Biomedical Research

Abstract

Background: Some studies suggested that miR-499 rs3746444 polymorphism was associated with the risk of Coronary Artery Disease (CAD). However, the results were still unclear. Therefore, we conducted a meta-analysis.

Method: An electronic literature search was conducted using the following database: PubMed, Embase and China National Knowledge Infrastructure (CNKI) till to June 2017. The strength of association was investigated by pooling Odds Ratio (OR) with its corresponding 95% Confidence Interval (CI).

Results: In total, four studies with 2642 cases and 2260 controls were included in this meta-analysis. MiR-499 rs3746444 polymorphism was significantly associated with an increased risk of CAD (OR=1.30; 95% CI, 1.00-1.69). In the race subgroup analysis, Asians with miR-499 rs3746444 polymorphism did not show increased CAD risk (OR=1.25; 95%CI, 0.89-1.76). In the subgroup analysis according to source of control, hospital-based studied showed significantly association (OR=1.44; 95% CI, 1.11-1.86).

Conclusion: In conclusion, this meta-analysis suggests that miR-499 rs3746444 polymorphism was associated with CAD risk.

Keywords

Coronary artery disease (CAD), MicroRNAs, Association

Introduction

Coronary Artery Disease (CAD) is the primary critical cardiovascular event, causing high morbidity and mortality all over the world [1]. CAD is driven by a complex interplay of multiple genetic and environmental factors that jointly give rise to a plethora of molecular interactions resulting in a complex and heterogeneous phenotype. Hypertension, diabetes, smoking and dyslipidaemia are other established risk factors for CAD [2].

MicroRNAs (miRNAs), a family of small non-coding RNAs 20-24 nucleotides (nt) in length, are evolutionarily conserved mediators of post-transcriptional gene regulation in eukaryotes [3]. Increasing evidence indicates that dysregulation of specific miRNAs contributes to the development and progression of CAD [4]. Wang et al. found that the T allele of rs2431697 was a risk factor of CAD in the Chinese population [5]. Faccini et al. found that let-7c, miR-145 or miR-155 were powerful markers for detecting CAD [6]. Wang et al. showed that the plasma miR-146a level is significantly increased in CAD patients with good coronary collateral circulation and significantly decreased in those with poor coronary collateral circulation [7]. Some studies suggested that miR-499 rs3746444 polymorphism was associated with the risk of CAD. However, the results were still unclear [8-11]. Therefore, we conducted a meta-analysis.

Methods

Search for publications

An electronic literature search was conducted using the following database: PubMed, Embase and China National Knowledge Infrastructure (CNKI) till to June, 2017. The following medical subject headings were used: “MicroRNA,” “Coronary artery disease,” and “CAD”. Electronic searches were supplemented with manual searches of reference lists of all retrieved review articles, primary studies, and abstracts from meetings to identify other studies not found in the electronic searches.

Inclusion criteria

The following inclusion criteria were used: (1) The study should evaluate the association between the miR-499 rs3746444 polymorphism and CAD; (2) The study should have a case-control design; (3) Sufficient data should have been provided in order to calculate Odds Ratios (OR) and 95% Confidence Intervals (CI).

Data extraction

Two investigators independently extracted data: the first author’s name, year of publication, country, ethnicity, numbers of cases and controls, source of control, and Hardy-Weinberg equilibrium (HWE).

Statistical analysis

The significance of the pooled OR’s was determined by the Ztest with a P value less than 0.05 considering statistically significant. The per-allele model was examined to assess this association. Heterogeneity among studies was assessed using the Q-test and the I² statistic, which describes the proportion of total variation attributable to between-study heterogeneity as opposed to random error or chance. In the presence of substantial heterogeneity (I²>50%), the DerSimonian and Laird random effect model was applied as the pooling method, otherwise, the fixed effect model was adopted. Statistical analyses were conducted in Revman 5.1 software (Nordic Cochrane Center, Copenhagen, Denmark). All the tests were two-sided.

Results

Study characteristics

Four case-control studies met inclusion criteria. In total, 2642 cases and 2260 controls were included in this meta-analysis. The baseline characteristics of each study included in this meta-analysis are showed in Table 1.

Table 1. Characteristics of included studies.

Results of the meta-analysis

Results of the meta-analysis are summarized in Table 2. MiR-499 rs3746444 polymorphism was significantly associated with an increased risk of CAD (OR=1.30; 95% CI, 1.00-1.69; Figure 1). In the race subgroup analysis, Asians with miR-499 rs3746444 polymorphism did not show increased CAD risk (OR=1.25; 95% CI, 0.89-1.76). In the subgroup analysis according to source of control, hospitalbased studied showed significantly association (OR=1.44; 95% CI, 1.11-1.86).

Figure 1: Meta-analysis for the association between miR-499 rs3746444 polymorphism and CAD risk.

Table 2. Summary of results from meta-analysis and subgroup analysis.

Discussion

This meta-analysis of 4 case-control studies aimed to investigate whether miR-499 rs3746444 polymorphism has an impact on the risk of CAD. We found that miR-499 rs3746444 polymorphism was significantly associated with an increased risk of CAD. In the race subgroup analysis, Asians with miR-499 rs3746444 polymorphism did not show increased CAD risk. In the subgroup analysis according to source of control, hospital-based studied showed significantly association.

