Publications by authors named "Weiliang Qiu"

103 Publications

MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation.

Thorax 2020 12 18;75(12):1047-1057. Epub 2020 Oct 18.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Introduction: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma.

Methods: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related mice were used for allergic models.

Results: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice.

Conclusion: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213771DOI Listing
December 2020

Genome-Wide Association Study: Functional Variant rs2076295 Regulates Desmoplakin Expression in Airway Epithelial Cells.

Am J Respir Crit Care Med 2020 11;202(9):1225-1236

Channing Division of Network Medicine and.

Genetic association studies have identified rs2076295 in association with idiopathic pulmonary fibrosis (IPF). We hypothesized that rs2076295 is the functional variant regulating () expression in human bronchial epithelial cells, and regulates extracellular matrix-related gene expression and cell migration, which is relevant to IPF development. To determine whether rs2076295 regulates expression and the function of DSP in airway epithelial cells. Using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 editing (including regional deletion, indel, CRISPR interference, and single-base editing), we modified rs2076295 and measured expression in edited 16HBE14o- and primary airway epithelial cells. Cellular integrity, migration, and genome-wide gene expression changes were examined in 16HBE14o- single colonies with knockout. The expression of and its relevant matrix genes was measured by quantitative PCR and also analyzed in single-cell RNA-sequencing data from control and IPF lungs. is expressed predominantly in bronchial and alveolar epithelial cells, with reduced expression in alveolar epithelial cells in IPF lungs. The deletion of the DNA region-spanning rs2076295 led to reduced expression of , and the edited rs2076295GG 16HBE14o- line has lower expression of than the rs2076295TT lines. Knockout of in 16HBE14o- cells decreased transepithelial resistance but increased cell migration, with increased expression of extracellular matrix-related genes, including and . Silencing of and abolished increased migration in -knockout cells. rs2076295 regulates expression in human airway epithelial cells. The loss of enhances extracellular matrix-related gene expression and promotes cell migration, which may contribute to the pathogenesis of IPF.
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http://dx.doi.org/10.1164/rccm.201910-1958OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605184PMC
November 2020

The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome.

PLoS One 2020 10;15(1):e0227616. Epub 2020 Jan 10.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care.

Method: Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline.

Results: 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively).

Conclusion: TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227616PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953865PMC
April 2020

Model-based clustering for identifying disease-associated SNPs in case-control genome-wide association studies.

Sci Rep 2019 09 23;9(1):13686. Epub 2019 Sep 23.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.

Genome-wide association studies (GWASs) aim to detect genetic risk factors for complex human diseases by identifying disease-associated single-nucleotide polymorphisms (SNPs). The traditional SNP-wise approach along with multiple testing adjustment is over-conservative and lack of power in many GWASs. In this article, we proposed a model-based clustering method that transforms the challenging high-dimension-small-sample-size problem to low-dimension-large-sample-size problem and borrows information across SNPs by grouping SNPs into three clusters. We pre-specify the patterns of clusters by minor allele frequencies of SNPs between cases and controls, and enforce the patterns with prior distributions. In the simulation studies our proposed novel model outperforms traditional SNP-wise approach by showing better controls of false discovery rate (FDR) and higher sensitivity. We re-analyzed two real studies to identifying SNPs associated with severe bortezomib-induced peripheral neuropathy (BiPN) in patients with multiple myeloma (MM). The original analysis in the literature failed to identify SNPs after FDR adjustment. Our proposed method not only detected the reported SNPs after FDR adjustment but also discovered a novel BiPN-associated SNP rs4351714 that has been reported to be related to MM in another study.
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http://dx.doi.org/10.1038/s41598-019-50229-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757104PMC
September 2019

The association between vitamin D status and clinical events in high-risk older patients with non-ST elevation acute coronary syndrome undergoing invasive management.

PLoS One 2019 12;14(6):e0217476. Epub 2019 Jun 12.

Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

There is a higher incidence of vitamin D deficiency in older adults. This may play a plausible mechanistic role in the occurrence of increased adverse events after non-ST elevation acute coronary syndrome (NSTEACS). This study investigated whether total vitamin D levels at the time of presentation predicted adverse outcomes in older adults undergoing invasive management of NSTEACS. Of the 629 patients screened, 300 high-risk older adults with NSTEACS managed by an invasive strategy were recruited. Serum total 25-hydroxyvitamin D was measured at index presentation. The primary outcome was defined as 1-year composite of all-cause mortality, acute coronary syndrome (ACS), unplanned repeat revascularisation, significant bleeding or stroke. Mean age was 80.5±4.8 years (61.9% male). Median vitamin D level was 29.5nmol/L [interquartile range IQR 16.0-53.0 nmol/L] and was split equally by the median for analysis forming two groups: high (median vitamin D 53.0 nmol/L [IQR 40.0-75.0]) and low (16.0 nmol/L [11.0-23.0]). The primary outcome occurred in 76 patients (25.9%); 32 (21.9%) in the low group and 44 (29.9%) in the high group, p = 0.12. Multivariable analyses showed no significant difference in the primary composite outcome at 1 year between the low and high group of baseline serum vitamin D (Hazard Ratio 1.20 [95% Confidence Interval 0.72-2.0], p = 0.48). Serum total vitamin D, measured at the time of angiography, was not associated with adverse outcomes at one year in this high-risk older cohort of patients with NSTEACS undergoing invasive management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561555PMC
March 2020

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.

