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author:("Qiu, weiland")
1.  Identifying a gene expression signature of frequent COPD exacerbations in peripheral blood using network methods 
Background
Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.
Methods
Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated.
Results
Individual genes were not found to be significantly associated with the number of exacerbations. However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association. A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection. Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections. The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations.
Conclusion
A distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness. While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-014-0072-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-014-0072-y
PMCID: PMC4302028  PMID: 25582225
Network analysis; Chronic obstructive pulmonary disease; Gene expression profiling; Biomarker
2.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
Background
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
Methods
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
Results
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Conclusions
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
doi:10.1186/1755-8794-7-48
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
3.  A genome-wide association study of bronchodilator response in asthmatics 
The pharmacogenomics journal  2013;14(1):41-47.
Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534,290 single nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215, and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (p=1.98×10−7) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (p=8.51×10−6). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
doi:10.1038/tpj.2013.5
PMCID: PMC3706515  PMID: 23508266
pharmacogenetics; asthma; bronchodilator response; genome-wide association study; albuterol
4.  Gene expression analysis uncovers novel Hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells 
Genomics  2013;101(5):263-272.
Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis.
doi:10.1016/j.ygeno.2013.02.010
PMCID: PMC3659826  PMID: 23459001
Hedgehog interacting protein (HHIP); Gene expression profiling; COPD (Chronic obstructive pulmonary disease); extracellular matrix (ECM); network modeling
5.  Assessing Discrimination of Risk Prediction Rules in a Clustered Data Setting* 
Lifetime data analysis  2012;19(2):242-256.
The AUC (area under ROC curve) is a commonly used metric to assess discrimination of risk prediction rules; however, standard errors of AUC are usually based on the Mann-Whitney U test that assumes independence of sampling units. For ophthalmologic applications, it is desirable to assess risk prediction rules based on eye-specific outcome variables which are generally highly, but not perfectly correlated in fellow eyes (eg. progression of individual eyes to age-related macular degeneration (AMD)). In this article, we use the extended Mann-Whitney U test (Rosner et al, 2009) for the case where subunits within a cluster may have different progression status and assess discrimination of different prediction rules in this setting. Both data analyses based on progression of AMD and simulation studies show reasonable accuracy of this extended Mann-Whitney U test to assess discrimination of eye-specific risk prediction rules.
doi:10.1007/s10985-012-9240-6
PMCID: PMC3622772  PMID: 23263872
risk prediction; ROC curves; clustered data; GEE
6.  A proteomic analysis of IVF follicular fluid in women ≤32 years old 
Fertility and sterility  2008;92(5):1569-1578.
Objective
To address the lack of predictors of IVF success by using proteomic biometrics.
Design
Experimental study of follicular fluid specimens from a prospective cohort of IVF patients.
Setting
Academic research laboratory and IVF program.
Patient(s)
Women ≤32 years old with <11 oocytes retrieved and no pregnancy were matched to women who had ≥ 11 oocytes and live birth (10 pairs). Year of cycle start and IVF down-regulation protocol were also matched.
Intervention(s)
Follicular fluid was separated by two-dimensional polyacrylamide gel electrophoresis followed by Sypro Ruby staining and comparison with PDQuest software. Logistic regression was incorporated to calculate the likelihood of live birth in relation to the protein spot of interest.
Main Outcome Measure(s)
Protein markers.
Result(s)
Liquid chromatography–tandem mass spectrometry and searching of sequence databases revealed 11 potential protein candidates. Haptoglobin alpha, predominantly fetal expressed T1 domain, mitochondrial integrity genome (ATPase), apolipoprotein H (beta-2 glycoprotein I), dihydrolipoyl dehydrogenase, lyzozyme C, fibrinogen alpha-chain, and immunoglobulin heavy chain V-III (region BRO) were found to have increased expression in the live birth group, whereas antithrombin, vitamin D–binding protein, and complement 3 were decreased. An ELISA confirmed a significantly lower level of antithrombin.
Conclusion(s)
Proteomic evaluation of follicular fluid is able to identify potential biomarkers of good versus poor responders in matched pairs of IVF patients.
doi:10.1016/j.fertnstert.2008.08.120
PMCID: PMC3916005  PMID: 18980758
Follicular fluid; infertility; IVF; pregnancy; proteomics
7.  Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease 
Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts.
Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201206-1013OC
PMCID: PMC3622441  PMID: 23144326
biomarker; chronic obstructive pulmonary disease; genome-wide association study
8.  Systemic Steroid Exposure Is Associated with Differential Methylation in Chronic Obstructive Pulmonary Disease 
Rationale: Systemic glucocorticoids are used therapeutically to treat a variety of medical conditions. Epigenetic processes such as DNA methylation may reflect exposure to glucocorticoids and may be involved in mediating the responses and side effects associated with these medications.
Objectives: To test the hypothesis that differences in DNA methylation are associated with current systemic steroid use.
Methods: We obtained DNA methylation data at 27,578 CpG sites in 14,475 genes throughout the genome in two large, independent cohorts: the International COPD Genetics Network (ndiscovery = 1,085) and the Boston Early Onset COPD study (nreplication = 369). Sites were tested for association with current systemic steroid use using generalized linear mixed models.
Measurements and Main Results: A total of 511 sites demonstrated significant differential methylation by systemic corticosteroid use in all three of our primary models. Pyrosequencing validation confirmed robust differential methylation at CpG sites annotated to genes such as SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, and RABGEF1. Functional annotation clustering demonstrated significant enrichment in intrinsic membrane components, hemostasis and coagulation, cellular ion homeostasis, leukocyte and lymphocyte activation and chemotaxis, protein transport, and responses to nutrients.
Conclusions: Our analyses suggest that systemic steroid use is associated with site-specific differential methylation throughout the genome. Differentially methylated CpG sites were found in biologically plausible and previously unsuspected pathways; these genes and pathways may be relevant in the development of novel targeted therapies.
doi:10.1164/rccm.201207-1280OC
PMCID: PMC3622442  PMID: 23065012
DNA methylation; glucocorticoids; chronic obstructive pulmonary disease
9.  Vitamin D related genes in lung development and asthma pathogenesis 
BMC Medical Genomics  2013;6:47.
Background
Poor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility. We hypothesized that vitamin D pathway genes are developmentally active in the fetal lung and that these developmental genes would be associated with asthma susceptibility and regulation in asthma.
Methods
Vitamin D pathway genes were derived from PubMed and Gene Ontology surveys. Principal component analysis was used to identify characteristic lung development genes.
Results
Vitamin D regulated genes were markedly over-represented in normal human (odds ratio OR 2.15, 95% confidence interval CI: 1.69-2.74) and mouse (OR 2.68, 95% CI: 2.12-3.39) developing lung transcriptomes. 38 vitamin D pathway genes were in both developing lung transcriptomes with >63% of genes more highly expressed in the later than earlier stages of development. In immortalized B-cells derived from 95 asthmatics and their unaffected siblings, 12 of the 38 (31.6%) vitamin D pathway lung development genes were significantly differentially expressed (OR 3.00, 95% CI: 1.43-6.21), whereas 11 (29%) genes were significantly differentially expressed in 43 control versus vitamin D treated immortalized B-cells from Childhood Asthma Management Program subjects (OR 2.62, 95% CI: 1.22-5.50). 4 genes, LAMP3, PIP5K1B, SCARB2 and TXNIP were identified in both groups; each displays significant biologic plausibility for a role in asthma.
Conclusions
Our findings demonstrate a significant association between early lung development and asthma–related phenotypes for vitamin D pathway genes, supporting a genomic mechanistic basis for the epidemiologic observations relating maternal vitamin D intake and childhood asthma susceptibility.
doi:10.1186/1755-8794-6-47
PMCID: PMC4228235  PMID: 24188128
Vitamin D; Cholecalciferol; Lung development; Asthma; Fetal programming
10.  Integration of Cell Phone Imaging with Microchip ELISA to Detect Ovarian Cancer HE4 Biomarker in Urine at the Point-of-Care 
Lab on a chip  2011;11(20):3411-3418.
