Polymorphisms in miRNAs Gene (146a, 149, 196a) and Susceptibility to ARV-associated Hepatotoxicity

Author(s): Hari Om Singh*, Sushma Jadhav, Dharmesh Samani, Tapan N. Dhole.

Journal Name: Current Genomics

Volume 20 , Issue 2 , 2019

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Abstract:

Background: Micro RNAs act as a regulatory layer for pharmacogenomics-related gene expression. It could play a role in the efficacy and toxicity of the drug. The SNPs in miRNA genes are linked with different functional consequences.

Methods: Hence, we examined the miR (146a G/C, 149C/T, and 196aC/T) polymorphisms in 34 patients with hepatotoxicity, 123 patients without hepatotoxicity, and 155 healthy controls using a PCRRFLP method.

Results: In patients with hepatotoxicity, miR196aCT genotype and combined genotype GCT showed a risk for hepatotoxicity severity with borderline significance (OR=2.08, P=0.07; OR=2.88, P=0.06). While comparing between patients with hepatotoxicity and healthy controls, the combined genotypes CCC and GCT have shown a susceptibility to hepatotoxicity severity (OR=2.89, P=0.05; OR=2.60, P=0.09). The miR196TT genotype was associated with the individuals of advanced HIV disease stage (OR=3.68, P=0.04). In HIV patients who consumed alcohol and did not have hepatotoxicity, the miR 196aCT genotype showed susceptibility to acquisition of hepatotoxicity with borderline significance (OR=2.36, P=0.06).

Discussion: The miR149TT and 196aTT genotypes showed a risk of acquisition of hepatotoxicity to nevirapine usage among HIV patients without hepatotoxicity (OR=4.19, P=0.07; OR=1.97, P=0.84). In HIV patients with and without hepatotoxicity, the miR 196aCT genotype showed a risk of acquisition of hepatotoxicity and its severity to the combined use of alcohol and nevirapine, respectively (OR=14.18, P=0.08; OR=2.29, P=0.08). In multivariate logistic regression, taking nevirapine, 196aCT genotype had an independent risk factor for hepatotoxicity severity (OR=5.98, P=0.005; OR=2.38, P=0.05).

Conclusion: In conclusion, miR196aC/T polymorphism and combined genotypes GCT and CCC may facilitate the risk for acquisition of hepatotoxicity and its severity.

Keywords: miRNA polymorphisms, NNRTI regimen, Genetic predisposition, HIV patients, ARV- associated hepatotoxicity.