Clin Exp Allergy 2019 09 15;49(9):1225-1234. Epub 2019 Aug 15.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known.

Objective: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma.

Methods: Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations.

Results: In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP.

Conclusion And Clinical Relevance: Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.
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http://dx.doi.org/10.1111/cea.13447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085934PMC
September 2019

An Investigation about Gene Modules Associated with hDPSC Differentiation for Adolescents.

Stem Cells Int 2019 4;2019:8913287. Epub 2019 Apr 4.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, USA.

Dental pulp stem cells (DPSCs) have the property of self-renewal and multidirectional differentiation so that they have the potential for future regenerative therapy of various diseases. The latest breakthrough in the biology of stem cells and the development of regenerative biology provides an effective strategy for regenerative therapy. However, in the medium promoting differentiation during long-term passage, DPSCs would lose their differentiation capability. Some efforts have been made to find genes influencing human DPSC (hDPSC) differentiation based on hDPSCs isolated from adults. However, hDPSC differentiation is a very complex process, which involves multiple genes and multielement interactions. The purpose of this study is to detect sets of correlated genes (i.e., gene modules) that are associated to hDPSC differentiation at the crown-completed stage of the third molars, by using weighted gene coexpression network analysis (WGCNA). Based on the gene expression dataset GSE10444 from Gene Expression Omnibus (GEO), we identified two significant gene modules: yellow module (742 genes) and salmon module (9 genes). The WEB-based Gene SeT AnaLysis Toolkit showed that the 742 genes in the yellow module were enriched in 59 KEGG pathways (including Wnt signaling pathway), while the 9 genes in the salmon module were enriched in one KEGG pathway (neurotrophin signaling pathway). There were 660 (7) genes upregulated at P10 and 82 (2) genes downregulated at P10 in the yellow (salmon) module. Our results provide new insights into the differentiation capability of hDPSCs.
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http://dx.doi.org/10.1155/2019/8913287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476005PMC
April 2019

First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers.

BMC Cancer 2019 Mar 28;19(1):279. Epub 2019 Mar 28.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.

Background: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors.

Methods: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored.

Results: No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed.

Conclusions: Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies.

Trial Registration: Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).
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http://dx.doi.org/10.1186/s12885-019-5471-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437929PMC
March 2019

Novel Data Transformations for RNA-seq Differential Expression Analysis.

Sci Rep 2019 03 18;9(1):4820. Epub 2019 Mar 18.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, USA.

We propose eight data transformations (r, r2, rv, rv2, l, l2, lv, and lv2) for RNA-seq data analysis aiming to make the transformed sample mean to be representative of the distribution center since it is not always possible to transform count data to satisfy the normality assumption. Simulation studies showed that for data sets with small (e.g., nCases = nControls = 3) or large sample size (e.g., nCases = nControls = 100) limma based on data from the l, l2, and r2 transformations performed better than limma based on data from the voom transformation in term of accuracy, FDR, and FNR. For datasets with moderate sample size (e.g., nCases = nControls = 30 or 50), limma with the rv and rv2 transformations performed similarly to limma with the voom transformation. Real data analysis results are consistent with simulation analysis results: limma with the r, l, r2, and l2 transformation performed better than limma with the voom transformation when sample sizes are small or large; limma with the rv and rv2 transformations performed similarly to limma with the voom transformation when sample sizes are moderate. We also observed from our data analyses that for datasets with large sample size, the gene-selection via the Wilcoxon rank sum test (a non-parametric two sample test method) based on the raw data outperformed limma based on the transformed data.
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http://dx.doi.org/10.1038/s41598-019-41315-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423143PMC
March 2019

Pilot study of DNA methylation, molecular aging markers and measures of health and well-being in aging.

Transl Psychiatry 2019 03 18;9(1):118. Epub 2019 Mar 18.

Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Relations of DNA methylation markers to other biological aging markers and to psychosocial, behavioral, and health measures remain unclear. The sample included 23 participants (n = 11 cases with psychiatric diagnoses and n = 12 controls without current or lifetime psychiatric disorder), balanced by age and sex. Genomic DNA was extracted from blood samples; the following were performed: genome-wide DNA methylation assay using Illumina 850k methylationEPIC; PCR assays for relative telomere length (RTL) and mitochondrial DNA copy number (mtCN). Exposures were: case status; depression and anxiety symptoms; psychosocial support; subjective and objective cognition. Outcomes were: DNA methylation age (DNAm age); RTL; mtCN; extrinsic and intrinsic epigenetic age acceleration (EEAA and IEAA). Stronger correlation with chronological age was observed for DNAm age (ρ = 0.86; p < 0.0001) compared to RTL (ρ = -0.53; p < 0.01); mtCN was not correlated with age. DNAm age was more strongly correlated with behavioral and health variables than RTL or mtCN; e.g., correlations with DNAm age: body mass index (ρ = 0.36; p = 0.10); smoking pack-years (ρ = 0.37; p = 0.08); physical activity (ρ = -0.56; p = 0.01); alcohol intake (ρ = 0.56; p = 0.01). DNAm age was inversely correlated with psychosocial support (ρ = -0.42; p = 0.048) and Modified Mini-Mental State score (ρ = -0.44; p = 0.01). Anxiety, psychosocial support, and objective cognition were significantly related to accelerated aging; depression and subjective cognition were not. In conclusion, DNAm age correlated more strongly with chronological age and key psychosocial, behavioral, and health variables than RTL or mtCN. Signals for associations with epigenetic aging were observed for psychosocial and neurobehavioral variables.
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http://dx.doi.org/10.1038/s41398-019-0446-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423054PMC
March 2019

Urine podoplanin heralds the onset of ischemia-reperfusion injury of the kidney.

Am J Physiol Renal Physiol 2019 05 13;316(5):F957-F965. Epub 2019 Mar 13.

Transplantation Research Center, Brigham and Women's Hospital , Boston, Massachusetts.

Ischemia-reperfusion injury represents one of the most common causes of acute kidney injury, a serious and often deadly condition that affects up to 20% of all hospitalized patients in the United States. However, the current standard assay used universally for the diagnosis of acute kidney injury, serum creatinine, does not detect renal damage early in its course. Serendipitously, we found that the immunofluorescent signal of the constitutive podocyte marker podoplanin fades in the glomerulus and intensifies in the tubulointerstitial compartment of the kidney shortly after ischemia-reperfusion injury in 8- to 10-wk-old male C57Bl/6j mice. Therefore, we sought to define the appearance and course of the podoplanin-positive signal in the kidney after ischemia-reperfusion injury. The tubulointerstitial podoplanin-positive signal increased as early as 2 h but persisted for 7 days after ischemia-reperfusion injury. In addition, the strength of this tubulointerstitial signal was directly proportional to the severity of ischemia, and its location shifted from the tubules to interstitial cells over time. Finally, we detected podoplanin in the urine of mice after ischemia, and we observed that an increase in the urine podoplanin-to-creatinine ratio correlated strongly with the onset of renal ischemia-reperfusion injury. Our findings indicate that the measurement of urine podoplanin harbors promising potential for use as a novel biomarker for the early detection of ischemia-reperfusion injury of the kidney.
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http://dx.doi.org/10.1152/ajprenal.00538.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580248PMC
May 2019

New Statistical Methods for Constructing Robust Differential Correlation Networks to characterize the interactions among microRNAs.

Sci Rep 2019 03 5;9(1):3499. Epub 2019 Mar 5.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, USA.

The interplay among microRNAs (miRNAs) plays an important role in the developments of complex human diseases. Co-expression networks can characterize the interactions among miRNAs. Differential correlation network is a powerful tool to investigate the differences of co-expression networks between cases and controls. To construct a differential correlation network, the Fisher's Z-transformation test is usually used. However, the Fisher's Z-transformation test requires the normality assumption, the violation of which would result in inflated Type I error rate. Several bootstrapping-based improvements for Fisher's Z test have been proposed. However, these methods are too computationally intensive to be used to construct differential correlation networks for high-throughput genomic data. In this article, we proposed six novel robust equal-correlation tests that are computationally efficient. The systematic simulation studies and a real microRNA data analysis showed that one of the six proposed tests (ST5) overall performed better than other methods.
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http://dx.doi.org/10.1038/s41598-019-40167-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401044PMC
March 2019

Coronary artery lesion phenotype in frail older patients with non-ST-elevation acute coronary syndrome undergoing invasive care.

EuroIntervention 2019 Jun 12;15(3):e261-e268. Epub 2019 Jun 12.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Aims: The association of frailty with coronary plaque phenotype among older patients with non-ST-elevation acute coronary syndrome (NSTEACS) is not known. The aim of this study was to evaluate the association of frailty with coronary plaque phenotype among older patients with NSTEACS.

Methods And Results: Older patients with NSTEACS who underwent invasive angiography were recruited. Frailty was measured using the Fried frailty score. Following angiography, patients underwent greyscale and virtual histology intravascular ultrasound (VH-IVUS) imaging. Of the 90 patients, 26 (28.9%) were robust, 49 (54.4%) patients were pre-frail, and 15 (16.7%) were frail. Mean age was 80.9±3.8 years; 59 (65.6%) were male. Compared to robust patients, the pre-frail group had a significantly greater presence of high-risk lesions including VH thin-cap fibroatheroma (TCFA, p=0.011), minimum lumen area (MLA) ≤4 mm2 (p=0.016), TCFA+MLA ≤4 mm2 (p=0.005), TCFA+plaque burden (PB) ≥70% (p=0.005) and TCFA+PB ≥70%+MLA ≤4 mm2 (p=0.003). By age- and sex-adjusted logistic regression analysis, frailty was found to be strongly and independently associated with the presence of TCFA (odds ratio [OR] 2.81, 95% confidence interval [CI]:1.06-7.48, p=0.039).