Ovarian cancer is asymptomatic at early stages and most patients present with advanced levels of disease. Lack of cost-effective methods that can achieve frequent, simple and non-invasive testing hinders early detection and causes high mortality in ovarian cancer patients. Here, we report a simple and inexpensive microchip ELISA-based detection module that employs a portable detection system, i.e., a cell phone/charge-coupled device (CCD) to quantify an ovarian cancer biomarker, HE4, in urine. Integration of a mobile application with a cell phone enabled immediate processing of microchip ELISA results, which eliminated the need for a bulky, expensive spectrophotometer. The HE4 level detected by a cell phone or a lensless CCD system was significantly elevated in urine samples from cancer patients (n = 19) than normal healthy controls (n = 20) (p < 0.001). Receiver operating characteristic (ROC) analyses showed that the microchip ELISA coupled with a cell phone running an automated analysis application had a sensitivity of 89.5% at a specificity of 90%. Under the same specificity, the microchip ELISA coupled with a CCD had a sensitivity of 84.2%. In conclusion, integration of microchip ELISA with cell phone/CCD-based colorimetric measurement technology can be used to detect HE4 biomarker at the point-of-care (POC), paving the way to create bedside technologies for diagnostics and treatment monitoring.
doi:10.1039/c1lc20479c
PMCID: PMC3767574  PMID: 21881677
11.  ITGB5 and AGFG1 variants are associated with severity of airway responsiveness 
BMC Medical Genetics  2013;14:86.
Background
Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
Methods
A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
Results
The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
Conclusions
Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
doi:10.1186/1471-2350-14-86
PMCID: PMC3765944  PMID: 23984888
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1
12.  Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome 
Human Molecular Genetics  2012;21(13):3073-3082.
The impact of cigarette smoking can persist for extended periods following smoking cessation and may involve epigenetic reprogramming. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to the latency between exposure and disease onset. Cross-sectional cohort data from subjects in the International COPD Genetics Network (n = 1085) and the Boston Early-Onset COPD study (n = 369) were analyzed as the discovery and replication cohorts, respectively. Genome-wide methylation data on 27 578 CpG sites in 14 475 genes were obtained on DNA from peripheral blood leukocytes using the Illumina HumanMethylation27K Beadchip in both cohorts. We identified 15 sites significantly associated with current smoking, 2 sites associated with cumulative smoke exposure, and, within the subset of former smokers, 3 sites associated with time since quitting cigarettes. Two loci, factor II receptor-like 3 (F2RL3) and G-protein-coupled receptor 15 (GPR15), were significantly associated in all three analyses and were validated by pyrosequencing. These findings (i) identify a novel locus (GPR15) associated with cigarette smoking and (ii) suggest the existence of dynamic, site-specific methylation changes in response to smoking which may contribute to the extended risks associated with cigarette smoking that persist after cessation.
doi:10.1093/hmg/dds135
PMCID: PMC3373248  PMID: 22492999
13.  Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma 
The New England journal of medicine  2011;365(13):1173-1183.
BACKGROUND
The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.
METHODS
We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects.
RESULTS
We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.
CONCLUSIONS
A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)
doi:10.1056/NEJMoa0911353
PMCID: PMC3667396  PMID: 21991891
14.  Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function 
Rationale: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure.
Objectives: To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease.
Methods: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n = 1,085 and 369 subjects).
Measurements and Main Results: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 × 10−23; FEV1/FVC, 1.5 × 10−35; FEV1, 2.2 × 10−40).
Conclusions: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This large-scale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.
doi:10.1164/rccm.201108-1382OC
PMCID: PMC3297093  PMID: 22161163
chronic obstructive pulmonary disease; epigenetics; DNA methylation; smoking
16.  Revascularization among patients with severe left ventricular dysfunction: a meta-analysis of observational studies 
European Journal of Heart Failure  2011;13(7):773-784.
Aims
Coronary artery bypass graft (CABG) surgery is the standard of care for the management of patients with severe three-vessel and left main coronary artery disease (CAD). However, the optimal strategy for management of patients with CAD and severe left ventricular (LV) dysfunction [ejection fraction (EF) ≤35%] is not clear. A meta-analysis of observational studies was performed to determine the operative mortality and long-term (5-year actuarial survival) outcomes among patients with severe LV dysfunction undergoing CABG.