[1]
O’Brien, M.E.; Clark, R.A.; Besch, C.L.; Myers, L.; Kissinger, P. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J. Acquir. Immune Defic. Syndr., 2003, 34(1), 407-414.
[2]
Reisler, R.L.S.; Servoss, J.; Robbins, G.; Theodore, D.; Murphy, R.; Chung, R. In: Incidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment trials. The 1st IAS Conference on HIV Pathogenesis and Treatment; 2001 July 8–11; Buenos Aires, Argentina.
[3]
Minzi, O.M.; Irunde, H.; Moshiro, C. HIV patients presenting common adverse drug events caused by highly active antiretroviral therapy in Tanzania. Tanzan. J. Health Res., 2009, 11(1), 5-10.
[4]
Nagpal, M.; Tayal, V.; Kumar, S.; Gupta, U. Adverse drug reactions to antiretroviral therapy in AIDS patients at a tertiary care hospital in India: A prospective observational study. Indian J. Med. Sci., 2010, 64(1), 245-252.
[5]
Ingelman-Sundberg, M.; Sim, S.C.; Gomez, A.; Rodriguez-Antona, C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol. Ther., 2007, 116(1), 496-526.
[6]
Pratedrat, P.; Sopipong, W.; Makkoch, J.; Praianantathavorn, K.; Chuaypen, N.; Tangkijvanich, P.; Payungporn, S. Single nucleotide polymorphisms in miR-149 (rs2292832) and miR-101-1 (rs7536540) are not associated with hepatocellular carcinoma in thai patients with hepatitis B virus infection. Asian Pac. J. Cancer Prev., 2015, 16(1), 6457-6461.
[7]
Swaminathan, G.; Navas-Martín, S.; Martín-García, J. MicroRNAs and HIV-1 infection: Antiviral activities and beyond. J. Mol. Biol., 2014, 426(1), 1178-1197.
[8]
Swaminathan, S.; Kelleher, A.D. MicroRNA modulation of key targets associated with T cell exhaustion in HIV-1 infection. Curr. Opin. HIV AIDS, 2014, 9(1), 464-471.
[9]
Biasin, M.; De Luca, M.; Gnudi, F.; Clerici, M. The genetic basis of resistance to HIV infection and disease progression. Expert Rev. Clin. Immunol., 2013, 9(1), 319-334.
[10]
Bartel, D.P. MicroRNA: genomics, biogenesis and function. Cell, 2004, 116(1), 281-297.
[11]
Dweep, H.; Gretz, N.; Felekkis, K. A schematic workflow for collecting information about the interaction between copy number variants and microRNAs using existing resources. Methods Mol. Biol., 2014, 1182(1), 307-320.
[12]
Munshi, S.U.; Panda, H.; Holla, P.; Rewari, B.B.; Jameel, S. MicroRNA-150 is a potential biomarker of HIV/AIDS disease progression and therapy. PLoS One, 2014, 9(1), e95920.
[13]
Zhou, Y.; Sun, L.; Wang, X.; Liang, H.; Ye, L.; Zhou, L.; Liang, B.Y.; Li, J.L.; Liu, M.Q.; Peng, J.S.; Zhou, D.J.; Gui, X.E.; Ho, W.Z. Short communication: HIV-1 infection suppresses circulating viral restriction microRNAs. AIDS Res. Hum. Retro, 2016, 32(1), 386-389.
[14]
Egaña-Gorroño, L.; Escribà, T.; Boulanger, N.; Guardo, A.C.; León, A.; Bargalló, M.E.; Garcia, F.; Gatell, J.M.; Plana, M.; Arnedo, M. HIVControllersConsortium of the AIDSSpanishNetwork. HIV controllers’ consortium of the AIDS Spanish network. Differential microRNA expression profile between stimulated PBMCs from HIV-1 infected elite controllers and viremicprogressors. PLoS One, 2014, 9(1), e106360.
[15]
Monteleone, K.; Selvaggi, C.; Cacciotti, G.; Falasca, F.; Mezzaroma, I.; D’Ettorre, G.; Turriziani, O.; Vullo, V.; Antonelli, G.; Scagnolari, C. MicroRNA-29 family expression and its relation to antiviral immune response and viro-immunological markers in HIV-1-infected patients. BMC Infect. Dis., 2015, 15(1), 51.