Conclusions: This is the first study to report the relationship between frailty phenotype and coronary plaque morphology among frail older NSTEACS patients. ClinicalTrials.gov Identifier: NCT01933581.
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http://dx.doi.org/10.4244/EIJ-D-18-00848DOI Listing
June 2019

Cognitive Decline in Older Patients With Non- ST Elevation Acute Coronary Syndrome.

J Am Heart Assoc 2019 02;8(4):e011218

1 Institute of Cellular Medicine Newcastle University Newcastle upon Tyne United Kingdom.

Background Dementia is a growing health burden of an aging population. This study aims to evaluate the prevalence of cognitive impairment and the predictors of cognitive decline at 1 year in older patients with non-ST-elevation acute coronary syndrome undergoing invasive care. Methods and Results Older patients with non-ST-elevation acute coronary syndrome were recruited into the ICON1 study. Cognition was evaluated using Montreal Cognitive Assessment. The composite major adverse cardiovascular events comprised death, myocardial infarction, unplanned revascularization, stroke, and significant bleeding at 1 year. Of 298 patients, 271 had cognitive assessment at baseline, and 211 (78%) had follow-up Montreal Cognitive Assessment at 1 year. Mean age was 80.5±4.8 years. There was a high prevalence (n=130, 48.0%) of undiagnosed cognitive impairment (Montreal Cognitive Assessment score <26) at baseline. Cognitive impairment patients were more likely to reach major adverse cardiovascular events by Kaplan-Meier analysis ( P=0.047). Seventy-four patients (35.1%) experienced cognitive decline (Montreal Cognitive Assessment score drop by ≥2 points) at 1 year. Recurrent myocardial infarction was independently associated with cognitive decline at 1 year (odds ratio 3.19, 95% confidence interval 1.18-8.63, P=0.02) after adjustment for age and sex. Conclusions In older patients undergoing invasive management of non-ST-elevation acute coronary syndrome, there is a high prevalence of undiagnosed cognitive impairment at baseline. Recurrent myocardial infarction is independently associated with cognitive decline at 1 year. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01933581.
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http://dx.doi.org/10.1161/JAHA.118.011218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405683PMC
February 2019

DNA methylation is associated with improvement in lung function on inhaled corticosteroids in pediatric asthmatics.

Pharmacogenet Genomics 2019 04;29(3):65-68

Channing Division of Network Medicine.

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known. We examined the association between peripheral blood DNA methylation and ICS treatment response in 152 pediatric persistent asthmatics from the Childhood Asthma Management Program. Response to ICS was measured by the percentage change in forced expiratory volume in 1 s (FEV1) 8 weeks after treatment initiation. The top CpG sites with a nominal P value less than 0.001 were correlated with gene expression using Pearson's and partial correlations. In 152 participants, mean±SD age was 9.8±2.0 years and median change in FEV1 after ICS initiation was 4.6% (interquartile range: 10.4%). A total of 545 CpG sites were differentially methylated (nominal P<0.05), and seven CpG sites had a nominal P value less than 0.001. Relative hypermethylation of cg20434811, cg02822723, cg14066280, cg27254601, and cg23913400 and relative hypomethylation of cg24937126 and cg24711626 were associated with an increase in FEV1 on ICS treatment. One CpG site was associated with gene expression. Relative hypermethylation of cg27254601 was associated with both an increase in FEV1 and BOLA2 expression (ρ=0.25, P=0.02). We identified a novel association between BOLA2 methylation, gene expression, and ICS response as measured by lung function. Pharmacoepigenetics has the potential to detect treatment sensitivity in persistent childhood asthma.
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http://dx.doi.org/10.1097/FPC.0000000000000366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399026PMC
April 2019

Gene expression changes in lymphoblastoid cell lines and primary B cells by dexamethasone.

Pharmacogenet Genomics 2019 04;29(3):58-64

Department of Medicine, Channing Division of Network Medicine.

Background: Human Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) have been thought to be a useful model system for pharmacogenomics studies. The purpose of this study was to determine the effect of Epstein-Barr virus transformation on gene expression changes by dexamethasone (Dex) in LCLs and primary B cells (PBCs) derived from the same individuals.

Patients And Methods: We prepared LCLs and purified PBCs from the same six male donors participating in the Childhood Asthma Management Program clinical trial, and compared mRNA profiles after 6 h incubation with Dex (10 mol/l) or sham buffer. We assessed differential expression and put the list of differentially expressed genes into the web interface of ConsensusPathDB to find the pathway-level interpretation of our genes specified. As a supplementary analysis, we looked at the expression of the Dex-regulated (inducing or repressing) genes in treatment-naive PBCs and LCLs (pre-Dex treatment) from the GSE30916 dataset.

