Abstract
Background
Coronary artery disease (CAD) is a complex disease resulting from a combination of environmental and genetic factors. We hypothesized that polymorphisms hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G might contribute to CAD susceptibility.
Methods
We studied the association between the three polymorphisms and the risk of CAD in a Chinese population using 435 CAD patients and 480 controls. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to perform the genotyping, and the differences were analysed.
Results
When the hsa-mir-499 rs3746444 TT homozygote genotype was used as the reference group, the TC, CC or TC/CC genotypes were associated with a significantly increased risk of CAD [TC vs. TT: adjusted odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02-1.94, p = 0.04; CC vs. TT: adjusted OR 3.14, 95% CI 1.77-5.56, p < 0.001; CC/TC vs. TT: adjusted OR 1.68, 95% CI 1.25-2.26, p < 0.001). In the recessive model, when the hsa-mir-499 rs3746444 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased risk of CAD (adjusted OR 2.87, 95% CI 1.63-5.04, p < 0.001). Risk factors such as diabetes mellitus (DM), hypertension, smoking and low high-density ipoprotein cholesterol (HDL-c) were also associated with a significantly increased risk for CAD. Logistic regression analyses revealed that IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms were not associated with risk of CAD.
Conclusions
These findings suggested that the functional polymorphism hsa-mir-499 rs3746444 T/C is associated with CAD susceptibility.
Keywords: Cardiovascular disease, Hsa-mir-499, Molecular epidemiology, Polymorphisms
INTRODUCTION
Micro-Ribonucleic Acids (miRNAs) are an abundant class of small non-coding, single-stranded ribonucleic acid (RNA) that form base-pairs with target mRNAs to negatively regulate their translational efficiency and stability.1 MiRNAs are involved in various biological processes, such as cell proliferation, cell death, stress resistance and fat metabolism.2 The single nucleotide polymorphism (SNP) rs3746444 T/C is located at the pre-miRNA region of hsa-miR-499. Previous studies have demonstrated that hsa-mir-499 rs3746444 T/C is related to many diseases, including cancers,3 autoimmune disease,4 inflamatory arthritis,5 and coronary artery disease (CAD).6-8 Previous studies revealed that the rs 3746444 T/C polymorphism conferred a risk for CAD, although others found no association between rs3746444 and CAD.9 Interleukin-1-receptor-associated kinase 1 (IRAK1), the target of another miRNA, hsa-miR-146a, is a signaling molecule transducing Toll/interleukin-1 receptor (TIR) activation.10 IRAK1 is a key intracellular signaling protein that is involved in pathogen-mediated inflammation, and its target genes include inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and IL-12] and costimulatory molecules.11,12 IRAK1 is constitutively activated in atherosclerosis patients.12 Complementary deoxyribonucleic acid (cDNA) microarray analysis revealed that IRAK1 is expressed at high levels in human coronary arteries.13 Genetic variants of IRAK1 were found to be associated with the plasma concentration of C-reactive protein (CRP) in Caucasian women.14 The IRAK1 rs3027898 A>C genotype was also reported to be associated with atherothrombotic cerebral infarction.15
The activation of nuclear factor-kappa B (NF-κB) is the most prominent event of the inflammatory response.16 Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of tumour-necrosis factor receptor-associated factor 6 (TRAF6) and IRAK1, which are the signaling components required for NF-κB and mitogen-activated protein kinase activation.17 Another NF-κB pathway signal, the receptor activation of the NF-κB ligand (RANKL), has been shown to be involved in disease pathogenesis.18 The C allele of RANKL polymorphism rs7984870 C/G might promote interactions between activated T cells and dendritic cells by increasing transcription levels upon stimulation.16 A significant association between RANKL polymorphisms and the occurrence of acute coronary syndrome (ACS) was previously observed.19
Few studies have focused on the influences of polymorphisms hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G on the susceptibility to CAD. Therefore, we performed a hospital-based case-control study to genotype a cohort of 435 CAD patients and 480 controls in a Chinese population.
