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A genetic variant in the microRNA-146a gene is associated with susceptibility to alcohol use disorders

Published online by Cambridge University Press:  15 April 2020

I. Novo-Veleiro
Affiliation:
Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
R. González-Sarmiento
Affiliation:
Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
C. Cieza-Borrella
Affiliation:
Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
I. Pastor
Affiliation:
Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
F.-J. Laso
Affiliation:
Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
M. Marcos*
Affiliation:
Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
*
*Corresponding author. Department of Internal Medicine, University Hospital of Salamanca, P° San Vicente, 58-156, Salamanca 37007, Spain. Tel.: +34 923291100x437; fax: +34 923294739. E-mail addresses: mmarcos@usal.es (M. Marcos).
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Abstract

Background:

Polymorphisms in the microRNA (miRNA) regulatory pathways are novel functional genetic variants whose association with alcoholism susceptibility has not been previously studied. Given the potential relationship between certain miRNAs and alcohol use disorders (AUDs), this study was designed to explore the association between two polymorphisms within hsa-miR-146a and hsa-miR-196a2 genes and susceptibility to these diseases.

Methods:

Three hundred and one male patients with AUDs and 156 sex-matched healthy volunteers were enrolled. Polymorphisms were genotyped using TaqMan® PCR assays. Allele and genotype frequencies were compared between groups and logistic regression analysis was also performed to analyze the model of inheritance.

Results:

There was a significantly higher prevalence of allele C carriers (47.8%) of the miR-146a G>C polymorphism (rs2910164) among patients with AUDs when compared with controls (35.9%), and multivariable logistic regression analysis showed that the C allele was associated with these AUDs (OR = 1.615, 95% CI 1.067–2.442; P = 0.023). Neither the genotype nor the allele distribution of miR-196a2 polymorphism (rs11614913) was significantly different between groups.

Conclusions:

This is the first genetic association study to explore the relationship of miRNA polymorphisms with AUDs and to show an association of the miR-146a C>G rs2910164 allelic variant with this disease.

