 95% CI for association with CAD. Assessment of
the quality of studies was performed using the Newcastle-
Ottawa Scale (NOS) as previously described [18]. Briefly,
two authors of this article separately evaluated the quali- ties based on eight items and scored the studies from 0 to
9 points. Studies with a score not less than seven points
were considered to be of high quality. Discrepancy was
resolved as described above.
Statistical Analyses. First, the genotype frequencies
of the OPG gene polymorphism among the controls of all
included studies were assessed under HWE using a χ2 goodness-
of-fit test. Odds ratios with corresponding 95% CIs
were used to estimate the strength of association between
OPG gene polymorphisms and CAD. The between-study
heterogeneity across all eligible comparisons was tested
by the χ2-based Q statistic. Heterogeneity was considered
significant when the p value was less than 0.10. When heterogeneity
existed, the random effects model was performed
to calculate the pooled OR of each eligible study, otherwise,
the fixed effect model was used. Generally, we assessed the
association between the OPG gene polymorphism and CAD
under five genetic models: allele, homozygote, heterozygote,
dominant and recessive models. Sensitivity analysis
was conducted through omitting one study at a time to examine
its influence on the overall estimate to evaluate the
stability of the meta-analysis. Publication bias was also
analyzed using the Egger’s linear regression test and funnel
plots and publication bias was considered present when the p value was less than 0.05. All statistical analyses were done
using STATA version 11.0 (STATA Corporation, College
Station, TX, USA). All p values were two-tailed.
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