MATERIAL AND METHODS
Study population
This case-control study included 435 consecutive patients with CAD from Tianjin TEDA International Cardiovascular Hospital between November 2011 and July 2012. The study also utilized 480 CAD-free controls who were inpatients used to exclude CAD by quantitative coronary angiography (QCA), also from Tianjin TEDA International Cardiovascular Hospital. All 435 CAD patients and 480 inpatients received QCA with a Cardiovascular Measurement System (Philips Integris and Philips Allura Xper) shortly after being admitted to the hospital, and coronary angiograms were analyzed by two experienced interventional cardiologists. CAD patients were defined as having angiographic coronary stenosis of at least 50% lumen reduction in at least one major epicardial coronary artery. Exclusion criteria were patients who did not meet the CAD diagnosis standard after QCA, and an inability to give written informed consent. The 480 CAD-free inpatients were considered as controls, whose pathologies included luminal narrowing < 50% and no obvious clinical symptom such as ST-elevation, and no myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting history. We have complied with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects and/or animals. Each subject was interviewed; after written informed consent was obtained, an approximate 2-ml venous blood sample was collected from each subject. Individuals who smoked once a day for over 1 year were defined as smokers. Subjects who consumed ≥ 3 alcoholic drinks a week for > 6 months were considered to be alcohol drinkers. Diabetes mellitus was defined as self-reported diabetes mellitus or nonfasting glucose levels ≥ 11.1 mmol/L (200 mg/dL). Hypertension was defined as blood pressure level exceeding 140/90 mmHg or use of antihypertensive therapy. The study was approved by the Ethical Committee of Tianjin Medical University.
Isolation of deoxyribonucleic acid (DNA) and genotyping by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)
Blood samples were collected using vacutainers and transferred to test tubes containing ethylenediamine tetra-acetic acid (EDTA). Genomic DNA was isolated from whole blood using the QIAamp DNA Blood Mini Kit (Qiagen, Germany). Genotyping was done by MALDI-TOF MS using the MassARRAY system (Sequenom, San Diego, CA, USA) as previously described.20 Completed genotyping reactions were spotted onto a 384-well spectroCHIP (Sequenom) using a MassARRAY Nanodispenser (Sequenom), and were analyzed by MALDI-TOF-MS. Genotype calling was done in real time with MassARRAY RT software (version 3.1; Sequenom), and was analyzed using MassARRAY Typer software (version 4.0; Sequenom). For quality control, repeated analyses were undertaken on 10% of the randomly selected samples.
Statistical analyses
Differences in demographics, variables, and genotypes of the hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms were evaluated by using a chi-squared test. The associations between hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G genotypes and risk of CAD were estimated by computing the odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analyses, and by using crude ORs. The Hardy-Weinberg equilibrium (HWE) was tested by a goodness-of-fit chi-squared test to compare the observed genotype frequencies to the expected frequencies among controls. All statistical analyses were done with SAS software (version 9.1.3; SAS Institute, Cary, NC, USA).
RESULTS
Characteristics of the study population
Subjects were adequately matched for age (p = 0.38) and sex (p = 0.40) for CAD cases and controls in Tianjin. The average body mass index (BMI) was not significantly different between CAD cases and the controls (p = 0.22). For the family disease history, 98 (22.5%) cases had a family history of CAD which was significantly higher than that of the controls (13.1%) (p < 0.001). There were more hypertension and diabetes mellitus in CAD cases than in controls (p = 0.009 and p = 0.009, respectively). The demographic and clinical characteristics of all subjects are summarized in Table 1. No significant differences occurred for hyperlipidemia between CAD cases and controls (p = 0.29). There were more smokers in CAD cases (56.8%) than those in the controls (44.0%) (p < 0.001). The level of fasting blood glucose, uric acid, serum creatinine, triglyceride and fibrinogen in CAD cases were higher than those of the controls, while the level of high density lipoprotein of CAD cases was significantly lower than that of the controls. Among 915 DNA samples (435 CAD patients and 480 controls in Tianjin), hsa-mir-499 rs3746444 T/C polymorphism was successful in 421 (96.8%) CAD cases and 464 (96.7%) controls. Genotyping was successful in 432 (99.3%) CAD patients and 476 (99.2%) controls for IRAK1 rs3027898 C/A and in 418 (96.1%) CAD patients and 468 (97.5%) controls for RANKL rs7984870 C/G (Table 2). The concordance rates of repeated analyses were 100%.
