Potential Impact of MicroRNA-423 Gene Variability in Coronary Artery Disease

Author(s): Chandan K. Jha, Rashid Mir *, Imadeldin Elfaki, Naina Khullar, Suriya Rehman, Jamsheed Javid, Shaheena Banu, Sukh Mohinder Singh Chahal.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 19 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Aim: Studies have evaluated the association of miRNA-423 C>A genotyping with the susceptibility to various diseases such cancers, atherosclerosis and inflammatory bowel disease but the results were contradictory. However, no studies have reported the association between miRNA-423 rs6505162 C>A polymorphism and susceptibility of coronary artery disease. MicroRNAs regulate expression of multiple genes involved in atherogenesis. Therefore, we investigated the association of microRNA-423C>T gene variations with susceptibility to coronary artery disease.

Methodology: This study was conducted on 100 coronary artery disease patients and 117 matched healthy controls. The genotyping of the microRNA-423 rs6505162C>A was performed by using Amplification refractory mutation system PCR method (ARMS-PCR).

Results: A significant difference was observed in the genotype distribution among the coronary artery disease cases and sex-matched healthy controls (P=0.048). The frequencies of all three genotypes CC, CA, AA reported in the patient’s samples were 55%, 41% and 4% and in the healthy controls samples were 55%, 41% and 4% respectively. Our findings showed that the microRNA-423 C>A variant was associated with an increased risk of coronary artery disease in codominant model (OR = 1.96, 95 % CI, 1.12-3.42; RR 1.35(1.05-1.75, p=0.017) of microRNA-423CA genotype and significant association in dominant model (OR 1.97, 95% CI (1.14-3.39), (CA+AA vs CC) and non-significant association for recessive model (OR=1.42, 95%CI=0.42-4.83, P=0.56, AA vs CC+CA).While, the A allele significantly increased the risk of coronary artery disease (OR =1.56, 95 % CI, 1.03-2.37; p=0.035) compared to C allele. Therefore, it was observed that more than 1.96, 1.97 and 1.56 fold increased risk of developing coronary artery disease.

Conclusion: Our findings indicated that microRNA-423 CA genotype and A allele are associated with an increased susceptibility to Coronary artery disease.

Keywords: MicroRNA-423, coronary artery disease (CAD), congenital heart disease (CHD), cerebrovascular disease, Amplification refractory mutation system PCR method (ARMS-PCR), polymorphism, genotype.