Methods and results
A systematic computerized literature search was performed and observational studies consisting of patients undergoing isolated CABG for CAD and severe LV dysfunction were included. Studies that did not report operative mortality, long-term (≥1 year) survival data, or pre-operative EF and multiple studies from the same group were excluded. In total, 4119 patients from 26 observational clinical studies were included. The estimated mean age was 63.9 years and 82.4% of patients were men. The mean (estimate) pre-operative EF was 24.7% (95% CI 22.5–27.0%). The operative mortality among patients (26 studies, n= 3621) who underwent on-pump CABG was 5.4%, n= 189 (95% CI 4.5–6.4%). The 5-year actuarial survival among patients (13 studies, n= 1980) who underwent on-pump CABG was 73.4%, n= 1483 (95% CI 68.7–77.7%). Patients who underwent off-pump CABG (7 studies, n= 498) tended to have reduced operative mortality of 4.4%, n= 20 (95% CI 2.8–6.4%). The mean (estimate) post-operative EF was 35.19% (95% CI 31.95–38.43%).
Conclusion
The present meta-analysis demonstrates that based on data from available observational clinical studies, CABG can be performed with acceptable operative mortality and 5-year actuarial survival in patients with severe LV dysfunction.
doi:10.1093/eurjhf/hfr037
PMCID: PMC3125123  PMID: 21478241
Coronary artery bypass surgery; Revascularization; Coronary artery disease; Meta-analysis; Observational studies
17.  Combining effects from rare and common genetic variants in an exome-wide association study of sequence data 
BMC Proceedings  2011;5(Suppl 9):S44.
Recent breakthroughs in next-generation sequencing technologies allow cost-effective methods for measuring a growing list of cellular properties, including DNA sequence and structural variation. Next-generation sequencing has the potential to revolutionize complex trait genetics by directly measuring common and rare genetic variants within a genome-wide context. Because for a given gene both rare and common causal variants can coexist and have independent effects on a trait, strategies that model the effects of both common and rare variants could enhance the power of identifying disease-associated genes. To date, little work has been done on integrating signals from common and rare variants into powerful statistics for finding disease genes in genome-wide association studies. In this analysis of the Genetic Analysis Workshop 17 data, we evaluate various strategies for association of rare, common, or a combination of both rare and common variants on quantitative phenotypes in unrelated individuals. We show that the analysis of common variants only using classical approaches can achieve higher power to detect causal genes than recently proposed rare variant methods and that strategies that combine association signals derived independently in rare and common variants can slightly increase the power compared to strategies that focus on the effect of either the rare variants or the common variants.
doi:10.1186/1753-6561-5-S9-S44
PMCID: PMC3287881  PMID: 22373328
18.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2011;6(9):e24395.
Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
doi:10.1371/journal.pone.0024395
PMCID: PMC3174957  PMID: 21949713
19.  Fatty Acid Synthase Polymorphisms, Tumor Expression, Body Mass Index, Prostate Cancer Risk, and Survival 
Journal of Clinical Oncology  2010;28(25):3958-3964.
Purpose
Fatty acid synthase (FASN) regulates de novo lipogenesis, body weight, and tumor growth. We examined whether common germline single nucleotide polymorphisms (SNPs) in the FASN gene affect prostate cancer (PCa) risk or PCa-specific mortality and whether these effects vary by body mass index (BMI).
Methods
In a prospective nested case-control study of 1,331 white patients with PCa and 1,267 age-matched controls, we examined associations of five common SNPs within FASN (and 5 kb upstream/downstream, R2 > 0.8) with PCa incidence and, among patients, PCa-specific death and tested for an interaction with BMI. Survival analyses were repeated for tumor FASN expression (n = 909).
Results
Four of the five SNPs were associated with lethal PCa. SNP rs1127678 was significantly related to higher BMI and interacted with BMI for both PCa risk (Pinteraction = .004) and PCa mortality (Pinteraction = .056). Among overweight men (BMI ≥ 25 kg/m2), but not leaner men, the homozygous variant allele carried a relative risk of advanced PCa of 2.49 (95% CI, 1.00 to 6.23) compared with lean men with the wild type. Overweight patients carrying the variant allele had a 2.04 (95% CI, 1.31 to 3.17) times higher risk of PCa mortality. Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (Pinteraction = .02).