Table 1. The distributions of the selected variables in the CAD cases and controls.
| Variable | CAD (n = 435) | Controls (n = 480) | p |
| Mean age, y | 61.30 (±9.71) | 60.79 (±7.54) | 0.38 |
| Woman, % | 155 (35.6) | 184 (38.3) | 0.40 |
| Mean BMI, kg/m2 | 25.99 (±3.28) | 26.24 (±2.75) | 0.22 |
| Family history of CAD, % | 98 (22.5) | 63 (13.1) | < 0.001 |
| Previous smoker, % | 247 (56.8) | 211 (44.0) | < 0.001 |
| Previous drinker, % | 82 (18.9) | 81 (16.9) | 0.44 |
| Hypertension, % | 305 (70.1) | 297 (61.9) | 0.009 |
| Hyperlipidemia, % | 274 (63.0) | 286 (59.6) | 0.29 |
| Diabetes mellitus, % | 113 (26.0) | 90 (18.8) | 0.009 |
| Previous stroke, % | 22 (5.1) | 11 (2.3) | 0.03 |
| Previous myocardial infarction, % | 100 (23.0) | — | — |
| Previous percutaneous coronary intervention, % | 221 (50.8) | — | — |
| Previous coronary artery bypass grafting, % | 41 (9.4) | — | — |
| Fasting blood glucose (mmol/l) | 5.92 (±2.25) | 5.41 (±1.07) | < 0.001 |
| Uric acid (μmol/l) | 325.82 (±85.40) | 312.60 (±79.60) | 0.02 |
| Creatinine (μmol/l) | 68.69 (±18.02) | 62.84 (±21.45) | < 0.001 |
| Total cholesterol (mmol/l) | 4.70 (±1.07) | 4.86 (±2.85) | 0.28 |
| Triglyceride (mmol/l) | 1.89 (±1.67) | 1.64 (±0.95) | 0.006 |
| High density lipoprotein (mmol/l) | 1.03 (±0.24) | 1.16 (±0.33) | < 0.001 |
| Low density lipoprotein (mmol/l) | 3.02 (±0.93) | 3.07 (±0.83) | 0.40 |
| Fibrinogen (g/l) | 2.74 (±0.64) | 2.61 (±0.62) | 0.002 |
| Aspirin, % | 427 (98.2) | 414 (88.5) | < 0.001 |
| Clopidogrel, % | 312 (71.7) | 15 (3.2) | < 0.001 |
| Nitroglycerin, % | 350 (80.6) | 61 (13.0) | < 0.001 |
| Angiotensin converting enzyme inhibitor, % | 148 (34.1) | 126 (27.0) | 0.02 |
| Angiotensin II receptor blockers, % | 97 (22.4) | 74 (15.8) | 0.01 |
| β-blocker, % | 333 (76.6) | 230 (49.1) | < 0.001 |
| Ca2+ antagonist, % | 171 (39.4) | 156 (33.3) | 0.06 |
| Statins, % | 418 (96.1) | 310 (66.2) | < 0.001 |
| Diuretics, % | 41 (9.5) | 21 (4.5) | 0.003 |
| Insulin, % | 37 (8.5) | 10 (2.1) | < 0.001 |
| Oral hypoglycemic drugs, % | 102 (23.5) | 55 (11.8) | < 0.001 |
BMI, body mass index; CAD, coronary artery disease; Ca2+, calcium channels. Bold values are statistically significant (p < 0.05); The medical information was available in 433-435 CAD cases and 465-468 non-CAD controls.
Table 2. Primary information for hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms.
| Genotyped SNPs | Chromosomes | Location | Regulome DB scorea | TFBSb | Splicing (ESE or ESS) c | MAFd for Chinese in database | MAF in our controls (n = 480) | p value for HWEe test in our controls | % Genotyping value |
| hsa-mir-499 rs3746444 T/C | 20 | Intron | 5 | Y | Y | 0.167 | 0.152 | < 0.05 | 96.7 |
| IRAK1 rs3027898 C/A | X | 3′ near gene | 4 | — | — | 0.165 | 0.181 | < 0.05 | 99.2 |
| RANKL rs7984870 C/G | 13 | Intron | No data | Y | — | 0.522 | 0.493 | 0.647 | 96.8 |
a http://www.regulomedb.org/; b TFBS, Transcription Factor Binding Site; c http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm; d MAF, minor allele frequency; e HWE, Hardy-Weinberg equilibrium.
Associations between hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms and risk of CAD
The genotype frequencies of the hsa-mir-499 rs 3746444 T/C polymorphism were 62.7% (TT), 26.1% (TC) and 11.2% (CC) in CAD patients, and 73.7% (TT), 22.2% (TC) and 4.1% (CC) in the controls (p < 0.001) (Table 3). When the hsa-mir-499 rs3746444 TT homozygote genotype was used as the reference group, the TC, CC or TC/CC genotypes were associated with a significantly increased risk for CAD (TC vs. TT: adjusted OR 1.41, 95% CI 1.02-1.94, p = 0.04; CC vs. TT: adjusted OR 3.14, 95% CI 1.77-5.56, p < 0.001; CC/TC vs. TT: adjusted OR 1.68, 95% CI 1.25-2.26, p < 0.001). In the recessive model, when the hsa-mir-499 rs3746444 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased risk for CAD (adjusted OR 2.87, 95% CI 1.63-5.04, p < 0.001).