Mendis, S.; Puska, P.; Norrving, B. Global atlas on cardiovascular disease prevention and control Policies, strategies and interventions. Eds: WHO; World Heart Federation; World,. 2011, 164.
Falk, E. Pathogenesis of atherosclerosis. J. Am. Coll. Cardiol., 2006, 47(8)(Suppl.), C7-C12.
Glass, C.K.; Witztum, J.L. Atherosclerosis. The road ahead. Cell, 2001, 104(4), 503-516.
Lubrano, V.; Balzan, S. Consolidated and emerging inflammatory markers in coronary artery disease. World J. Exp. Med., 2015, 5(1), 21-32.
Mackesy, D.Z.; Goalstone, M.L. Insulin augments tumor necrosis factor-alpha stimulated expression of vascular cell adhesion molecule-1 in vascular endothelial cells. J. Inflamm. (Lond.), 2011, 8, 34.
Tousoulis, D.; Oikonomou, E.; Economou, E.K.; Crea, F.; Kaski, J.C. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur. Heart J., 2016, 37(22), 1723-1732.
Hu, W.; Coller, J. What comes first: Translational repression or mRNA degradation? The deepening mystery of microRNA function. Cell Res., 2012, 22(9), 1322-1324.
Fiannaca, A.; La Rosa, M.; La Paglia, L.; Rizzo, R.; Urso, A. nRC: Non-coding RNA classifier based on structural features. BioData Min., 2017, 10, 27.
Matoulkova, E.; Michalova, E.; Vojtesek, B.; Hrstka, R. The role of the 3′ untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol., 2012, 9(5), 563-576.
Behm-Ansmant, I.; Rehwinkel, J.; Izaurralde, E. MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay. Cold Spring Harb. Symp. Quant. Biol., 2006, 71, 523-530.
Djuranovic, S.; Nahvi, A.; Green, R. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science, 2012, 336(6078), 237-240.
Srivastava, K.; Tyagi, K. Single nucleotide polymorphisms of microRNA in cardiovascular diseases. Clinica chimica acta; international J. Clin. Chem., 2018, 478, 101-110.
Borghini, A.; Andreassi, M.G. Genetic polymorphisms offer insight into the causal role of microRNA in coronary artery disease. Atherosclerosis, 2018, 269, 63-70.
Feinberg, M.W.; Moore, K.J. MicroRNA Regulation of Atherosclerosis. Circ. Res., 2016, 118(4), 703-720.
Lorenzen, J.M.; Kielstein, J.T.; Hafer, C.; Gupta, S.K.; Kumpers, P.; Faulhaber-Walter, R.; Haller, H.; Fliser, D.; Thum, T. Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin. J. Am. Soc. Nephrol. CJASN, 2011, 6(7), 1540-1546.
Bauters, C.; Kumarswamy, R.; Holzmann, A.; Bretthauer, J.; Anker, S.D.; Pinet, F.; Thum, T. Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction. Int. J. Cardiol., 2013, 168(3), 1837-1840.
Su, X.; Hu, Y.; Li, Y.; Cao, J.L.; Wang, X.Q.; Ma, X.; Xia, H.F. The polymorphism of rs6505162 in the MIR423 coding region and recurrent pregnancy loss. Reproduction, 2015, 150(1), 65-76.
Yin, J.; Wang, X.; Zheng, L.; Shi, Y.; Wang, L.; Shao, A.; Tang, W.; Ding, G.; Liu, C.; Liu, R.; Chen, S.; Gu, H. Hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A polymorphisms are associated with the risk of esophageal cancer in a Chinese population. PLoS One, 2013, 8(11), e80570.
Smith, R.A.; Jedlinski, D.J.; Gabrovska, P.N.; Weinstein, S.R.; Haupt, L.; Griffiths, L.R. A genetic variant located in miR-423 is associated with reduced breast cancer risk. Cancer Genomics Proteomics, 2012, 9(3), 115-118.
Badimon, L.; Vilahur, G. Thrombosis formation on atherosclerotic lesions and plaque rupture. J. Int. Medi, 2014, 276(6), 618-632.
Fleg, J.L.; Stone, G.W.; Fayad, Z.A.; Granada, J.F.; Hatsukami, T.S.; Kolodgie, F.D.; Ohayon, J.; Pettigrew, R.; Sabatine, M.S.; Tearney, G.J.; Waxman, S.; Domanski, M.J.; Srinivas, P.R.; Narula, J. Detection of high-risk atherosclerotic plaque: Report of the NHLBI working group on current status and future directions. JACC Cardiovasc. Imaging, 2012, 5(9), 941-955.
Fuster, V.; Moreno, P.R.; Fayad, Z.A.; Corti, R.; Badimon, J.J. Atherothrombosis and high-risk plaque: part I: Evolving concepts. J. Am. Coll. Cardiol., 2005, 46(6), 937-954.
