Browsing by Author "Wei, Rongrong"

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    Epidermal Growth Factor Receptor (EGFR) Pathway Genes and Interstitial Lung Disease: An Association Study
    (Springer Nature, 2014-05-13) Li, Chong; Wei, Rongrong; Jones-Hall, Yava L.; Vittal, Ragini; Zhang, Min; Liu, Wanqing; Medicine, School of Medicine
    The etiology and pathogenesis of idiopathic interstitial lung disease (ILD) remain incompletely understood. Genetic susceptibility to ILD has been demonstrated in previous studies. It is well known that EGFR inhibitors can induce ILD in human lung cancer patient with ethnic differences, which prompted us to hypothesize that genetic variation in EGFR pathway genes confer susceptibility to ILD. We aimed in this study to investigate whether functional polymorphisms of EGFR and its ligands genes (EGF and TGFA) were associated with ILD. Three EGFR [-216G/T (rs712830), -191A/C (rs712829), 497R > K(A/G) (rs2227983)], one EGF [61A/G, (rs4444903)] and one TGFA (rs3821262C/T) polymorphisms previously demonstrated to alter gene functions were genotyped in 229 sporadic idiopathic ILD patients and 693 normal healthy individuals. Allelic and genotypic association tests between these polymorphisms and ILD were performed. The EGF 61A/G polymorphism was significantly associated with elevated risk of ILD, with the frequency of G allele significantly increased in the ILD patient population (OR = 1.33, 95%CI = 1.07-1.66, P = 0.0099). None of the other polymorphisms were associated with risk of ILD. Our study suggested that the EGF 61A/G polymorphism may be associated with sporadic ILD. While a false positive finding cannot be excluded, independent studies are warranted to further validate this result.
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    Genetic Polymorphism of Cytochrome P450 4F2, Vitamin E Level and Histological Response in Adults and Children with Nonalcoholic Fatty Liver Disease Who Participated in PIVENS and TONIC Clinical Trials
    (Public Library of Science, 2014-04-23) Athinarayanan, Shaminie; Wei, Rongrong; Zhang, Min; Bai, Shaochun; Traber, Maret G.; Yates, Katherine; Cummings, Oscar W.; Molleston, Jean; Liu, Wanqing; Chalasani, Naga; Medical and Molecular Genetics, School of Medicine
    Vitamin E improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but with significant inter-individual variability in its efficacy. Cytochrome P450 4F2 (CYP4F2) is the major enzyme metabolizing Vit E, with two common genetic variants (V433M, rs2108622 and W12G, rs3093105) found to alter its activity. We investigated the relationship between CYP4F2 genotypes, α-tocopherol levels and histological improvement in these two trials. V433M and W12G variants were genotyped in TONIC (n = 155) and PIVENS (n = 213) DNA samples. The relationships between CYP4F2 genotypes, plasma α-tocopherol levels at baseline and weeks 48 (w48) and 96 (w96) and histological end points (overall improvement in liver histology and resolution of NASH) were investigated. As a result, the V433M genotype was significantly associated with baseline plasma α-tocopherol in the TONIC trial (p = 0.004), but not in PIVENS. Among those receiving Vit E treatment, CYP4F2 V433M genotype was associated with significantly decreased plasma α-tocopherol levels at w48 (p = 0.003 for PIVENS and p = 0.026 for TONIC) but not at w96. The w96 α-tocopherol level was significantly associated with resolution of NASH (p = 0.006) and overall histology improvement (p = 0.021)in the PIVENS, but not in the TONIC trial. There was no significant association between CYP4F2 genotypes and histological end points in either trial. Our study suggested the a moderate role of CYP4F2 polymorphisms in affecting the pharmacokinetics of Vit E as a therapeutic agent. In addition, there may be age-dependent relationship between CYP4F2 genetic variability and Vit E pharmacokinetics in NAFLD.