Table 3. Logistic regression analysis of associations between hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms and risk of CAD.
| Genotype | CAD cases (n = 435) | Controls (n = 480) | OR (95% CI) | p | Adjusted ORa (95% CI) | p | ||
| n | % | n | % | |||||
| hsa-mir-499 rs3746444 T/C | ||||||||
| TT | 264 | 62.7 | 342 | 73.7 | 1 | — | 1 | — |
| TC | 110 | 26.1 | 103 | 22.2 | 1.38 (1.01-1.89) | 0.04 | 1.41 (1.02-1.94) | 0.04 |
| CC | 47 | 11.2 | 19 | 4.1 | 3.20 (1.84-5.59) | < 0.001 | 3.14 (1.77-5.56) | < 0.001 |
| TC+CC | 157 | 37.3 | 122 | 26.3 | 1.67 (1.25-2.22) | < 0.001 | 1.68 (1.25-2.26) | < 0.001 |
| TT+TC | 374 | 88.8 | 445 | 95.9 | 1 | — | 1 | — |
| CC | 47 | 11.2 | 19 | 4.1 | 2.94 (1.70-5.10) | < 0.001 | 2.87 (1.63-5.04) | < 0.001 |
| C allele | 204 | 24.2 | 141 | 15.2 | ||||
| IRAK1 rs3027898 C/A | ||||||||
| CC | 328 | 75.9 | 348 | 73.1 | 1 | — | 1 | — |
| CA | 59 | 13.7 | 84 | 17.6 | 0.75 (0.52-1.07) | 0.12 | 0.76 (0.52-1.11) | 0.15 |
| AA | 45 | 10.4 | 44 | 9.2 | 1.09 (0.70-1.69) | 0.72 | 1.01 (0.64-1.59) | 0.97 |
| CA+AA | 104 | 24.1 | 128 | 26.9 | 0.86 (0.64-1.16) | 0.33 | 0.85 (0.62-1.16) | 0.30 |
| CC+CA | 387 | 89.6 | 432 | 90.8 | 1 | — | 1 | — |
| AA | 45 | 10.4 | 44 | 9.2 | 1.14 (0.74-1.77) | 0.55 | 1.06 (0.68-1.66) | 0.80 |
| A allele | 149 | 17.2 | 172 | 18.1 | ||||
| RANKL rs7984870 C/G | ||||||||
| CC | 95 | 22.7 | 123 | 26.3 | 1 | — | 1 | — |
| CG | 209 | 50 | 229 | 48.9 | 1.18 (0.85-1.64) | 0.32 | 1.15 (0.82-1.61) | 0.43 |
| GG | 114 | 27.3 | 116 | 24.8 | 1.27 (0.88-1.85) | 0.21 | 1.16 (0.79-1.71) | 0.44 |
| CG+GG | 323 | 77.3 | 345 | 73.7 | 1.21 (0.89-1.65) | 0.22 | 1.15 (0.84-1.59) | 0.38 |
| CC+CG | 304 | 72.7 | 352 | 75.2 | 1 | — | 1 | — |
| GG | 114 | 27.3 | 116 | 24.8 | 1.14 (0.84-1.54) | 0.40 | 1.06 (0.78-1.45) | 0.71 |
| G allele | 437 | 52.3 | 461 | 49.3 |
a Adjusted for age, sex, smoking, drinking, hypertension, diabetes mellitus, family history of CAD; Bold values are statistically significant (p < 0.05). CI, confidence interval; OR, odds ratio.
None of the IRAK1 rs3027898 C/A and RANKL rs 7984870 C/G polymorphisms achieved a significant difference in the genotype distributions between cases and controls. Logistic regression analyses revealed that IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms were not associated with the risk of CAD (Table 3). In our research, we also found some risk factors such as diabetes mellitus, hypertension, smoking and low HDLc were associated with a significantly increased risk for CAD (DM: OR 1.62, 95% CI 1.11-2.19, p = 0.009, hypertension: OR 1.40, 95% CI 1.04-1.88, p = 0.009, smoking: OR 1.67, 95% CI 1.31-2.46, p < 0.001, HDL-c: OR 2.08, 95% CI 1.44-3.01, p < 0.001).