Morales, S.; Gulppi, F.; Gonzalez-Hormazabal, P.; Fernandez-Ramires, R.; Bravo, T.; Reyes, J.M.; Gomez, F.; Waugh, E.; Jara, L. Association of single nucleotide polymorphisms in Pre-miR-27a, Pre-miR-196a2, Pre-miR-423, miR-608 and Pre-miR-618 with breast cancer susceptibility in a South American population. BMC Genet., 2016, 17(1), 109.
Jia, W.; Zeng, L.; Luo, S.; Bai, F.; Zhong, R.; Wu, L.; Huang, G.L.; Pu, X. Association of microRNA-423 rs6505162 C>A polymorphism with susceptibility and metastasis of colorectal carcinoma. Medicine (Baltimore), 2018, 97(6), e9846.
Nariman-Saleh-Fam, Z.; Bastami, M.; Somi, M.H.; Behjati, F.; Mansoori, Y.; Daraei, A.; Saadatian, Z.; Nariman-Saleh-Fam, L.; Mahmoodzadeh, H.; Makhdoumi, Y.; Tabrizi, F.V.; Ebrahimi-Sharif, B.; Hezarian, A.; Naghashi, S.; Abbaszadegan, M.R.; Tavakkoly-Bazzaz, J. miRNA-related polymorphisms in mir-423 (rs6505162) and pex6 (rs1129186) and risk of esophageal squamous cell carcinoma in an iranian cohort. Genet. Test. Mol. Biomarkers, 2017, 21(6), 382-390.
Vegter, E.L.; van der Meer, P.; de Windt, L.J.; Pinto, Y.M.; Voors, A.A. MicroRNAs in heart failure: From biomarker to target for therapy. Eur. J. Heart Fail., 2016, 18(5), 457-468.
Nabialek, E.; Wanha, W.; Kula, D.; Jadczyk, T.; Krajewska, M.; Kowalowka, A.; Dworowy, S.; Hrycek, E.; Wludarczyk, W.; Parma, Z.; Michalewska-Wludarczyk, A.; Pawlowski, T.; Ochala, B.; Jarzab, B.; Tendera, M.; Wojakowski, W. Circulating microRNAs (miR-423-5p, miR-208a and miR-1) in acute myocardial infarction and stable coronary heart disease. Minerva Cardioangiol., 2013, 61(6), 627-637.
Luo, P.; He, T.; Jiang, R.; Li, G. MicroRNA-423-5p targets O-GlcNAc transferase to induce apoptosis in cardiomyocytes. Mol. Med. Rep., 2015, 12(1), 1163-1168.
Medford, H.M.; Marsh, S.A. The role of O-GlcNAc transferase in regulating the gene transcription of developing and failing hearts. Future Cardiol., 2014, 10(6), 801-812.
Zachara, N.E. The roles of O-linked beta-N-acetylglucosamine in cardiovascular physiology and disease. Am. J. Physiol. Heart Circ. Physiol., 2012, 302(10), H1905-H1918.
Fulop, N.; Marchase, R.B.; Chatham, J.C. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc. Res., 2007, 73(2), 288-297.
Crossland, R.E.; Norden, J.; Kralj Juric, M.; Pearce, K.F.; Lendrem, C.; Bibby, L.A.; Collin, M.; Greinix, H.T.; Dickinson, A.M. Serum and Extracellular Vesicle MicroRNAs miR-423, miR-199, and miR-93* As Biomarkers for Acute Graft-versus-Host Disease. Front. Immunol., 2017, 8, 1446.
Wang, W.; Gao, J.; Wang, F. MiR-663a/MiR-423-5p are involved in the pathogenesis of lupus nephritis via modulating the activation of NF-kappaB by targeting TNIP2. Am. J. Transl. Res., 2017, 9(8), 3796-3803.
Pamukcu, B.; Lip, G.Y.; Shantsila, E. The nuclear factor-kappa B pathway in atherosclerosis: a potential therapeutic target for atherothrombotic vascular disease. Thromb. Res., 2011, 128(2), 117-123.
Baker, R.G.; Hayden, M.S.; Ghosh, S. NF-kappaB, inflammation, and metabolic disease. Cell Metab., 2011, 13(1), 11-22.
Li, B.; Li, H.; Ye, W.; Huang, X.; Han, Y.; Wang, J.; Du, S.; Huang, G.; He, Z. Association of hsa-miR-423 rs6505162 polymorphism with risk of nasopharyngeal carcinoma in Southern Chinese population. Int. J. Clin. Exp. Med., 2017, 10(2), 3289-3296.
Umar, M.; Upadhyay, R.; Prakash, G.; Kumar, S.; Ghoshal, U.C.; Mittal, B. Evaluation of common genetic variants in pre-microRNA in susceptibility and prognosis of esophageal cancer. Mol. Carcinog., 2013, 52(Suppl. 1), E10-E18.
Wang, Y.; Vogelsang, M.; Schafer, G.; Matejcic, M.; Parker, M.I. MicroRNA polymorphisms and environmental smoke exposure as risk factors for oesophageal squamous cell carcinoma. PLoS One, 2013, 8(10), e78520.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [67 - 74]
Pages: 8
DOI: 10.2174/1871530318666181005095724
Price: $58

Article Metrics

PDF: 18
PRC: 1