@article{Hanlon2018,
title = {Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: a cross-sectional UK Biobank study.},
author = {P Hanlon and BI Nicholl and BD Jani and R McQueenie and D Lee and KI Gallacher FS Mair },
url = {https://www.ncbi.nlm.nih.gov/pubmed/29332840},
year = {2018},
date = {2018-01-14},
journal = {BMJ Open},
abstract = {This study aims: (1) to describe the pattern and extent of multimorbidity and polypharmacy in UK Biobank participants with chronic obstructive pulmonary disease (COPD) and (2) to identify which comorbidities are associated with increased risk of adverse drug reactions (ADRs) resulting from polypharmacy.

DESIGN:

Cross-sectional.

SETTING:

Community cohort.

PARTICIPANTS:

UK Biobank participants comparing self-reported COPD (n=8317) with no COPD (n=494 323).

OUTCOMES:

Multimorbidity (≥4 conditions) and polypharmacy (≥5 medications) in participants with COPD versus those without. Risk of ADRs (taking ≥3 medications associated with falls, constipation, urinary retention, central nervous system (CNS) depression, bleeding or renal injury) in relation to the presence of COPD and individual comorbidities.

RESULTS:

Multimorbidity was more common in participants with COPD than those without (17% vs 4%). Polypharmacy was highly prevalent (52% with COPD taking ≥5 medications vs 18% in those without COPD). Adjusting for age, sex and socioeconomic status, those with COPD were significantly more likely than those without to be prescribed ≥3 medications contributing to falls (OR 2.27, 95% CI 2.13 to 2.42), constipation (OR 3.42, 95% CI 3.10 to 3.77), urinary retention (OR 3.38, 95% CI 2.94 to 3.87), CNS depression (OR 3.75, 95% CI 3.31 to 4.25), bleeding (OR 4.61, 95% CI 3.35 to 6.19) and renal injury (OR 2.22, 95% CI 1.86 to 2.62). Concomitant cardiovascular disease was associated with the greatest risk of taking ≥3 medications associated with falls/renal injury. Concomitant mental health conditions were most strongly associated with medications linked with CNS depression/urinary retention/bleeding.

CONCLUSIONS:

Multimorbidity is common in COPD and associated with high levels of polypharmacy. Co-prescription of drugs with various ADRs is common. Future research should examine the effects on healthcare outcomes of co-prescribing multiple drugs with similar potential ADRs. Clinical guidelines should emphasise assessment of multimorbidity and ADR risk.},
keywords = {14151, COPD, multimorbidity},
pubstate = {published},
tppubtype = {article}
}

@article{Amaral2017,
title = {Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank.},
author = {AFS Amaral and DP Strachan and PGJ Burney and DL Jarvis},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28075609},
year = {2017},
date = {2017-05-01},
journal = {American Journal of Respiratory and Critical Care Medicine},
abstract = {RATIONALE:

The prevalence of chronic obstructive pulmonary disease (COPD) is increasing faster among women than among men.

OBJECTIVES:

To examine sex differences in the risk of airflow obstruction (a COPD hallmark) in relation to smoking history.

METHODS:

We analyzed 149,075 women and 100,252 men taking part in the UK Biobank who had provided spirometry measurements and information on smoking. The association of airflow obstruction with smoking characteristics was assessed by sex using regression analysis. The shape of this relationship was examined using restricted cubic splines.

MEASUREMENTS AND MAIN RESULTS:

The association of airflow obstruction with smoking status was stronger in women (odds ratio for ex-smokers [ORex], 1.44; ORcurrent, 3.45) than in men (ORex, 1.25; ORcurrent, 3.06) (P for interaction = 5.6 × 10-4). In both sexes, the association of airflow obstruction with cigarettes per day, smoking duration, and pack-years did not follow a linear pattern, with the increase in risk at lower doses being steeper among women. For equal doses of exposure, sex differences were present in both ex-smokers and current smokers for cigarettes per day (P for interactionex = 6.0 × 10-8; P for interactioncurrent = 1.1 × 10-5), smoking duration (P for interactionex = 7.9 × 10-4; P for interactioncurrent = 0.004), and pack-years (P for interactionex = 6.6 × 10-18; P for interactioncurrent = 1.3 × 10-6). Overall, those who started smoking before age 18 years were more likely to have airflow obstruction, but a sex difference in this association was not clear. For equal time since quitting, the reduction in risk among women seemed less marked than among men.