Results: By hierarchical clustering, we found clustering of probes by cell types but not by individuals irrespective of Dex treatment. We observed that the Dex-regulated genes significantly overlapped in PBCs and LCLs. In addition, the expression of these genes showed significant correlations between treatment-naive PBCs and LCLs. Common genes showing significantly decreased expressions by the Dex treatment in both cells were enriched in immune responses and proinflammatory signaling pathways.

Conclusion: Taken together, these results suggest the uses of LCLs are representative of the primary biologic effects of corticosteroids treatment.
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http://dx.doi.org/10.1097/FPC.0000000000000365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172499PMC
April 2019

Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease.

J Mol Med (Berl) 2018 12 23;96(12):1375-1385. Epub 2018 Oct 23.

Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, 02115, USA.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia. However, the Long-term Oxygen Treatment Trial (LOTT), a large randomized trial, found no benefit of oxygen therapy in COPD patients with moderate hypoxemia. We hypothesized that there may be differences in response to oxygen which depend on genotype or gene expression. In a genome-wide time-to-event analysis of the primary outcome of death or hospitalization in 331 subjects, 97 single nucleotide polymorphisms (SNPs) showed evidence of interaction with oxygen therapy at P < 1e-5, including 7 SNPs near arylsulfatase B (ARSB; P = 6e-6). In microarray expression profiling on 51 whole blood samples from 37 individuals, at screening and/or at 12-month follow-up, ARSB expression was associated with the primary outcome depending on oxygen treatment. The significant SNPs were conditional expression quantitative trait loci for ARSB expression. In a network analysis of genes affected by long-term oxygen, two observed clusters including 26 co-expressed genes were enriched in mitochondrial function. Using data from the observational COPDGene Study, we validated the expression of 25 of these 26 genes, plus ARSB. The effect of long-term oxygen therapy in COPD varied based on ARSB expression and genotype. ARSB has previously been shown to be associated with hypoxemia in human bronchial and colonic epithelial cells and in a mouse model. In peripheral blood, long-term oxygen treatment affected expression of mitochondrial-related genes, a biologically relevant pathway in COPD. SNPs and expression of ARSB are associated with response to long-term oxygen in COPD. The ARSB SNPs were expression quantitative trait loci depending on oxygen therapy. Genes differentially expressed by long-term oxygen were enriched in mitochondrial functions. This suggests a potential biomarker to personalize use of long-term oxygen in COPD.
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http://dx.doi.org/10.1007/s00109-018-1708-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240374PMC
December 2018

One-year clinical outcomes in older patients with non-ST elevation acute coronary syndrome undergoing coronary angiography: An analysis of the ICON1 study.

Int J Cardiol 2019 Jan 28;274:45-51. Epub 2018 Sep 28.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK. Electronic address:

Aims: The aim of this prospective, observational study was to identify predictors of adverse outcome at one year, following invasive care of older patients with non-ST-elevation acute coronary syndrome (NSTEACS) according to frailty status.

Methods: Older patients (aged ≥ 75 years), presenting with NSTEACS, undergoing invasive coronary angiography with a view to revascularisation, underwent assessment of frailty, cognition, functional status and quality of life. Participants were categorised as robust, pre-frail or frail using the Fried criteria. The primary outcome comprised a composite of all-cause mortality, myocardial infarction, stroke, unplanned revascularisation and major bleeding, at one year. Cox proportional hazards regression was used to derive a multivariate risk score.

Results: Overall, the composite endpoint was observed in 81 participants (29%). There was a significant difference in the occurrence of the primary outcome in the 3 frailty groups (robust 18.0%, pre-frail 27.5% and frail 39%; p = 0.03; hazard ratio (HR) for frail vs. robust: 2.79, 95% Confidence Interval [CI] 1.28-6.08). Fried frailty classification, age (categorised as ≥85 years), raised Killip class, systolic blood pressure on admission, history of peripheral vascular disease (PVD), problems dressing self and implantation of a bare metal stent were identified as predictors of adverse events at one year, with a C-statistic of 0.77 (95% CI 0.71-0.83). A point-based clinical risk score (FRAIL-HEART) was defined, which had a C-statistic of 0.70 (95% CI 0.63-0.77) and significantly outperformed the GRACE 2 score.

Conclusion: Frailty is associated with adverse clinical outcomes, following invasive management of older patients with NSTEACS. The derived risk models may enable improved risk stratification in practice.
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http://dx.doi.org/10.1016/j.ijcard.2018.09.086DOI Listing
January 2019

Impact of Preeclampsia on the Relationship between Maternal Asthma and Offspring Asthma. An Observation from the VDAART Clinical Trial.

Am J Respir Crit Care Med 2019 01;199(1):32-42

1 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Rationale: Maternal asthma and preeclampsia have independently been reported to be associated with increased asthma incidence in children of affected mothers. Maternal asthma is also associated with increased risk of preeclampsia development. However, the joint effect of these maternal conditions on child asthma risk is unknown.

Objectives: To study whether development of preeclampsia among pregnant women with asthma was associated with higher risk of childhood asthma in the VDAART (Vitamin D Antenatal Asthma Reduction Trial).