Zhang et al. found that rs3746444 could increase breast cancer risk in Asians and in general populations [12]. Zheng et al. suggest that miR-146a and miR-196a2 polymorphisms are associated with increased risk of hepatocellular carcinoma [13]. Luo et al. miR-499A>G (rs3746444) was related to ischemic stroke and G allele and AG genotype may increase the risk of ischemic stroke in the population of Guangxi in China [14]. Yang et al. indicated that miR-499 rs3746444 polymorphism was not significantly associated with the risk for RA [15]. Shan et al. showed that miR-499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of biliary atresia [16]. Cai et al. indicated that miR-499 rs3746444 might contribute to GC risk [17].

Several limitations of this meta-analysis should be considered. First, there were only 4 studies were included, and only one study was conducted in Caucasian. Therefore, more studies with large sample sizes are needed. Second, the overall outcomes were based on individual unadjusted ORs. The unadjusted ORs may lead to confounding bias due to lack of individual information of each study. Third, the inconsistency of the base line characteristics between the studies, such as age and gender, might increase the selection bias.

In conclusion, this meta-analysis suggests that individuals with miR-499 rs3746444 polymorphism might have an increased CAD risk.

Conflicts of Interest

None.

References

1. Ladapo JA, Goldfeld KS, Douglas PS. Projected morbidity and mortality from missed diagnoses of coronary artery disease in the United States. Int J Cardiol 2015; 195: 250-252.
2. Mc Cullough PA. Coronary artery disease. Clin J Am Soc Nephrol 2007; 2: 611-616.
3. Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 2003; 113: 673-676.
4. Malik R, Mushtaque RS, Siddiqui UA, Younus A, Aziz MA, Humayun C, Mansoor K, Latif MA, Waheed S, Assad S, Khan I, Bukhari SM, DelCampo D, Adus A, Gannarapu S. Association between coronary artery disease and MicroRNA: Literature review and clinical perspective. Cureus 2017; 9: e1188.
5. Wang Y, Wang X, Li Z, Chen L, Zhou L, Li C, Ouyang DS. Two single nucleotide polymorphisms (rs2431697 and rs2910164) of miR-146a are associated with risk of coronary artery disease. Int J Environ Res Public Health 2017; 14: 514.
6. Faccini J, Ruidavets JB, Cordelier P, Martins F, Maoret JJ, Bongard V, Ferrières J, Roncalli J, Elbaz M, Vindis C. Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease. Sci Rep 2017; 7: 42916.
7. Wang J, Yan Y, Song D, Liu B. Reduced Plasma miR-146a is a predictor of poor coronary collateral circulation in patients with coronary artery disease. Biomed Res Int 2016; 2016: 4285942
8. Zhi H, Wang L, Ma G, Ye X, Yu X, Zhu Y, Zhang Y, Zhang J, Wang B. Polymorphisms of miRNAs genes are associated with the risk and prognosis of coronary artery disease. Clin Res Cardiol 2012; 101: 289-296.
9. Xu J, Hu Z, Xu Z, Gu H, Yi L, Cao H, Chen J, Tian T, Liang J, Lin Y, Qiu W, Ma H, Shen H, Chen Y. Functional variant in microRNA-196a2 contributes to the susceptibility of congenital heart disease in a Chinese population. Hum Mutat 2009; 30: 1231-1236.
10. Labbaf A, Ghaedi H, Alipoor B, Omrani MD, Kazerouni F, Shanaki M, Ghaffarzadeh M, Pashaiefar H, Rahimipour A. The pre-mir-499 variant rs3746444 may contribute to coronary artery disease susceptibility: A case-control and meta-analysis study. Clin Lab 2017; 63: 587-595.
11. Chen W, Shao D, Gu H, Gong J, Zhang J. Hsa-mir-499 rs3746444 T/C Polymorphism is associated with increased risk of coronary artery disease in a Chinese population. Acta Cardiol Sin 2017; 33: 34-40.
12. Zhang H, Zhang Y, Yan W, Wang W, Zhao X, Ma X, Gao X, Zhang S. Association between three functional microRNA polymorphisms (miR-499 rs3746444, miR-196a rs11614913 and miR-146a rs2910164) and breast cancer risk: a meta-analysis. Oncotarget 2017; 8: 393-407.
13. Zheng L, Zhuang C, Zhao J, Ming L. Functional miR-146a, miR-149, miR-196a2 and miR-499 polymorphisms and the susceptibility to hepatocellular carcinoma: An updated meta-analysis. Clin Res Hepatol Gastroenterol 2017; 2210-7401.
14. Luo HC, Luo QS, Wang CF, Lei M, Li BL, Wei YS. Association of miR-146a, miR-149, miR-196a2, miR-499 gene Polymorphisms with ischemic stroke in a Chinese people. Oncotarget 2017.
15. Yang XK, Li P, Zhang C, Leng RX, Li S, Liu J, Li BZ, Pan HF, Ye DQ. Association between IRAK1 rs3027898 and miRNA-499 rs3746444 polymorphisms and rheumatoid arthritis: A case control study and meta-analysis. Z Rheumatol 2016.
16. Shan Y, Shen N, Han L, Chen Q, Zhang J, Long X, Xia Q. MicroRNA-499 Rs3746444 polymorphism and biliary atresia. Dig Liver Dis 2016; 48: 423-428.
17. Cai M, Zhang Y, Ma Y, Li W, Min P, Qiu J, Xu W, Zhang M, Li M, Li L, Liu Y, Yang D, Zhang J, Cheng F. Association between microRNA-499 polymorphism and gastric cancer risk in Chinese population. Bull Cancer 2015; 102: 973-978.