Genetic variant in the promoter region of microRNA‑137 reduces the warfarin maintenance dose in patients with atrial fibrillation

Tian,Zhen; Yang,Yushuang; Feng,Zhaohui; Wu,Donghui; Yang,Wei; Liu,Dongna

doi:10.3892/mmr.2019.10205

Genetic variant in the promoter region of microRNA‑137 reduces the warfarin maintenance dose in patients with atrial fibrillation

Authors:
- Zhen Tian
- Yushuang Yang
- Zhaohui Feng
- Donghui Wu
- Wei Yang
- Dongna Liu
View Affiliations

Affiliations: Department of Cardiology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Department of Orthopedics, People's Hospital of Jilin Province, Changchun, Jilin 130033, P.R. China, Department of Psychology, Changchun Sixth Hospital, Changchun, Jilin 130033, P.R. China
Published online on: April 30, 2019 https://doi.org/10.3892/mmr.2019.10205
Pages: 5361-5367

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

A substantial body of research has confirmed that Vitamin K epoxide reductase complex subunit 1 (VKORC1) plays a role in contributing to the high interpatient variability in the warfarin maintenance dose. The aim of the present study was to examine the impact of SNPs of miR‑137 on the warfarin maintenance dose. Computational analysis and luciferase assay were used to search the targets of miR‑137, and luciferase assay was also used to confirm the effect of the polymorphisms on the transcription of the promoter. The regulatory relationship between miR‑137 and VKORC1 was detected using real‑time PCR. We then performed statistical analysis to find the warfarin maintenance dose in the different groups. A total of 155 subjects were enrolled in our research, and the characteristics of the patients were collected. Using computational analysis, we identified that miR‑137 binds to the VKORC1 3'untranslated region (3'UTR) and regulates the expression of VKORC1. This hypothesis was confirmed by luciferase reporter assay as miR‑137 significantly reduced the VKORC1 3'UTR luciferase activity, while the luciferase activity of mutant VKORC1 3'UTR was similar to the scramble control. According to the result of the luciferase reporter assay, we found that miR‑137 SNP with the presence of the A allele apparently reduced the luciferase activity. Using real‑time PCR, we revealed that miR‑137 negatively regulated the expression of VKORC1 in a concentration‑dependent manner in liver cells. Furthermore, no difference was noted regarding the warfarin maintenance dose between the different age or gender groups, and furthermore AC + AA carriers showed a markedly higher warfarin maintenance dose than CC carriers. These findings collectively provide support that VKORC1 is a direct target of miR‑137 and the miR‑137 rs2660304 polymorphism is associated with warfarin maintenance dose in patients with atrial fibrillation. The rs2660304 polymorphism is a potential biomarker for predicting the clinical efficacy of warfarin in these patients.