Methods: A total of 806 pregnant women and their offspring at high risk of asthma or atopy, who were followed from VDAART enrollment (10-18 wk of gestation) through the child's third birthday, were included in this cohort analysis. Preeclampsia status was determined by chart review, obstetrician diagnosis, and adjudication by a panel of obstetricians. Child asthma was the main outcome as determined by parental report of a physician diagnosis, and the risk of child asthma was also examined if accompanied by recurrent wheeze. The main risk variable of interest was a four-level ordered variable defined for each mother, with values without asthma without preeclampsia, without asthma with preeclampsia, with asthma without preeclampsia, and with asthma with preeclampsia during their pregnancy. We examined the trend of outcome proportions across these categories. To account for differences in maternal and child characteristics, we used a Weibull regression model for interval-censored data to compare the incidence of child asthma by age of 3 years across the maternal variable categories.

Measurements And Main Results: The incidence of asthma in 3-year-old children was 9.90% (44/445), 17.95% (7/39), 22.11% (65/294), and 32.14% (9/28) among those born to mothers without asthma and without preeclampsia, mothers without asthma with preeclampsia, mothers with asthma without preeclampsia, and mothers with asthma with preeclampsia, respectively. The incidences demonstrated an increasing trend in risk of child asthma across the maternal groups (P for trend <0.001). After accounting for potential confounders and using time to report of childhood asthma as analysis outcome, risk of asthma was greater among children born to mothers with asthma without preeclampsia, compared with mothers without asthma without preeclampsia (adjusted hazard ratio, 2.18; 95% confidence interval, 1.46-3.26). This risk was 50% greater for children born to mothers with asthma who developed preeclampsia during pregnancy (adjusted hazard ratio, 2.68; 95% confidence interval, 1.30-5.61). The trend in asthma and recurrent wheeze proportions across the maternal groups' children also indicated a higher risk for children born to mothers with asthma with preeclampsia (adjusted hazard ratio, 4.73; 95% confidence interval, 2.20-10.07; P for trend <0.001).

Conclusions: Preeclampsia is associated with increased risk of early life childhood asthma in children less than 3 years old over and above that associated with maternal asthma alone. The results implicate the interplay between maternal factors as strong predictors of offspring asthma and in utero maternal-fetal immune perturbations and developmental dysregulations associated with preeclampsia.
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http://dx.doi.org/10.1164/rccm.201804-0770OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353019PMC
January 2019

Integrative epigenomic analysis in differentiated human primary bronchial epithelial cells exposed to cigarette smoke.

Sci Rep 2018 08 24;8(1):12750. Epub 2018 Aug 24.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.

Cigarette smoke (CS) is one of the major risk factors for many pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. The first line of defense for CS exposure is the bronchial epithelial cells. Elucidation of the epigenetic changes during CS exposure is key to gaining a mechanistic understanding into how mature and differentiated bronchial epithelial cells respond to CS. Therefore, we performed epigenomic profiling in conjunction with transcriptional profiling in well-differentiated human bronchial epithelial (HBE) cells cultured in air-liquid interface (ALI) exposed to the vapor phase of CS. The genome-wide enrichment of histone 3 lysine 27 acetylation was detected by chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) in HBE cells and suggested the plausible binding of specific transcription factors related to CS exposure. Additionally, interrogation of ChIP-Seq data with gene expression profiling of HBE cells after CS exposure for different durations (3 hours, 2 days, 4 days) suggested that earlier epigenetic changes (3 hours after CS exposure) may be associated with later gene expression changes induced by CS exposure (4 days). The integration of epigenetics and gene expression data revealed signaling pathways related to CS-induced epigenetic changes in HBE cells that may identify novel regulatory pathways related to CS-induced COPD.
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http://dx.doi.org/10.1038/s41598-018-30781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109173PMC
August 2018

Detecting Differentially Variable MicroRNAs via Model-Based Clustering.

Int J Genomics 2018 12;2018:6591634. Epub 2018 Jul 12.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

Identifying differentially variable (DV) genomic probes is becoming a new approach to detect novel genomic risk factors for complex human diseases. The test is the standard equal-variance test in statistics. For high-throughput genomic data, the probe-wise test has been successfully used to detect biologically relevant DNA methylation marks that have different variances between two groups of subjects (e.g., cases versus controls). In addition to DNA methylation, microRNA (miRNA) is another important mechanism of epigenetics. However, to the best of our knowledge, no studies have identified DV miRNAs. In this article, we proposed a novel model-based clustering method to improve the power of the probe-wise test to detect DV miRNAs. We imposed special structures on covariance matrices for each cluster of miRNAs based on the prior information about the relationship between variances in cases and controls and about the independence among them. Simulation studies showed that the proposed method seems promising in detecting DV probes. Based on two real datasets about human hepatocellular carcinoma (HCC), we identified 7 DV-only miRNAs (hsa-miR-1826, hsa-miR-191, hsa-miR-194-star, hsa-miR-222, hsa-miR-502-3p, hsa-miR-93, and hsa-miR-99b) using the proposed method, one (hsa-miR-1826) of which has not yet been reported to be related to HCC in the literature.
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http://dx.doi.org/10.1155/2018/6591634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079429PMC
July 2018

Expression network analysis reveals cord blood vitamin D-associated genes affecting risk of early life wheeze.