[16]
Barichievy, S.; Naidoo, J.; Mhlanga, M.M. Non-coding RNAs and HIV: Viral manipulation of host dark matter to shape the cellular environment. Front. Genet., 2015, 6(1), 108.
[17]
Rice, A.P. Roles of microRNAs and long-noncoding RNAs in human immunodeficiency virus replication. Wiley Interdiscip. Rev. RNA, 2015, 6(1), 661-670.
[18]
Peckham-Gregory, E.C.; Thapa, D.R.; Martinson, J.; Duggal, P.; Penugonda, S.; Bream, J.H.; Chang, P.Y.; Dandekar, S. Chang, S.C.; Detels, R.; Martínez-Maza, O.; Zhang, Z.F.; Hussain S.K. MicroRNA-related polymorphisms and non-Hodgkin lymphoma susceptibility in the multicenter AIDS cohort study. Cancer Epidemiol., 2016, 45(1), 47-57.
[19]
The emerging role of MIR- 146a in the control of hematopoiesis, immune function and cancer. J. Hematol. Oncol., 2010, 5(13), 1-10.
[http://dx.doi.org/10.1186/1756-8722-5-13]
[20]
Wang, A.X.; Xu, B.; Tong, N.; Chen, S.Q.; Yang, Y.; Zhang, X.W.; Jiang, H.; Liu, N.; Liu, J.; Hu, X.N.; Sha, G.Z.; Chen, M. Meta-analysis confirms that a common G/C variant in the pre-miR-146a gene contributes to cancer susceptibility and that ethnicity gender and smoking status are risk. Genet. Mol. Res., 2012, 11(3), 3051-3062.
[21]
Yue, C.; Wang, M.; Ding, B.; Wang, W.; Fu, S.; Zhou, D.; Zhang, Z.; Han, S. Polymorphism of the pre-miRNA146a is associated with risk of cervical cancer in a Chinese population. Gynecol. Oncol., 2011, 122(1), 33-37.
[22]
Palmieri, A.; Carinci, F.; Martinelli, M.; Pezzetti, F.; Girardi, A.; Cura, F.; Rubini, C.; Scapoli, L. Role of the MiR146a polymorphism in the origin and progression of oral squamous cell carcinoma. Eur. J. Oral Sci., 2014, 122(3), 198-201.
[23]
Lian, H.; Wang, L.; Zhang, J. Increased risk of breast cancer associated with CC genotype of hsa-miRNA146a rs2910164 polymorphism in Europeans. PLoS One, 2012, 7, e31615.
[24]
Qi, P.; Wang, L.; Zhou, B.; Yao, W.J.; Xu, S.; Zhou, Y.; Xie, Z.B. Associations of miRNA polymorphisms and expression levels with breast cancer risk in the Chinese population. Genet. Mol. Res., 2015, 14(2), 6289-6296.
[25]
Wang, Z.; Zhang, L.; Shi, X.; Xu, H.; Wang, T.; Bian, J. Association between two common polymorphisms and risk of hepatocellular carcinoma: Evidence from an updated meta-analysis. Biomed Res. Int., 2014, 2014(1)
[http://dx.doi.org/10.1155/2014/468605]
[26]
Chu, Y.H.; Tzeng, S S,L.; Lin, C.W.; Chien, M.H.; Chen, M.K.; Yang, S.F. Impacts of miRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer. PLoS One., 2012, 7(6), e39777.
[http://dx.doi.org/10.1371/journal. pone.0039777]
[27]
Min, K.T.; Kim, J.W.; Jeon, Y.J.; Jang, M.J.; Chong, S.Y.; Oh, D.; Kim, N.K. Association of the miRNA146a C>G, 149C>T, 196a2C>T and 499A>G polymorphism with colorectal cancer in the Korean population. Mol. Carcinog., 2012, 51(Suppl. 1), 65-73.
[28]
Du, W.; Ma, X.L.; Zhao, C.; Liu, T.; Du, Y.L.; Kong, W.Q.; Wei, B.L.; Yu, J.Y.; Li, Y.Y.; Huang, J.W.; Li, Z.K.; Liu, L. Associations of single nucleotide polymorphisms in miR-146a, miR-196a, miR-149 and miR-499 with colorectal cancer susceptibility. Asian Pac. J. Cancer Prev., 2014, 15(2), 1047-1055.
[29]
Tian, T.; Shu, Y.; Chen, J.; Hu, Z.; Xu, L.; Jin, G.; Liang, J.; Liu, P. Zhou, X.; Miao, R.; Ma, H.; Chen, Y.; Shen, H. A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol. Biomarkers Prev., 2009, 18(4), 1183-1187.