View Figures

View References

1	Yoshizawa, Hayashi H, Tashiro Y, Sakawa S, Moriwaki H, Akimoto T, Doi O, Kimura M, Kawarasaki Y, Inoue K and Itoh K: Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in japanese patients. Thromb Res. 124:161–166. 2009. View Article : Google Scholar : PubMed/NCBI
2	Kidane AG, Burriesci G, Cornejo P, Dooley A, Sarkar S, Bonhoeffer P, Edirisinghe M and Seifalian AM: Current developments and future prospects for heart valve replacement therapy. J Biomed Mater Res B Appl Biomater. 88:290–303. 2009. View Article : Google Scholar : PubMed/NCBI
3	Glurich I, Burmester JK and Caldwell MD: Understanding the pharmacogenetic approach to warfarin dosing. Heart Fail Rev. 15:239–248. 2010. View Article : Google Scholar : PubMed/NCBI
4	Arellano-Rodrigo E: Home monitoring of warfarin effects. N Engl J Med. 364:378–379. 2011. View Article : Google Scholar : PubMed/NCBI
5	Inui M, Martello G and Piccolo S: MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 11:252–263. 2010. View Article : Google Scholar : PubMed/NCBI
6	Chen CZ, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar : PubMed/NCBI
7	Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M and Stoffel M: miR-375 maintains normal pancreatic alpha-and beta-cell mass. Proc Natl Acad Sci USA. 106:5813–5818. 2009. View Article : Google Scholar : PubMed/NCBI
8	Hornstein E, Mansfield JH, Yekta S, Hu JK, Harfe BD, McManus MT, Baskerville S, Bartel DP and Tabin CJ: The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature. 438:671–674. 2005. View Article : Google Scholar : PubMed/NCBI
9	Borel C and Antonarakis SE: Functional genetic variation of human miRNAs and phenotypic consequences. Mamm Genome. 19:503–509. 2008. View Article : Google Scholar : PubMed/NCBI
10	Saetrom P, Biesinger J, Li SM, Smith D, Thomas LF, Majzoub K, Rivas GE, Alluin J, Rossi JJ, Krontiris TG, et al: A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Res. 69:7459–7465. 2009. View Article : Google Scholar : PubMed/NCBI
11	Ryan BM, Robles AI and Harris CC: Genetic variation in microRNA networks: The implications for cancer research. Nat Rev Cancer. 10:389–402. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gamazon ER, Ziliak D, Im HK, LaCroix B, Park DS, Cox NJ and Huang RS: Genetic architecture of microRNA expression: Implications for the transcriptome and complex traits. Am J Hum Genet. 90:1046–1063. 2012. View Article : Google Scholar : PubMed/NCBI
13	Sridharan K, Modi T, Bendkhale S, Kulkarni D, Gogtay NJ and Thatte UM: Association of genetic polymorphisms of CYP2C9 and VKORC1 with bleeding following warfarin: A case-control study. Curr Clin Pharmacol. 11:62–68. 2016. View Article : Google Scholar : PubMed/NCBI
14	Warburton A, Breen G, Bubb VJ and Quinn JP: A GWAS SNP for schizophrenia is linked to the internal MIR137 promoter and supports differential Allele-Specific expression. Schizophr Bull. 42:1003–1008. 2016. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL and Rettie AE: Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 352:2285–2293. 2005. View Article : Google Scholar : PubMed/NCBI
17	D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E and Margaglione M: A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 105:645–649. 2005. View Article : Google Scholar : PubMed/NCBI
18	Shomron N: MicroRNAs and pharmacogenomics. Pharmacogenomics. 11:629–632. 2010. View Article : Google Scholar : PubMed/NCBI
19	Peréz-Andreu V, Teruel R, Corral J, Roldán V, García-Barberá N, Salloum-Asfar S, Gómez-Lechón MJ, Bourgeois S, Deloukas P, Wadelius M, et al: miR-133a regulates vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the vitamin K cycle. Mol Med. 18:1466–1472. 2013. View Article : Google Scholar : PubMed/NCBI
20	Ainle FN, Mumford A, Tallon E, McCarthy D and Murphy K: A vitamin K epoxide reductase complex subunit 1 mutation in an Irish patient with warfarin resistance. Ir J Med Sci. 177:159–161. 2008. View Article : Google Scholar : PubMed/NCBI
21	Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, et al: A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 14:1745–1751. 2005. View Article : Google Scholar : PubMed/NCBI
22	Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA and Sadée W: Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood. 112:1013–1021. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kealey C, Chen Z, Christie J, Thorn CF, Whitehead AS, Price M, Samaha FF and Kimmel SE: Warfarin and cytochrome P450 2C9 genotype: Possible ethnic variation in warfarin sensitivity. Pharmacogenomics. 8:217–225. 2007. View Article : Google Scholar : PubMed/NCBI
24	Schelleman H, Chen Z, Kealey C, Whitehead AS, Christie J, Price M, Brensinger CM, Newcomb CW, Thorn CF, Samaha FF and Kimmel SE: Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther. 81:742–747. 2007. View Article : Google Scholar : PubMed/NCBI
25	Kimmel SE, Christie J, Kealey C, Chen Z, Price M, Thorn CF, Brensinger CM, Newcomb CW and Whitehead AS: Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans. Pharmacogenomics J. 8:53–60. 2008. View Article : Google Scholar : PubMed/NCBI
26	Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, Amariglio N, Cohen Y, Ken-Dror G, Almog S and Gak E: A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood. 109:2477–2480. 2007. View Article : Google Scholar : PubMed/NCBI
27	Mahmoudi E and Cairns MJ: MiR-137: An important player in neural development and neoplastic transformation. Mol Psychiatry. 22:44–55. 2017. View Article : Google Scholar : PubMed/NCBI
28	Neault M, Mallette FA and Richard S: miR-137 modulates a tumor suppressor network-inducing senescence in pancreatic cancer cells. Cell Rep. 14:1966–1978. 2016. View Article : Google Scholar : PubMed/NCBI