Effects of ADIPOQ polymorphisms on individual susceptibility to coronary artery disease: a meta-analysis

ABSTRACT Whether adiponectin (ADIPOQ) polymorphisms affect individual susceptibility to coronary artery disease (CAD) remains controversial. Therefore, we performed this meta-analysis to better analyse associations between ADIPOQ polymorphisms and CAD. PubMed, Web of Science, Embase and CNKI were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally, 51 studies were eligible for analyses. In overall analyses, significant associations with the susceptibility to CAD were detected for rs266729 (overdominant model: p= 0.03, OR = 1.11, 95% CI 1.01–1.22), rs822395 (recessive model: p= 0.007, OR = 1.21, 95% CI 1.05–1.40) and rs2241766 (dominant model: p= 0.0009, OR = 0.82, 95% CI 0.73–0.92; recessive model: p= 0.04, OR = 1.29, 95% CI 1.02–1.64; allele model: p< 0.0001, OR = 0.80, 95% CI 0.73–0.88) polymorphisms. Further subgroup analyses by ethnicity revealed that rs1501299 polymorphism was significantly associated with the susceptibility to CAD in East Asians, while rs2241766 polymorphism was significantly associated with the susceptibility to CAD in Caucasians, East Asians and South Asians. In summary, our findings indicated that rs266729, rs822395, rs1501299 and rs2241766 polymorphisms were all significantly associated with the susceptibility to CAD in certain populations.


Introduction
Coronary artery disease (CAD) is the leading cause of death and disability worldwide [1,2]. So far, the exact pathogenesis of CAD is still unclear. Nevertheless, plenty of evidence supported that genetic factors may play a crucial part in its development. First, family clustering of CAD was observed extensively, and past twin studies proved that the heredity grade of CAD was over 50% [3,4]. Second, numerous genetic variants were found to be associated with an increased susceptibility to CAD by previous genetic association studies, and screening of common causal variants was also proved to be an efficient way to predict the individual risk of developing CAD [5,6]. Overall, these findings jointly supported that genetic predisposition to CAD is important for its occurrence and development.
Adiponectin (ADIPOQ), a multifunctional adipocytokine that is predominantly secreted by adipocytes, plays a central role in regulating energy and material metabolism [7]. Previous studies showed that adiponectin has both anti-atherogenic and anti-inflammatory properties [8,9]. Furthermore, the expression level of adiponectin was also significantly decreased in patients with CAD [10,11]. In summary, these pieces of evidence jointly suggested that adiponectin might exert favourable protection effects against CAD. Therefore, functional ADIPOQ genetic polymorphisms, which may alter the expression level of adiponectin, may also affect individual susceptibility to CAD. So far, several studies already tried to investigate associations between ADIPOQ polymorphisms and CAD, but the results of these studies were controversial, especially when they were conducted in different populations [12][13][14][15][16][17][18][19]. Previous studies failed to reach a consensus regarding associations between ADIPOQ polymorphisms and CAD partially because of their relatively small sample sizes. Thus, we performed the present meta-analysis to explore the relationship between ADIPOQ polymorphisms and CAD in a larger pooled sample size. Additionally, we also aimed to elucidate the potential effects of ethnic background on associations between ADIPOQ polymorphisms and CAD.
Science, Embase and China National Knowledge Infrastructure (CNKI) were searched for potentially eligible articles using the combination of following terms: (adiponectin OR ADIPOQ) AND (polymorphism OR variant OR mutation OR genotype OR allele) AND (coronary heart disease OR coronary artery disease OR angina pectoris OR acute coronary syndrome OR myocardial infarction). We also reviewed the reference lists of all retrieved articles to identify other potentially eligible studies. The initial search was conducted in July 2018 and the latest update was performed in December 2018.
To test the research hypothesis of this meta-analysis, included studies must satisfy the following criteria: (1) case-control study on associations between ADIPOQ polymorphisms and CAD; (2) provide genotypic and/or allelic frequency of investigated ADIPOQ polymorphisms; and (3) full text in English or Chinese available. Studies were excluded if one of the following criteria was fulfilled: (1) not relevant to ADIPOQ polymorphisms and CAD; (2) case reports or case series; and (3) abstracts, reviews, comments, letters and conference presentations. In the case of duplicate reports by the same authors, we only included the most recent study for analyses.