CONCLUSIONS:

Exposed to the same dose of smoking, women showed a higher risk of airflow obstruction than men. This could partly explain the increasingly smaller sex difference in the prevalence of COPD, especially in countries where smoking patterns have become similar between women and men.},
keywords = {412, COPD, smoking, Women},
pubstate = {published},
tppubtype = {article}
}

@article{LVWain2017,
title = {Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets},
author = {Louise V Wain and Martin D Tobin},
url = {http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3787.html},
year = {2017},
date = {2017-02-06},
journal = {Nature Genetics},
abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (~6 alleles) (95% confidence interval) = 1.24 (1.20–1.27), P = 5.05 × 10−49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.},
note = {Louise V Wain, Nick Shrine, María Soler Artigas, A Mesut Erzurumluoglu, Boris Noyvert, Lara Bossini-Castillo, Ma'en Obeidat, Amanda P Henry, Michael A Portelli, Robert J Hall, Charlotte K Billington, Tracy L Rimington, Anthony G Fenech, Catherine John, Tineka Blake, Victoria E Jackson, Richard J Allen, Bram P Prins, Understanding Society Scientific Group, Archie Campbell, David J Porteous, Marjo-Riitta Jarvelin, Matthias Wielscher, Alan L James, Jennie Hui, Nicholas J Wareham, Jing Hua Zhao, James F Wilson, Peter K Joshi, Beate Stubbe, Rajesh Rawal, Holger Schulz, Medea Imboden, Nicole M Probst-Hensch, Stefan Karrasch, Christian Gieger, Ian J Deary, Sarah E Harris, Jonathan Marten, Igor Rudan, Stefan Enroth, Ulf Gyllensten, Shona M Kerr, Ozren Polasek, Mika Kähönen, Ida Surakka, Veronique Vitart, Caroline Hayward, Terho Lehtimäki, Olli T Raitakari, David M Evans, A John Henderson, Craig E Pennell, Carol A Wang, Peter D Sly, Emily S Wan, Robert Busch, Brian D Hobbs, Augusto A Litonjua, David W Sparrow, Amund Gulsvik, Per S Bakke, James D Crapo, Terri H Beaty, Nadia N Hansel, Rasika A Mathias, Ingo Ruczinski, Kathleen C Barnes, Yohan Bossé, Philippe Joubert, Maarten van den Berge, Corry-Anke Brandsma, Peter D Paré, Don D Sin, David C Nickle, Ke Hao, Omri Gottesman, Frederick E Dewey, Shannon E Bruse, David J Carey, H Lester Kirchner, Geisinger-Regeneron DiscovEHR Collaboration, Stefan Jonsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Thorarinn Gislason, Kari Stefansson, Claudia Schurmann, Girish Nadkarni, Erwin P Bottinger, Ruth J F Loos, Robin G Walters, Zhengming Chen, Iona Y Millwood, Julien Vaucher, Om P Kurmi, Liming Li, Anna L Hansell, Chris Brightling, Eleftheria Zeggini, Michael H Cho, Edwin K Silverman, Ian Sayers, Gosia Trynka, Andrew P Morris, David P Strachan, Ian P Hall and Martin D Tobin},
keywords = {648, COPD, featured, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Artigas2017,
title = {Targeted Sequencing of Lung Function Loci in Chronic Obstructive Pulmonary Disease Cases and Controls},
author = {María Soler Artigas, Louise V. Wain , Nick Shrine, Tricia M. McKeever, UK BiLEVE , Ian Sayers, Ian P. Hall, Martin D. Tobin
},
url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170222},
year = {2017},
date = {2017-01-23},
journal = {PLOS One},
abstract = {Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD},
keywords = {648, COPD, GWAS, lung function},
pubstate = {published},
tppubtype = {article}
}

