Dataset Information

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

ABSTRACT: Background:Micro RNAs act as a regulatory layer for pharmacogenomics-related gene ex-pression. 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 pa-tients with hepatotoxicity, 123 patients without hepatotoxicity, and 155 healthy controls using a PCR-RFLP 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.

SUBMITTER: Singh HO

PROVIDER: S-EPMC6728905 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Singh Hari Om HO Jadhav Sushma S Samani Dharmesh D Dhole Tapan N TN

Current genomics 20190201 2

<h4>Background</h4>Micro RNAs act as a regulatory layer for pharmacogenomics-related gene ex-pression. It could play a role in the efficacy and toxicity of the drug. The SNPs in miRNA genes are linked with different functional consequences.<h4>Methods</h4>Hence, we examined the miR (146a G/C, 149C/T, and 196aC/T) polymorphisms in 34 pa-tients with hepatotoxicity, 123 patients without hepatotoxicity, and 155 healthy controls using a PCR-RFLP method.<h4>Results</h4>In patients with hepatotoxicity, ...[more]

PMID: 31555064

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Project description:Background: Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences. This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies. Methods: PubMed, Embase, Scopus, and ScienceDirect databases were searched until 9 April 2018 to identify eligible studies. Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI). Studies that met the following criteria were excluded: review articles, meta-analysis, abstracts or conference papers; duplicate publications; studies on animals or cell-lines; studies without a case-control design; studies that did not report genotype frequencies. Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832. Stratified analysis according to quality scores, genotyping method, ethnicity, broad cancer category and cancer type was also performed. Results: Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population. The association was only significant in Asians but not Caucasians. In subgroup analysis, significant associations were found in high quality studies, gynecological cancers, ovarian, breast, and hepatocellular cancer. Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians. However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model. Conclusions: The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians. Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer. This study had some limitations such as significant heterogeneity in most contrasts, limited number of studies enrolling Africans or Caucasians ancestry and lack of adjustment for covariates and environmental interactions.

Project description:BackgroundMicroRNA-146a (miR-146a) was a key negative regulator of autoimmunity. V-Ets oncogene homolog 1 (Ets-1) was demonstrated to bind to the miR-146a promoter region and markedly affects miR-146a promoter activity. This study aimed to investigate the association of miR-146a and Ets-1 gene polymorphisms with pediatric uveitis in a Han Chinese population.Methodology/principal findingsA total of 520 patients and 1204 healthy controls were included in the present study. Five single-nucleotide polymorphisms (SNPs), miR-146a/rs2910164, miR-146a/rs57095329, miR-146a/rs6864584, ets-1/rs1128334 and ets-1/rs10893872 were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. The expression of Ets-1 in peripheral blood mononuclear cells from genotyped healthy controls was tested by real-time PCR. Two SNPs (rs2910164 and rs10893872) were associated with pediatric uveitis in this study. The frequencies of the rs2910164 GG genotype and G allele were significantly increased (Pc = 3.11×10(-4); Pc = 2.75×10(-6)) while the CC genotype and C allele were significantly decreased (Pc = 0.001; Pc = 2.75×10(-6)) in patients compared with normal controls. The frequencies of the rs10893872 CC genotype and C allele were significantly increased (Pc = 3.89×10(-4); Pc = 0.01) while the CT genotype and T allele were significantly decreased (Pc = 0.004; Pc = 0.01) in patients compared with normal controls. The SNP rs2910164 GG genotype and G/C allele were also associated with the presence of microvascular leakage as detected by fundus fluorescein angiography in pediatric uveitis (Pc = 0.01; Pc = 0.005, respectively). Ets-1 expression in rs10893872 CC carriers was significantly higher than in CT and TT individuals (Pc = 0.013). There was no association of the other three SNPs with pediatric uveitis.ConclusionsThis study shows that miR-146a and Ets-1 are both associated with pediatric uveitis in Han Chinese. SNP rs10893872 may affect the genetic predisposition to pediatric uveitis by modulating expression of Ets-1.

Dataset Information

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

Publications

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

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