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    Integrated miR-mRNA Network Underlying Hepatic Fat Accumulation in Humans
    Srivastava, Rajneesh; Wang, Xiaoliang; Lin, Jingmei; Wei, Rongrong; Chaturvedi, Praneet; Chalasani, Naga P.; Janga, Sarath Chandra; Liu, Wanqing
    Background: An integrate miRs and mRNAs analysis in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) is lacking. We aimed to identify miRs as well as the miR-mRNA regulatory network involved in hepatic fat accumulation and human NAFLD. Materials and Methods: Hepatic fat content (HFC) was measured, and liver histology was characterized for 73 liver tissue samples. MicroRNAs and mRNAs significantly associated with HFC were identified based on genome-wide mRNA and miR expression profiling data. These miRs and mRNAs were further used to build miR-mRNA association networks in NAFLD and normal samples based on the potential miR-mRNA targeting, as well as to conduct a pathway enrichment analysis. Results: We identified 62 miRs significantly correlated with HFC (p<0.05), with miR-518b and miR-19b demonstrated to be the most significant positive and negative correlation with HFC, respectively (p<0.008 for both). Many miRs that were previously associated with NAFLD/NASH were also observed. Integrated network analysis indicated that a few miRs-30b*, 616, 17*, 129-5p, 204, and 20a controlled >80% of HFC-associated mRNAs in this network, and the regulation network was significantly rewired from normal to NAFLD. Pathway analyses revealed that inflammation pathways mediated by chemokine and cytokine signaling, Wnt signaling, lntegrin signaling and Natural killer cell mediated cytotoxicity were enriched (p<0.05) in hepatic fat accumulation.
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    Relationship between Differential Hepatic microRNA Expression and Decreased Hepatic Cytochrome P450 3A Activity in Cirrhosis
    (2013-09) Vuppalanchi, Raj; Liang, Tiebing; Goswami, Chirayu Pankaj; Nalamasu, Rohit; Li, Lang; Jones, David; Wei, Rongrong; Liu, Wanqing; Sarasani, Vishal; Janga, Sarath Chandra; Chalasani, Naga
    Background and Aim Liver cirrhosis is associated with decreased hepatic cytochrome P4503A (CYP3A) activity but the pathogenesis of this phenomenon is not well elucidated. In this study, we examined if certain microRNAs (miRNA) are associated with decreased hepatic CYP3A activity in cirrhosis. Methods Hepatic CYP3A activity and miRNA microarray expression profiles were measured in cirrhotic (n=28) and normal (n=12) liver tissue. Hepatic CYP3A activity was measured via midazolam hydroxylation in human liver microsomes. Additionally, hepatic CYP3A4 protein concentration and the expression of CYP3A4 mRNA were measured. Analyses were conducted to identify miRNAs which were differentially expressed between two groups but also were significantly associated with lower hepatic CYP3A activity. Results Hepatic CYP3A activity in cirrhotic livers was 1.7-fold lower than in the normal livers (0.28 ± 0.06 vs. 0.47 ± 0.07mL* min-1*mg protein-1 (mean ± SEM), P=0.02). Six microRNAs (miR-155, miR-454, miR-582-5p, let-7f-1*, miR-181d, and miR-500) had >1.2-fold increase in cirrhotic livers and also had significant negative correlation with hepatic CYP3A activity (range of r = -0.44 to -0.52, P <0.05). Notably, miR-155, a known regulator of liver inflammation, had the highest fold increase in cirrhotic livers (2.2-fold, P=4.16E-08) and significantly correlated with hepatic CYP3A activity (r=-0.50, P=0.017). The relative expression (2-ΔΔCt mean ± SEM) of hepatic CYP3A4 mRNA was significantly higher in cirrhotic livers (21.76 ± 2.65 vs. 5.91 ± 1.29, P=2.04E-07) but their levels did not significantly correlate with hepatic CYP3A activity (r=-0.43, P=0.08). Conclusion The strong association between certain miRNAs, notably miR-155, and lower hepatic CYP3A activity suggest that altered miRNA expression may regulate hepatic CYP3A activity.