GSK Research and Development

Verona, Italy

GSK Research and Development

Verona, Italy

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Celli B.R.,Harvard University | Pinto-Plata V.M.,University of Liverpool | Calverley P.M.A.,University of Liverpool | Vanfleteren L.E.G.W.,Maastricht University | And 10 more authors.
Respiratory Medicine | Year: 2016

Exercise-induced oxygen desaturation (EID) is related to mortality in patients with chronic obstructive pulmonary disease (COPD). We investigated: (1) the prevalence of EID; (2) the relative-weight of several physiological determinants of EID including pulmonary emphysema, and (3) the relationship of EID with certain patients' clinical characteristics. Data from 2050 COPD patients (age: 63.3 ± 7.1years; FEV1: 48.7 ± 15.7%pred.) were analyzed. The occurrence of EID (SpO2post ≤88%) at the six-minute walking test (6MWT) was investigated in association with emphysema quantified by computed-tomography (QCT), and several clinical characteristics. 435 patients (21%) exhibited EID. Subjects with EID had more QCT-emphysema, lower exercise capacity and worse health-status (BODE, ADO indexes) compared to non-EID. Determinant of EID were obesity (BMI≥30 kg/m2), impaired FEV1 (≤44%pred.), moderate or worse emphysema, and low SpO2 at rest (≤93%). Linear regression indicated that each 1-point increase on the ADO-score independently elevates odds ratio (≤1.5fold) for EID. About one in five COPD patients in the ECLIPSE cohort present EID. Advanced emphysema is associated with EID. In addition, obesity, severe airflow limitation, and low resting oxygen saturation increase the risk for EID. Patients with EID in GOLD stage II have higher odds to have moderate or worse emphysema compared those with EID in GOLD stage III-IV. Emphysematous patients with high ADO-score should be monitored for EID. © 2016 Elsevier Ltd


Wouters E.F.M.,Maastricht University | Pinto-Plata V.M.,University of Liverpool | Bakke P.S.,University of Bergen | Agusti A.,University of Barcelona | And 8 more authors.
Respiratory Medicine | Year: 2015

In addition to the six-min walk distance (6 MWD), other six-min walk test (6 MWT) derived variables, such as mean walk-speed (6MWSpeed), 6-min walk-work (6 MWW), distance-saturation product (DSP), exercise-induced oxygen desaturation (EID), and unintended stops may be useful for the prediction of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). We studied the association between 6 MWT-derived variables and mortality as well as hospitalization in COPD patients and compared it with the BODE index. A three-year prospective study (ECLIPSE) to evaluate the prognostic value of 6 MWT-derived variables in 2010 COPD patients. Cox's proportional-hazard regressions were performed to estimate 3-year mortality and hospitalization. During the follow-up, 193 subjects died and 622 were hospitalized. An adjusted Cox's regression model of hazard ratio [HR] for impaired 6 MWT-derived variables was significant referring to: mortality (6 MWD ≤334 m [2.30], 6MWSpeed ≤0.9 m/sec [2.15], 6 MWW ≤20000 m kg [2.17], DSP ≤290 m% [2.70], EID ≤88% [1.75], unintended stops [1.99]; and hospitalization (6 MWW ≤27000 m kg [1.23], EID ≤88% [1.25], BODE index ≥3 points [1.40]; all p ≤ 0.05). The 6 MWT-derived variables have an additional predictive value of mortality in patients with COPD. The 6 MWW, EID and the BODE index refine the prognosis of hospitalization. © 2015 Elsevier Ltd. All rights reserved.


Xu W.,University of Toronto | Cohen-Woods S.,King's College London | Chen Q.,Cancer Care Ontario | Noor A.,Campbell Family Mental Health Research Institute | And 21 more authors.
BMC Medical Genetics | Year: 2014

Background: Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).Methods: Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.Results: Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.Conclusions: The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16. © 2014 Xu et al.; licensee BioMed Central Ltd.


Hosang G.M.,King's College London | Uher R.,King's College London | Keers R.,King's College London | Cohen-Woods S.,King's College London | And 8 more authors.
Journal of Affective Disorders | Year: 2010

Background: Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val66Met polymorphism and stressful life events (SLEs) in bipolar disorder. Method: A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val66Met polymorphism (rs6265). Results: Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene × environment interaction). Limitations: The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. Discussion: The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder. © 2010 Elsevier B.V. All rights reserved.


Noor A.,Campbell Family Mental Health Research Institute | Lionel A.C.,Applied Genomics | Lionel A.C.,University of Toronto | Cohen-Woods S.,King's College London | And 23 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2014

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD. © 2014 Wiley Periodicals, Inc.

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