@article{Matteis2016,
title = {Occupations associated with COPD risk in the large population-based UK Biobank cohort study},
author = {S De Matteis, D Jarvis, S Hutchings,A Darnton, D Fishwick,S Sadhra,L Rushton,P Cullinan},
url = {http://www.ncbi.nlm.nih.gov/pubmed/27001997},
year = {2016},
date = {2016-03-21},
journal = {Occupational and Environmental Medicine},
abstract = {OBJECTIVES:

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Exposure to occupational hazards is an important preventable risk factor but the contribution of specific occupations to COPD risk in a general population is uncertain. Our aim was to investigate the association of COPD with occupation in the UK population.

METHODS:

In 2006-2010, the UK Biobank cohort recruited 502 649 adults aged 40-69 years. COPD cases were identified by prebronchodilator forced expiratory volume in 1 s/forced vital capacity
RESULTS:

Of the 353 occupations reported by 228 614 current working participants, several showed significantly increased COPD risk. Those at highest COPD risk were seafarers (PR=2.64; 95% CI 1.59 to 4.38), coal mine operatives (PR=2.30; 95% CI 1.00 to 5.31), cleaners (industrial: PR=1.96; 95% CI 1.16 to 3.31 and domestic: PR=1.43; 95% CI 1.28 to 1.59), roofers/tilers (PR=1.86; 95% CI 1.29 to 2.67), packers/bottlers/canners/fillers (PR=1.60; 95% CI 1.15 to 2.22), horticultural trades (PR=1.55; 95% CI 0.97 to 2.50), food/drink/tobacco process operatives (PR=1.46; 95% CI 1.11 to 1.93), floorers/wall tilers (PR=1.41; 95% CI 1.00 to 2.00), chemical/related process operatives (PR=1.39; 95% CI 0.98 to 1.97), postal workers/couriers (PR=1.35; 95% CI 1.15 to 1.59), labourers in building/woodworking trades (PR=1.32; 95% CI 1.04 to 1.68), school mid-day assistants (PR=1.32; 95% CI 1.01 to 1.74) and kitchen/catering assistants (PR=1.30; 95% CI 1.10 to 1.53). Associations were similar in analyses restricted to never-smokers and non-asthmatics.

CONCLUSIONS:

Selected occupations are associated with increased COPD risk in a large cross-sectional population-based UK study. Further analyses should confirm the extent to which these associations reflect exposures still of concern and where strengthened preventive action may be needed.},
keywords = {227, COPD, work},
pubstate = {published},
tppubtype = {article}
}

@article{Jackson2016,
title = {Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12},
author = {Victoria E Jackson, Ioanna Ntalla, Ian Sayers, Richard Morris, Peter Whincup, Juan-Pablo Casas, Antoinette Amuzu, Minkyoung Choi, Caroline Dale, Meena Kumari, Jorgen Engmann, Noor Kalsheker, Sally Chappell, Tamar Guetta-Baranes, Tricia M McKeever, Colin N A Palmer, Roger Tavendale, John W Holloway, Avan A Sayer, Elaine M Dennison, Cyrus Cooper, Mona Bafadhel, Bethan Barker, Chris Brightling, Charlotte E Bolton, Michelle E John, Stuart G Parker, Miriam F Moffat, Andrew J Wardlaw, Martin J Connolly, David J Porteous, Blair H Smith, Sandosh Padmanabhan, Lynne Hocking, Kathleen E Stirrups, Panos Deloukas, David P Strachan, Ian P Hall, Martin D Tobin, Louise V Wain },
url = {http://thorax.bmj.com/content/early/2016/02/25/thoraxjnl-2015-207876.abstract},
year = {2016},
date = {2016-02-25},
journal = {Thorax},
abstract = {
Background Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.

Objective To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.

Methods 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.

Results Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).

Conclusions This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
},
keywords = {648, COPD, genetics},
pubstate = {published},
tppubtype = {article}
}