Conclusion
FASN germline polymorphisms were significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men.
doi:10.1200/JCO.2009.27.0793
PMCID: PMC2940394  PMID: 20679621
20.  Measurement error correction for the cumulative average model in the survival analysis of nutritional data: application to Nurses’ Health Study 
Lifetime data analysis  2009;16(1):136-153.
The use of the cumulative average model to investigate the association between disease incidence and repeated measurements of exposures in medical follow-up studies can be dated back to the 1960s (Kahn and Dawber, J Chron Dis 19:611–620, 1966). This model takes advantage of all prior data and thus should provide a statistically more powerful test of disease-exposure associations. Measurement error in covariates is common for medical follow-up studies. Many methods have been proposed to correct for measurement error. To the best of our knowledge, no methods have been proposed yet to correct for measurement error in the cumulative average model. In this article, we propose a regression calibration approach to correct relative risk estimates for measurement error. The approach is illustrated with data from the Nurses’ Health Study relating incident breast cancer between 1980 and 2002 to time-dependent measures of calorie-adjusted saturated fat intake, controlling for total caloric intake, alcohol intake, and baseline age.
doi:10.1007/s10985-009-9124-6
PMCID: PMC2809827  PMID: 19757039
Measurement error; Regression calibration; Nutritional data
21.  A 25 Year Prospective Study of Plasma Adiponectin and Leptin Concentrations and Prostate Cancer Risk and Survival 
Clinical chemistry  2009;56(1):34-43.
Background
Adipocytokines may mediate the association between adiposity and lethal prostate cancer outcomes.
Methods
In the Physicians’ Health Study, we prospectively examined the association of prediagnostic plasma concentrations of adiponectin and leptin with risk of developing incident prostate cancer (654 case diagnosed 1982-2000 and 644 age-matched controls) and, among cases, risk of dying from prostate cancer by 2007.
Results
Adiponectin concentrations were not associated with risk of overall prostate cancer. However, men with higher adiponectin concentrations had lower risk of developing high grade or lethal cancer (metastatic or fatal disease). The relative risk (95% confidence interval) comparing the highest to the lowest quintile (Q5 vs. Q1) was 0.25 (0.07-0.87; Ptrend=0.02) for lethal cancer. Among all the cases, higher adiponectin concentrations predicted lower prostate cancer-specific mortality (hazard ratio, HR Q5 vs. Q1=0.39; 0.17-0.85; Ptrend=0.02), independent of body mass index (BMI), plasma C-peptide (a marker of insulin secretion), leptin, clinical stage and tumor grade. This inverse association was apparent mainly among men whose BMI ≥25 kg/m2 (HR Q5 vs. Q1=0.10; 0.01-0.78; Ptrend=0.02), but not among men of normal weight (Ptrend=0.51). Although the correlation of leptin concentrations with BMI (r=0.58, P <0.001) was stronger than that of adiponectin (r=−0.17, P<0.001), leptin was unrelated to prostate cancer risk or mortality.
Conclusion
Higher prediagnostic adiponectin (but not leptin) concentrations predispose men to a lower risk of developing high grade prostate cancer and a lower risk of subsequently dying from the cancer, suggesting a mechanistic link between obesity and poor PCa outcome.
doi:10.1373/clinchem.2009.133272
PMCID: PMC2858593  PMID: 19910504
Adiponectin; obesity; prostate cancer; risk; survival
22.  Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort 
Journal of Clinical Oncology  2009;27(30):4980-4985.
Purpose
To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa.
Participants and Methods
We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.
Results
From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.
Conclusion
In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients.
doi:10.1200/JCO.2008.21.2613
PMCID: PMC2799054  PMID: 19720918
23.  Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium 
Objectives
It is essential to understand the molecular basis of ovarian cancer etiology and tumor development to provide more effective preventive and therapeutic approaches to reduce mortality. Particularly, the molecular targets and pathways involved in early malignant transformation are still not clear. Pro-inflammatory lipids and pathways have been reported to play significant roles in ovarian cancer progression and metastasis. The major objective of this study was to explore and determine whether platelet activating factor (PAF) and receptor associated networking pathways might significantly induce malignant potential in BRCA1-mutant at-risk epithelial cells.