[30]
Hasani, S.S.; Hashemi, M. Eskandari-Nasab, E.; Naderi, M.; Omrani, M.; Sheybani-Nasab, M. A function polymorphism in the miR-146a gene is associated with the risk of childhood acute lymphoblastic leukemia: A preliminary report. Tumour Biol., 2014, 35(1), 219-225.
[31]
Orsós, Z.; Szanyi, I.; Csejtei, A.; Gerlinger, I.; Ember, I.; Kiss, I. Association of premiR-146a rs2910164 polymorphism with the risk of head and neck cancer. Anticancer Res., 2013, 33(1), 341-346.
[32]
Xu, Z.; Zhang, L.; Cao, H.; Bai, B. MiR-146a rs2910164 G/C polymorphism and gastric cancer susceptibility: A meta-analysis. BMC Med. Genet., 2014, 15(117)
[http://dx.doi.org/10.1186/s12881-014-0117-2]
[33]
Maharaj, N.R.; Ramkaran, P.; Pillay, S.; Chuturgoon, A.A. MicroRNA-27a rs895819 is associated with obesity in HIV infected preeclamptic Black South African women on HAART. BMC Med. Genet., 2014, 15, 117.
[34]
Huang, G.L.; Lu, Y.; Pu, X.X.; He, Y.X.; Chen, M.L.; Li, Y.Z.; Tang, S.Y.; Che, H.; He, Z. Association study between miR149 gene polymorphism and nasopharyngeal carcinoma. Biomed. Rep., 2013, 1(4), 599-603.
[35]
Bansal, C.; Sharma, K.L.; Misra, S.; Srivastava, A.N.; Mittal, B.; Singh, U.S. Common genetic variants in pre-microRNAs and risk of breast cancer in the North Indian population. Ecancermedicalscience, 2014, 8(473)
[http://dx.doi.org/10.3332/ecancer.2014.473]
[36]
Sushma, P.S.; Jamil, K.; Kumar, P.U.; Satyanarayana, U.; Ramakrishna, M.; Triveni, B. Genetic variation in micrornas and risk of oral squamous cell carcinoma in south indian population. Asian Pac. J. Cancer Prev., 2015, 16(17), 7589-7594.
[37]
Chansing, K.; Pakakasama, S.; Hongeng, S.; Thongmee, A.; Pongstaporn, W. Lack of association between the mir146a polymorphism and susceptibility to thai childhood acute lymphoblastic leukemia. Asian Pac. J. Cancer Prev., 2016, 17(5), 2435-2438.
[38]
Chen, X.J.; Zhou, T.Y.; Chen, M.; Li, N.; Liu, F. Association of the miRNA146ars2910164C>GPolymorphism with head and neckcancerrisk: A meta-analysis. Asian Pac. J. Cancer Prev., 2015, 16, 3871-3874.
[39]
Kim, W.H.; Min, K.T.; Jeon, Y.J.; Kwon, C.I.; Ko, K.H.; Park, P.W.; Hong, S.P.; Rim, K.S.; Kwon, S.W.; Hwang, S.G. Kim. N.K. Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population. Gene, 2012, 504(1), 92-97.
[40]
Slaby, O.; Bienertova-Vasku, J.; Svoboda, M.; Vyzula, R. Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. J. Cell. Mol. Med., 2012, 16(1), 8-21.
[41]
Palmer, L.J.; Cardon, L.R. Shaking the tree: Mapping complex disease genes with linkage disequilibrium. Lancet, 2005, 366(9492), 1223-1234.
[42]
Samet, J.H.; Cheng, D.M.; Libman, H.; Nunes, D.P.; Alperen, J.K.; Saitz, R. Alcohol consumption and HIV disease progression. J. Acquir. Immune Defic. Syndr., 2007, 46(2), 194-199.
[43]
Feldman, J.G.; Minkoff, H.; Schneider, M.F.; Gange, S.J.; Cohen, M.; Watts, D.H.; Gandhi, M.; Mocharnuk, R.S.; Anastos, K. Association of cigarette smoking with HIV prognosis among women in the HAART era: a report from the women’s interagency HIV study. Am. J. Public Health, 2006, 96(6), 1060-1065.


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Article Details

VOLUME: 20
ISSUE: 2
Year: 2019
Page: [134 - 150]
Pages: 17
DOI: 10.2174/1389202920666190325161439
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