Thorax 2019 02 18;74(2):200-202. Epub 2018 Jul 18.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Cord blood 25-hydroxyvitamin D (25OHD) has been reported in association with risk of early life recurrent wheeze. In a subset of infants who participated in the Vitamin D Antenatal Asthma Reduction Trial, we demonstrated that higher cord blood 25OHD at birth (>31 ng/mL) was associated with a reduced risk of recurrent wheeze in the first year of life. We then identified a module of co-expressed genes associated with cord blood 25OHD levels >31 ng/mL. Genes in this module are involved in biological and immune pathways related to development and progression of asthma pathogenesis including the Notch1 and transforming growth factor-beta signalling pathways.
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http://dx.doi.org/10.1136/thoraxjnl-2018-211962DOI Listing
February 2019

Application of empirical Bayes methods to predict the rate of decline in ERG at the individual level among patients with retinitis pigmentosa.

Stat Med 2018 07 31;37(17):2586-2598. Epub 2018 May 31.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.

Retinitis pigmentosa is one of the most common forms of inherited retinal degeneration. The electroretinogram (ERG) can be used to determine the severity of retinitis pigmentosa-the lower the ERG amplitude, the more severe the disease is. In practice for career, lifestyle, and treatment counseling, it is of interest to predict the ERG amplitude of a patient at a future time. One approach is prediction based on the average rate of decline for individual patients. However, there is considerable variation both in initial amplitude and in rate of decline. In this article, we propose an empirical Bayes (EB) approach to incorporate the variations in initial amplitude and rate of decline for the prediction of ERG amplitude at the individual level. We applied the EB method to a collection of ERGs from 898 patients with 3 or more visits over 5 or more years of follow-up tested in the Berman-Gund Laboratory and observed that the predicted values at the last (kth) visit obtained by using the proposed method based on data for the first k-1 visits are highly correlated with the observed values at the kth visit (Spearman correlation =0.93) and have a higher correlation with the observed values than those obtained based on either the population average decline rate or those obtained based on the individual decline rate. The mean square errors for predicted values obtained by the EB method are also smaller than those predicted by the other methods.
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http://dx.doi.org/10.1002/sim.7662DOI Listing
July 2018

Robust joint score tests in the application of DNA methylation data analysis.

BMC Bioinformatics 2018 05 18;19(1):174. Epub 2018 May 18.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, 02115, USA.

Background: Recently differential variability has been showed to be valuable in evaluating the association of DNA methylation to the risks of complex human diseases. The statistical tests based on both differential methylation level and differential variability can be more powerful than those based only on differential methylation level. Anh and Wang (2013) proposed a joint score test (AW) to simultaneously detect for differential methylation and differential variability. However, AW's method seems to be quite conservative and has not been fully compared with existing joint tests.

Results: We proposed three improved joint score tests, namely iAW.Lev, iAW.BF, and iAW.TM, and have made extensive comparisons with the joint likelihood ratio test (jointLRT), the Kolmogorov-Smirnov (KS) test, and the AW test. Systematic simulation studies showed that: 1) the three improved tests performed better (i.e., having larger power, while keeping nominal Type I error rates) than the other three tests for data with outliers and having different variances between cases and controls; 2) for data from normal distributions, the three improved tests had slightly lower power than jointLRT and AW. The analyses of two Illumina HumanMethylation27 data sets GSE37020 and GSE20080 and one Illumina Infinium MethylationEPIC data set GSE107080 demonstrated that three improved tests had higher true validation rates than those from jointLRT, KS, and AW.

Conclusions: The three proposed joint score tests are robust against the violation of normality assumption and presence of outlying observations in comparison with other three existing tests. Among the three proposed tests, iAW.BF seems to be the most robust and effective one for all simulated scenarios and also in real data analyses.
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http://dx.doi.org/10.1186/s12859-018-2185-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960098PMC
May 2018

The effect of interaction between EtOH dosage and exposure time on gene expression in DPSC.

Genomics 2019 05 27;111(3):500-507. Epub 2018 Mar 27.

Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.

Alcohol (EtOH) dosage and exposure time can affect gene expression. However, whether there exists synergistic effect is unknown. Here, we analyzed the hDPSC gene microarray dataset GSE57255 downloaded from Gene Expression Omnibus and found that the interaction between EtOH dosage and exposure time on gene expression are statistically significant for two probes: 201917_s_at near gene SLC25A36 and 217649_at near gene ZFAND5. GeneMania showed that SLC25A36 and ZFAND5 were related to 20 genes, three of which had alcohol-related functions. WebGestalt revealed that the 22 genes were enriched in 10 KEGG pathways, four of which are related to alcoholic diseases. We explored the possible nonlinear interaction effect and got 172 gene probes with significant p-values. However, no significantly enriched pathways based on the 172 probes were detected. Our analyses indicated a possible molecular mechanism that could help explain why alcohol consumption has both deleterious and beneficial effects on human health.
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http://dx.doi.org/10.1016/j.ygeno.2018.03.009DOI Listing
May 2019

Role of local CpG DNA methylation in mediating the 17q21 asthma susceptibility gasdermin B (GSDMB)/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression quantitative trait locus.