Type
Original articles
Copyright
Copyright © Elsevier Masson SAS 2014

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Footnotes

1

M. Marcos and F.-J. Laso are both senior authors of this paper.

References

Alfonso-Loeches, S., Guerri, C.Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Crit Rev Clin Lab Sci 2011;48:1947.CrossRefGoogle ScholarPubMed
Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A.M., Sanchez-Vera, I., Guerri, C.Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 2010;30:82858295.CrossRefGoogle ScholarPubMed
APA. Diagnosis and Statistical Manual of Mental Disorders (DSM-IV). 4th ed, text revisedWashington: American Psychiatric Association; 2000.Google Scholar
Biernacka, J.M., Geske, J.R., Schneekloth, T.D., Frye, M.A., Cunningham, J.M., Choi, D.S.et al.Replication of genome wide association studies of alcohol dependence: support for association with variation in ADH1C. PLoS One 2013;8:e58798.CrossRefGoogle ScholarPubMed
Catucci, I., Yang, R., Verderio, P., Pizzamiglio, S., Heesen, L., Hemminki, K.et al.Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases. Hum Mutat 2010;31:E1052E1057.CrossRefGoogle ScholarPubMed
Chatzikyriakidou, A., Voulgari, P.V., Georgiou, I., Drosos, A.A.A polymorphism in the 3’-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility. Joint Bone Spine 2010;77:411413.CrossRefGoogle Scholar
Clark, K.H., Wiley, C.A., Bradberry, C.W.Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res 2013;23:174188.CrossRefGoogle ScholarPubMed
Contet, C.Gene expression under the influence: transcriptional profiling of ethanol in the brain. Curr Psychopharmacol 2012;1:301314.CrossRefGoogle Scholar
Crabbe, J.C., Phillips, T.J., Harris, R.A., Arends, M.A., Koob, G.F.Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 2006;11:195269.CrossRefGoogle ScholarPubMed
Crews, F.T., Zou, J., Qin, L.Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 2011;25(Suppl. 1):S4S12.CrossRefGoogle ScholarPubMed
Dupont, W.D., Plummer, W.D. Jr.Power and sample size calculations for studies involving linear regression. Control Clin Trials 1998;19:589601.CrossRefGoogle ScholarPubMed
Esteller, M.Non-coding RNAs in human disease. Nat Rev Genet 2011;12:861874.CrossRefGoogle ScholarPubMed
Fernandez-Lizarbe, S., Pascual, M., Guerri, C.Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol 2009;183:47334744.CrossRefGoogle ScholarPubMed
Gual, A., Contel, M., Segura, L., Ribas, A., Colom, J.[The ISCA (Systematic Interview of Alcohol Consumption), a new instrument to detect risky drinking]. Med Clin (Barc) 2001;117:685689.CrossRefGoogle Scholar
Hou, J., Wang, P., Lin, L., Liu, X., Ma, F., An, H.et al.MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol 2009;183:21502158.CrossRefGoogle ScholarPubMed
Iyer, A., Zurolo, E., Prabowo, A., Fluiter, K., Spliet, W.G., van Rijen, P.C.et al.MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One 2012;7:e44789.CrossRefGoogle ScholarPubMed
Jazdzewski, K., Murray, E.L., Franssila, K., Jarzab, B., Schoenberg, D.R., de la Chapelle, A.Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A 2008;105:72697274.CrossRefGoogle ScholarPubMed
Kelley, K.W., Dantzer, R.Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders. Brain Behav Immun 2011;25(Suppl. 1):S13S20.CrossRefGoogle ScholarPubMed
Kohnke, M.D.Approach to the genetics of alcoholism: a review based on pathophysiology. Biochem Pharmacol 2008;75:160177.CrossRefGoogle ScholarPubMed
Lewohl, J.M., Nunez, Y.O., Dodd, P.R., Tiwari, G.R., Harris, R.A., Mayfield, R.D.Up-regulation of microRNAs in brain of human alcoholics. Alcohol Clin Exp Res 2011;35:19281937.CrossRefGoogle ScholarPubMed
Li, J., Li, J., Liu, X., Qin, S., Guan, Y., Liu, Y.et al.MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction. EMBO Mol Med 2013;5:14021414.CrossRefGoogle ScholarPubMed
Lippai, D., Bala, S., Csak, T., Kurt-Jones, E.A., Szabo, G.Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice. PLoS One 2013;8:e70945.CrossRefGoogle Scholar
Lofgren, S.E., Frostegard, J., Truedsson, L., Pons-Estel, B.A., D’Alfonso, S., Witte, T.et al.Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun 2012;13:268274.CrossRefGoogle ScholarPubMed
Lucas, S.M., Rothwell, N.J., Gibson, R.M.The role of inflammation in CNS injury and disease. Br J Pharmacol 2006;147(Suppl. 1):S232S240.CrossRefGoogle ScholarPubMed
Lukiw, W.J., Zhao, Y., Cui, J.G.An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 2008;283:3131531322.CrossRefGoogle ScholarPubMed
Manzardo, A.M., Gunewardena, S., Butler, M.G.Over-expression of the miRNA cluster at chromosome 14q32 in the alcoholic brain correlates with suppression of predicted target mRNA required for oligodendrocyte proliferation. Gene 2013;526:356363.CrossRefGoogle ScholarPubMed
Mishra, P.J., Bertino, J.R.MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 2009;10:399416.CrossRefGoogle ScholarPubMed
Nunez, Y.O., Truitt, J.M., Gorini, G., Ponomareva, O.N., Blednov, Y.A., Harris, R.A.et al.Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence. BMC Genomics 2013;14:725.CrossRefGoogle ScholarPubMed
Pietrzykowski, A.Z., Friesen, R.M., Martin, G.E., Puig, S.I., Nowak, C.L., Wynne, P.M.et al.Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 2008;59:274287.CrossRefGoogle Scholar
Posada, D., Buckley, T.R.Model selection and model averaging in phylogenetics: advantages of akaike information criterion and bayesian approaches over likelihood ratio tests. Syst Biol 2004;53:793808.CrossRefGoogle ScholarPubMed
Prescott, C.A., Kendler, K.S.Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 1999;156:3440.CrossRefGoogle Scholar
Reed, T., Page, W.F., Viken, R.J., Christian, J.C.Genetic predisposition to organ-specific endpoints of alcoholism. Alcohol Clin Exp Res 1996;20:15281533.CrossRefGoogle ScholarPubMed
Samochowiec, J., Kucharska-Mazur, J., Grzywacz, A., Jablonski, M., Rommelspacher, H., Samochowiec, A.et al.Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence. Neurosci Lett 2006;410:15.CrossRefGoogle ScholarPubMed
Shen, J., Ambrosone, C.B., DiCioccio, R.A., Odunsi, K., Lele, S.B., Zhao, H.A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis 2008;29:19631966.CrossRefGoogle Scholar
Taganov, K.D., Boldin, M.P., Chang, K.J., Baltimore, D.NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 2006;103:1248112486.CrossRefGoogle ScholarPubMed
Tapocik, J.D., Solomon, M., Flanigan, M., Meinhardt, M., Barbier, E., Schank, J.R.et al.Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence. Pharmacogenomics J 2013;13:286296.CrossRefGoogle ScholarPubMed
Valles, S.L., Blanco, A.M., Pascual, M., Guerri, C.Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 2004;14:365371.CrossRefGoogle ScholarPubMed
Wang, J., Wang, Q., Liu, H., Shao, N., Tan, B., Zhang, G.et al.The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms with cancer risk: a meta-analysis of 32 studies. Mutagenesis 2012;27:779788.CrossRefGoogle ScholarPubMed
Xu, B., Feng, N.H., Li, P.C., Tao, J., Wu, D., Zhang, Z.D.et al.A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate 2010;70:467472.CrossRefGoogle ScholarPubMed
Xu, T., Zhu, Y., Wei, Q.K., Yuan, Y., Zhou, F., Ge, Y.Y.et al.A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis 2008;29:21262131.CrossRefGoogle ScholarPubMed
Xu, W., Xu, J., Liu, S., Chen, B., Wang, X., Li, Y.et al.Effects of common polymorphisms rs11614913 in miR-196a2 and rs2910164 in miR-146a on cancer susceptibility: a meta-analysis. PLoS One 2011;6:e20471.CrossRefGoogle ScholarPubMed
Yan, J., Aliev, F., Webb, B.T., Kendler, K.S., Williamson, V.S., Edenberg, H.J.et al.Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. Addict Biol 2013 [Published online, ahead of print].Google ScholarPubMed
Zhao, J.L., Rao, D.S., Boldin, M.P., Taganov, K.D., O’Connell, R.M., Baltimore, D.NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A 2011;108:91849189.CrossRefGoogle ScholarPubMed
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