DNA methylation and smoking in Korean adults: epigenome-wide association study

Lee, Mi Kyeong,Hong, Yoonki,Kim, Sun-Young,London, Stephanie J.,Kim, Woo Jin BioMed Central 2016 CLINICAL EPIGENETICS Vol.8 No.-

<P><B>Background</B></P><P>Exposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases. However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood. Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes. There are few data on regional methylation changes in relation to smoking. Few data link differential methylation in blood to differential gene expression in lung tissue.</P><P><B>Results</B></P><P>We identified 108 significant (false discovery rate (FDR) < 0.05) differentially methylated probes (DMPs) and 87 significant differentially methylated regions (DMRs) (multiple-testing corrected <I>p</I> < 0.01) in current compared to never smokers from our EWAS of cotinine-validated smoking in blood DNA from a Korean chronic obstructive pulmonary disease cohort (<I>n</I> = 100 including 31 current, 30 former, and 39 never smokers) using Illumina HumanMethylation450 BeadChip. Of the 108 DMPs (FDR < 0.05), nine CpGs were statistically significant based on Bonferroni correction and 93 were novel including five that mapped to loci previously associated with smoking. Of the 87 DMRs, 66 were mapped to novel loci. Methylation correlated with urine cotinine levels in current smokers at six DMPs, with pack-years in current smokers at six DMPs, and with duration of smoking cessation in former smokers at eight DMPs. Of the 143 genes to which our significant DMPs or DMRs annotated, gene expression levels at 20 genes were associated with pack-years in lung tissue transcriptome data of smokers (Asan Biobank, <I>n</I> = 188).</P><P><B>Conclusions</B></P><P>Our study of differential methylation in Koreans confirmed previous findings from non-Asian populations and revealed novel loci in relation to smoking. Smoking-related differential methylation in blood is associated with gene expression in lung tissue, an important target of adverse health effects of smoking, supporting the potential functional importance of methylation in smoking-related disease.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13148-016-0266-6) contains supplementary material, which is available to authorized users.</P>

Epigenome-wide association study of chronic obstructive pulmonary disease and lung function in Koreans

Lee, Mi Kyeong,Hong, Yoonki,Kim, Sun-Young,Kim, Woo Jin,London, Stephanie J Future Medicine Ltd 2017 Epigenomics Vol.9 No.7

<P><B>Aim:</B></P><P>To identify differentially methylated probes (DMPs) and regions (DMRs) in relation to chronic obstructive pulmonary disease (COPD) and lung function traits.</P><P><B>Methods:</B></P><P>We performed an epigenome-wide association study of COPD and spirometric parameters, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC, in blood DNA using the Infinium HumanMethylation450 (n = 100, a Korean COPD cohort).</P><P><B>Results:</B></P><P>We found one significant DMP (cg03559389, <I>DIP2C</I>) and 104 significant DMRs after multiple-testing correction. Of these, 34 DMRs mapped to genes differential expressed with respect to the same trait. Five of the genes were associated with more than two traits: <I>CTU2, USP36, ZNF516, KLK10</I> and <I>CPT1B</I>.</P><P><B>Conclusion:</B></P><P>We identified novel differential methylation loci related to COPD and lung function in blood DNA in Koreans and confirmed previous findings in non-Asians. Epigenetic modification could contribute to the etiology of these phenotypes.</P>

Treatment of chronic graft-versus-host disease: Past, present and future

Paul J. Martin,Yoshihiro Inamoto,Paul A. Carpenter,Stephanie J. Lee,Mary E.D. Flowers 대한혈액학회 2011 Blood Research Vol.46 No.3

Chronic GVHD was recognized as a complication of allogeneic hematopoietic cell transplantation more than 30 years ago, but progress has been slowed by the limited insight into the pathogenesis of the disease and the mechanisms that lead to development of immunological tolerance. Only 6 randomized phase III treatment studies have been reported. Results of retrospective studies and prospective phase II clinical trials suggested overall benefit from treatment with mycophenolate mofetil or thalidomide, but these results were not substantiated by phase III studies of initial systemic treatment for chronic GVHD. A comprehensive review of published reports showed numerous deficiencies in studies of secondary treatment for chronic GVHD. Fewer than 10% of reports documented an effort to minimize patient selection bias, used a consistent treatment regimen, or tested a formal statistical hypothesis that was based on a contemporaneous or historical benchmark. In order to enable valid comparison of the results from different studies, eligibility criteria, definitions of individual organ and overall response, and time of assessment should be standardized. Improved treatments are more likely to emerge if reviewers and journal editors hold authors to higher standards in evaluating manuscripts for publication.