DISCUSSION
We determined the association between polymorphisms hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G and the risk of CAD in a Chinese population. We found that the hsa-mir-499 rs3746444 T/C polymorphisms might be associated with the increased risk of CAD.
MiRNAs have been investigated as potential diagnostic biomarkers in patients with acute myocardial infarction.21,22 An miRNA array analysis indicated that miR-499 was produced almost exclusively in the heart.23 MiR-499 levels were significantly elevated in patients with myocardial infarction; miR-499 levels also reflected myocardial damage in cardiovascular disease.24
MiR-499 is located in the intron 20 of human cardiac β-myosin heavy chain 7B gene (MYH7B), and is particularly expressed in skeletal muscle, cardiac cells and brain tissue.25 It has been shown that miR-499 can protect cardiomyocyte apoptosis by inhibiting mitochondrial apoptosis pathway,26 and the knock-down of miR-499 induces myocardial apoptosis and increases the infarct size.27 In addition, miR-499 regulates the expression of inflammatory cytokines, including TNF-α, annexin A1, CRP, IL-2, IL-2R, IL-6, IL-17Rβ, IL-18R, and IL-23α.5 Rs 3746444 is located in the stem region of the miR-499, and may damage the secondary structure stability and thus affect the miRNA maturation process and binding affinities to its target genes.28 It is reasonable that rs 3746444 may contribute to the susceptibility to various diseases by regulating distinct sets of downstream genes.
Many studies have shown that hsa-mir-499 polymorphism rs3746444 T/C was associated with the increased risk of breast cancer, dilated cardiomyopathy, inflammatory arthritis, autoimmune diseases and coronary artery disease.28,29 Hsa-mir-499 polymorphism rs3746444 T/C polymorphism was also investigated in lung cancer and coal workers’ pneumoconiosis, but no association was identified.18,30 Meta-analysis from Song et al. indicated associations between the miR-499 rs374644 and inflammatory arthritis.31 A few studies have suggested that miR-499 rs374644 might be involved in the pathogenesis of autoimmune diseases, but the results remain conflicting.32 Wang et al. found that the hsa-mir-499 mutated homozygote was associated with a 3.23-fold significantly increased risk of CAD, which is consistent with our results.8 Potential mechanism for such an association might be due to impaired ability to inhibit apoptosis and inflammation.
Genetic polymorphisms often vary between ethnic groups. In the present study, with 480 controls, we reported that the allele frequency of hsa-mir-499 rs3746444 T/C (0.152) was similar to that reported in Chinese populations (0.167). We have identified DNA features and regulatory elements that contain the coordinates of the SNP (http://www.regulomedb.org/), indicating that hsa-mir-499 SNP rs3746444 T/C SNP is functional (Table 2).
Considering hsa-mir-499 rs3746444 T/C mutant alleles in the control group, ORs, CAD samples and control samples, the power of our analysis (α = 0.05) was 0.864 in 435 CAD cases and 480 controls with an OR = 1.68 for hsa-mir-499 rs3746444 T/C.
However, several limitations of the present study also need to be addressed. First, this was a hospital-based case-control study, and the subjects were not fully representative of the general population; thus, selection bias was unavoidable. Second, the polymorphisms investigated, based on their functional considerations, may not offer a comprehensive view of the genetic variability of hsa-mir-499, IRAK1 and RANKL. Third, because of the relatively moderate number of patients evaluated, a single case-control study is not sufficient to fully interpret the relationship between polymorphisms hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G and susceptibility to CAD. Studies with larger numbers of subjects are necessary to confirm our findings. Finally, environmental factors differ between Chinese and other populations. CAD risk is likely to be influenced by gene-gene and gene-environment interactions; therefore, the hsa-mir-499, IRAK1 and RANKL genes may be associated with different degrees of genetic risk in different ethnic groups and under different environmental exposures.
CONCLUSIONS
In conclusion, the present study provided strong evidence that the hsa-mir-499 rs3746444 T/C polymorphism might be associated with increased risk of CAD. However, our results were obtained from a moderate-sized sample and further studies are needed to confirm the results.
Acknowledgments
We appreciate all patients who participated in this study. This study was supported in part by Social Development Foundation of Zhenjiang (SH2014087), Development fundation of NJMU (2013NJMU154) and National Natural Science Foundation of China (No.30901230, 30900630 and 81101889).
CONFLICT OF INTEREST
None of the authors has any potential financial conflict of interest related to this manuscript.
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