J Allergy Clin Immunol 2018 06 31;141(6):2282-2286.e6. Epub 2018 Jan 31.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; Pulmonary Genetics Center and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaci.2017.11.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994185PMC
June 2018

Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease.

Hum Genomics 2018 01 15;12(1). Epub 2018 Jan 15.

Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.

Background: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) significantly associated with chronic obstructive pulmonary disease (COPD). However, many genetic variants show suggestive evidence for association but do not meet the strict threshold for genome-wide significance. Integrative analysis of multiple omics datasets has the potential to identify novel genes involved in disease pathogenesis by leveraging these variants in a functional, regulatory context.

Results: We performed expression quantitative trait locus (eQTL) analysis using genome-wide SNP genotyping and gene expression profiling of lung tissue samples from 86 COPD cases and 31 controls, testing for SNPs associated with gene expression levels. These results were integrated with a prior COPD GWAS using an ensemble statistical and network methods approach to identify relevant genes and observe them in the context of overall genetic control of gene expression to highlight co-regulated genes and disease pathways. We identified 250,312 unique SNPs and 4997 genes in the cis(local)-eQTL analysis (5% false discovery rate). The top gene from the integrative analysis was MAPT, a gene recently identified in an independent GWAS of lung function. The genes HNRNPAB and PCBP2 with RNA binding activity and the gene ACVR1B were identified in network communities with validated disease relevance.

Conclusions: The integration of lung tissue gene expression with genome-wide SNP genotyping and subsequent intersection with prior GWAS and omics studies highlighted candidate genes within COPD loci and in communities harboring known COPD genes. This integration also identified novel disease genes in sub-threshold regions that would otherwise have been missed through GWAS.
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http://dx.doi.org/10.1186/s40246-018-0132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769240PMC
January 2018

Application of Weighted Gene Co-expression Network Analysis for Data from Paired Design.

Sci Rep 2018 01 12;8(1):622. Epub 2018 Jan 12.

Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.

Investigating how genes jointly affect complex human diseases is important, yet challenging. The network approach (e.g., weighted gene co-expression network analysis (WGCNA)) is a powerful tool. However, genomic data usually contain substantial batch effects, which could mask true genomic signals. Paired design is a powerful tool that can reduce batch effects. However, it is currently unclear how to appropriately apply WGCNA to genomic data from paired design. In this paper, we modified the current WGCNA pipeline to analyse high-throughput genomic data from paired design. We illustrated the modified WGCNA pipeline by analysing the miRNA dataset provided by Shiah et al. (2014), which contains forty oral squamous cell carcinoma (OSCC) specimens and their matched non-tumourous epithelial counterparts. OSCC is the sixth most common cancer worldwide. The modified WGCNA pipeline identified two sets of novel miRNAs associated with OSCC, in addition to the existing miRNAs reported by Shiah et al. (2014). Thus, this work will be of great interest to readers of various scientific disciplines, in particular, genetic and genomic scientists as well as medical scientists working on cancer.
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http://dx.doi.org/10.1038/s41598-017-18705-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766625PMC
January 2018

The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma.

Pharmacogenomics J 2018 09 3;18(5):665-677. Epub 2018 Jan 3.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB production in LCLs following zileuton treatment (i.e., 'poor' responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.
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http://dx.doi.org/10.1038/s41397-017-0006-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150906PMC
September 2018

Deep Learning Methods for Predicting Disease Status Using Genomic Data.

J Biom Biostat 2018 11;9(5). Epub 2018 Dec 11.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, 181 Longwood Avenue, Boston MA 02115, USA.

Predicting disease status for a complex human disease using genomic data is an important, yet challenging, step in personalized medicine. Among many challenges, the so-called curse of dimensionality problem results in unsatisfied performances of many state-of-art machine learning algorithms. A major recent advance in machine learning is the rapid development of deep learning algorithms that can efficiently extract meaningful features from high-dimensional and complex datasets through a stacked and hierarchical learning process. Deep learning has shown breakthrough performance in several areas including image recognition, natural language processing, and speech recognition. However, the performance of deep learning in predicting disease status using genomic datasets is still not well studied. In this article, we performed a review on the four relevant articles that we found through our thorough literature search. All four articles first used auto-encoders to project high-dimensional genomic data to a low dimensional space and then applied the state-of-the-art machine learning algorithms to predict disease status based on the low-dimensional representations. These deep learning approaches outperformed existing prediction methods, such as prediction based on transcript-wise screening and prediction based on principal component analysis. The limitations of the current deep learning approach and possible improvements were also discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530791PMC
December 2018