Chemical Modification of Environmentally Sensitive Plants with Ga Biosynthesis Inhibitors in Response to SO2 Stress

(Edward H . Lee),(Jae Kyun Byun),(Stephanie J . Wilding) 영남대학교 자원문제연구소 1987 資源問題硏究 Vol.6 No.-

A New Gibberellin Biosyathesis Inhibitor , Paelobutrazol (PPsss) , Confers Ineressed SO2 Tolerance on Snap Bean Plants

(Edward H . Lee),(Jae Kyun Byun),(Stephanie J . Wilding) 영남대학교 자원문제연구소 1987 資源問題硏究 Vol.6 No.-

Off-Target Effect of doublecortin Family shRNA on Neuronal Migration Associated with Endogenous MicroRNA Dysregulation

Baek, S.,Kerjan, G.,Bielas, Stephanie L.,Lee, J.,Fenstermaker, Ali G.,Novarino, G.,Gleeson, Joseph G. Cell Press 2014 Neuron Vol.82 No.6

Acute gene inactivation using short hairpin RNA (shRNA, knockdown) in developing brain is a powerful technique to study genetic function; however, discrepancies between knockdown and knockout murine phenotypes have left unanswered questions. For example, doublecortin (Dcx) knockdown but not knockout shows a neocortical neuronal migration phenotype. Here we report that in utero electroporation of shRNA, but not siRNA or miRNA, to Dcx demonstrates a migration phenotype in Dcx knockouts akin to the effect in wild-type mice, suggesting shRNA-mediated off-target toxicity. This effect was not limited to Dcx, as it was observed in Dclk1 knockouts, as well as with a fraction of scrambled shRNAs, suggesting a sequence-dependent but not sequence-specific effect. Profiling RNAs from electroporated cells showed a defect in endogenous let7 miRNA levels, and disruption of let7 or Dicer recapitulated the migration defect. The results suggest that shRNA-mediated knockdown can produce untoward migration effects by altering endogenous miRNA pathways.

In vivo tumour imaging employing regional delivery of novel Gallium radiolabelled polymer composites

Ross W. Stephens,Gregory D. Tredwell,Jessica L. Bell,Karen J. Knox,Lee A. Philip,Tim J. Senden,Michael J. Tapner,Stephanie A. Bickley,Marcel R. Tanudji,Stephen K. Jones 한국생체재료학회 2021 생체재료학회지 Vol.25 No.2

Background: Understanding the regional vascular delivery of particles to tumour sites is a prerequisite for developing new diagnostic and therapeutic composites for treatment of oncology patients. We describe a novel imageable 67Ga-radiolabelled polymer composite that is biocompatible in an animal tumour model and can be used for preclinical imaging investigations of the transit of different sized particles through arterial networks of normal and tumour-bearing organs. Results: Radiolabelling of polymer microspheres with 67Ga was achieved using a simple mix and wash method, with tannic acid as an immobilising agent. Final in vitro binding yields after autoclaving averaged 94.7%. In vivo stability of the composite was demonstrated in New Zealand white rabbits by intravenous administration, and intrahepatic artery instillations were made in normal and VX2 tumour implanted rabbit livers. Stability of radiolabel was sufficient for rabbit lung and liver imaging over at least 3 hours and 1 hour respectively, with lung retention of radiolabel over 91%, and retention in both normal and VX2 implanted livers of over 95%. SPECT-CT imaging of anaesthetised animals and planar imaging of excised livers showed visible accumulation of radiolabel in tumours. Importantly, microsphere administration and complete liver dispersal was more easily achieved with 8 μm diameter MS than with 30 μm MS, and the smaller microspheres provided more distinct and localised tumour imaging. Conclusion: This method of producing 67Ga-radiolabelled polymer microspheres is suitable for SPECT-CT imaging of the regional vascular delivery of microspheres to tumour sites in animal models. Sharper distinction of model tumours from normal liver was obtained with smaller MS, and tumour resolution may be further improved by the use of 68Ga instead of 67Ga, to enable PET imaging.

Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1

Ha Choi, Ji,Wah Yee, Sook,Kim, Mee J.,Nguyen, Loan,Ho Lee, Jeong,Kang, Ji-One,Hesselson, Stephanie,Castro, Richard A.,Stryke, Doug,Johns, Susan J.,Kwok, Pui-Yan,Ferrin, Thomas E.,Goo Lee, Min,Black, B Lippincott Williams Wilkins, Inc. 2009 Pharmacogenetics and genomics Vol.19 No.10

OBJECTIVES: Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations. METHODS: We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays. RESULTS: Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.–66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.–66T>C. Results from electrophoretic mobility shift assays showed that the g.–66T allele, exhibited greater binding to AP-1 than the g.–66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.–66T>C. These data suggest that the reduced transcriptional activity of g.–66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.–66T>C in comparison with samples from individuals who were homozygous for the g.–66T allele. CONCLUSION: Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.–66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.