Methods
BRCA1-mutant ovarian epithelial cell lines including (HOSE-636, HOSE-642), BRCA1-mutant ovarian cancer cell (UWB1.289), wild type normal ovarian epithelial cell (HOSE-E6E7) and cancerous cell line (OVCA429), and the non-malignant BRCA1-mutant distal fallopian tube (fimbria) tissue specimens were used in this study. Mutation analysis, kinase microarray, western blot, immune staining, co-immune precipitation, cell cycle, apoptosis, proliferation and bioinformatic pathway analysis were applied.
Results
We found that PAF, as a potent pro-inflammatory mediator, induced significant anti-apoptotic effect in BRCA1-mutant ovarian surface epithelial cells, but not in wild type HOSE cells. With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM PAF treatment only in BRCA1-mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSE-E6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that elevated PAFR expression is associated with protein-protein interactions of PAFR-FAK and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells.
Conclusion
Previous studies showed that potent inflammatory lipid mediators such as PAF and its receptor (PAFR) significantly contribute to cancer progression and metastasis. Our findings suggest that these potent inflammatory lipids and receptor pathways are significantly involved in the early malignant transformation through PAFR-FAK-STAT1 networking and to block apoptosis pathway in BRCA1 dysfunctional at-risk ovarian epithelium.
doi:10.1186/1477-7827-8-74
PMCID: PMC2903602  PMID: 20576130
24.  A long-term survival analysis of prediagnostic body mass index, plasma C-peptide concentration, and prostate cancer-specific mortality among men with prostate cancer 
The lancet oncology  2008;9(11):1039-1047.
Summary
Background
Excess body mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinemia is a candidate mediator, but prospective data are sparse. We assessed the influence of prediagnostic BMI and plasma C-peptide (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis.
Methods
BMI was available at baseline (1982) and in 1990 among 2,546 men who developed prostate cancer (281 prostate cancer deaths). Baseline C-peptide concentration were available in 827 men (117 prostate cancer deaths). We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death.
Findings
Compared with men of normal weight (BMI<25 kg/m2) at baseline, overweight men (BMI 25–29.9 kg/m2) and obese men (BMI≥30 kg/m2) had significantly higher risk of prostate cancer mortality; the proportional hazard ratio (HR)s (95% confidence interval, CI) were 1.47 (1.16–1.88) for overweight and 2.66 (1.62–4.39; Ptrend<0.0001) for obesity. The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991–2007) or using BMI obtained in 1990. Men with C-peptide concentrations in the highest quartile (high), versus the lowest quartile (low), also had higher risk (HR=2.38; 1.31–4.30). Compared with men with BMI<25 kg/m2 and low C-peptide concentrations, those with BMI≥25 kg/m2 and high C-peptide concentration had a four times higher risk (HR=4.12; 1.97–8.61; Pinteraction=0.001) independent of clinical predictors.
Interpretation
Excess body weight and high plasma concentration of C-peptide each predispose men with a subsequent diagnosis of prostate cancer to increased likelihood of dying of this disease; those with both factors have the worst outcome.
doi:10.1016/S1470-2045(08)70235-3
PMCID: PMC2651222  PMID: 18835745
25.  A Marginal Mixture Model for Selecting Differentially Expressed Genes across Two Types of Tissue Samples 
Bayesian hierarchical models that characterize the distributions of (transformed) gene profiles have been proven very useful and flexible in selecting differentially expressed genes across different types of tissue samples (e.g. Lo and Gottardo, 2007). However, the marginal mean and variance of these models are assumed to be the same for different gene clusters and for different tissue types. Moreover, it is not easy to determine which of the many competing Bayesian hierarchical models provides the best fit for a specific microarray data set. To address these two issues, we propose a marginal mixture model that directly models the marginal distribution of transformed gene profiles. Specifically, we approximate the marginal distributions of transformed gene profiles via a mixture of three-component multivariate Normal distributions, each component of which has the same structures of marginal mean vector and covariance matrix as those for Bayesian hierarchical models, but the values can differ. Based on the proposed model, a method is derived to select genes differentially expressed across two types of tissue samples. The derived gene selection method performs well on a real microarray data set and consistently has the best performance (based on class agreement indices) compared with several other gene selection methods on simulated microarray data sets generated from three different mixture models.
doi:10.2202/1557-4679.1093
PMCID: PMC2835454  PMID: 20231912

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