Data extraction and quality assessment
We extracted the following information from eligible studies: (a) name of the first author; (b) year of publication; (c) country and ethnicity of participants; (d) sample size; and (e) genotypic distributions of ADIPOQ polymorphisms in cases and controls. The probability value (p value) of Hardy-Weinberg equilibrium (HWE) was also calculated.
We used the Newcastle-Ottawa scale (NOS) to evaluate the quality of eligible studies [21]. The NOS has a score range of 0 to 9, and studies with a score of more than 7 were thought to be of high quality.
Two reviewers conducted data extraction and quality assessment independently. When necessary, we wrote to the corresponding authors for extra information. Any disagreement between two reviewers was solved by discussion until a consensus was reached.

Statistical analyses
In the current study, we performed statistical analyses by using Review Manager Version 5.3.3. We calculated ORs and 95% CIs to estimate potential associations between ADIPOQ polymorphisms and CAD in dominant, recessive, overdominant and allele models, and statistical significances of pooled analyses were determined by the Z test, with a p value of 0.05 or less was defined as statistically significant. All investigated ADIPOQ polymorphisms contain a major allele (M) and a minor allele (m), and the definitions of all genetic comparisons were as follows: dominant comparison is defined as MM versus Mm + mm, recessive comparison is defined as mm vs. MM +Mm, overdominant comparison is defined as Mm versus MM + mm, and the allele comparison is defined as M versus m. Between-study heterogeneities were evaluated by I 2 statistic. Random-effect models would be used for analyses if I 2 was greater than 50% (Der Simonian-Laird method). Otherwise, analyses would be conducted with fixed-effect models (Mantel-Haenszel method). Subgroup analyses were subsequently carried out by ethnicity and type of disease. Stabilities of synthetic results were tested in sensitivity analyses. Publication biases were assessed by funnel plots.

Characteristics of included studies
We found 434 potentially relevant articles. Among these articles, totally 51 eligible studies were finally included for synthetic analyses (see Figure 1). The NOS score of eligible articles ranged from 7 to 8, which indicated that all the included studies were of high quality. Baseline characteristics of the included studies are summarized in Table 1.

Sensitivity analyses
We performed sensitivity analyses by excluding studies that deviated from HWE. No alterations of results were detected in sensitivity analyses, which suggested that our findings were statistically reliable.

Publication biases
Publication biases were evaluated with funnel plots. We did not find obvious asymmetry of funnel plots in any comparisons, which indicated that our findings were unlikely to be impacted by severe publication biases (see supplementary Figure 2).

Discussion
To the best of our knowledge, this is so far the most comprehensive meta-analysis on associations between ADIPOQ polymorphisms and CAD, and our pooled analyses demonstrated that rs266729, rs822395, rs1501299 and rs2241766 polymorphisms were all significantly correlated with the susceptibility to CAD in certain populations.
There are several points that need to be addressed about this meta-analysis. First, previous experimental studies showed that mutant alleles of investigated polymorphisms were correlated with decreased adiponectin generation, which may partially explain our positive findings [12][13][14][15][16][17][18][19]. Second, it is also notable that the trends of associations in different ethnicities were not always consistent, and this may be attributed to ethnic differences in genotypic distributions of investigated polymorphisms. However, it is also possible that these inconsistent findings may have resulted from a complex interaction of both genetic and environmental factors. Third, the pathogenic mechanism of CAD is highly complex, and hence, it is unlikely that a single genetic polymorphism could significantly contribute to its development. As a result, to better illustrate potential    associations of certain genetic polymorphisms with CAD, we strongly recommend further studies to perform haplotype analyses and explore potential genegene interactions. Some limitations of this meta-analysis should also be noted when interpreting our findings. First, our pooled analyses were based on unadjusted estimations due to lack of raw data, and we have to admit that failure to perform further adjusted analyses may impact the reliability of our findings [22,23]. Second, since our pooled analyses were based on case-control studies, despite our positive findings, future prospective studies are still needed to examine whether there is a direct causal relationship between ADIPOQ polymorphisms and CAD [24,25]. Third, associations between ADIPOQ polymorphisms and CAD may also be modified by gene-gene and gene-environmental interactions. However, most studies did not consider these potential interactions, which impeded us to conduct relevant analyses [26,27]. Considering the above-mentioned limitations, our findings should be interpreted with caution.
In conclusion, our meta-analysis suggested that rs266729, rs822395, rs1501299 and rs2241766 polymorphisms were all significantly correlated with the susceptibility to CAD in certain populations. However, further welldesigned studies are still warranted to confirm our findings.

Authors' contributions
Zhiyuan WANG and Jingquan ZHONG conceived the study and participated in its design. Zhiyuan WANG and Jinglan DIAO conducted the systematic literature review. Xin YUE performed data analyses. Zhiyuan WANG and Jingquan ZHONG drafted the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Disclosure statement
No potential conflict of interest was reported by the authors.

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent
For this type of study, formal consent is not required.