Publications by authors named "Megan Hardin"

24 Publications

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Seven Pillars of Small Airways Disease in Asthma and COPD - Supporting Opportunities for Novel Therapies.

Chest 2021 Apr 2. Epub 2021 Apr 2.

Research and Early Development, Respiratory, Inflammation, and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA.

Identification of pathological changes in early and mild obstructive lung disease has revealed the importance of the small airways and their contribution to symptoms. Indeed, significant small airways dysfunction has been found before any overt airway obstruction is detectable by conventional spirometry techniques. However, most therapies for the treatment of obstructive lung disease target the physiological changes and associated symptoms that result from chronic lung disease, rather than directly targeting the specific underlying causes of airflow disruption or the drivers of disease progression. In addition, while spirometry is the current standard for diagnosis and monitoring of response to therapy, the most widely used measure, forced expiratory volume in 1 second, does not align with the pathological changes in early or mild disease and may not align with symptoms or exacerbation frequency in individual patient. Newer functional and imaging techniques allow more effective assessment of small airways dysfunction; however, significant gaps in our understanding remain. Improving our knowledge of the role of small airways dysfunction in early disease in the airways, along with the identification of novel endpoints to measure sub-clinical changes in this region, i.e. those not captured as symptoms or identified through standard FEV, may lead to the development of novel therapies that directly combat early airways disease processes with a view to slowing disease progression and reversing damage. This expert opinion paper will discuss small airways disease in the context of asthma and COPD and highlight gaps in current knowledge that impede earlier identification of obstructive lung disease and the development and standardization of novel small airways-specific endpoints for use in clinical trials.
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http://dx.doi.org/10.1016/j.chest.2021.03.047DOI Listing
April 2021

Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial.

J Am Acad Dermatol 2020 Nov 20;83(5):1282-1293. Epub 2020 Jun 20.

Regeneron Pharmaceuticals, Inc, Tarrytown New York. Electronic address:

Background: Children with severe atopic dermatitis (AD) have limited treatment options.

Objective: We report the efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies.

Methods: In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight <30 kg; 200 mg q2w, baseline weight ≥30 kg), or placebo; with concomitant medium-potency TCS.

Results: Both the q4w and q2w dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children <30 kg and 200 mg q2w in children ≥30 kg. Conjunctivitis and injection-site reactions were more common with dupilumab + TCS than with placebo + TCS.

Limitations: Short-term 16-week treatment period; severe AD only.

Conclusion: Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.
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http://dx.doi.org/10.1016/j.jaad.2020.06.054DOI Listing
November 2020

Clinical Approach to the Therapy of Asthma-COPD Overlap.

Chest 2019 01 2;155(1):168-177. Epub 2018 Aug 2.

Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY.

Over the last few years, there has been a renewed interest in patients with characteristics of both asthma and COPD. Although the precise definition of asthma-COPD overlap (ACO) is still controversial, patients with overlapping features are frequently encountered in clinical practice, and may indeed have worse clinical outcomes and increased health-care utilization than those with asthma or COPD. Therefore, there is a critical need to set a framework for the therapeutic approach of such patients. There are key distinctions in the therapy between asthma and COPD, particularly regarding the initial choice of therapy. However, there is considerable overlap in the use of existing medications for both diseases. Furthermore, novel therapies approved for asthma, such as monoclonal antibodies, may have a role in patients with COPD and ACO. The use of biomarkers, such as peripheral blood eosinophils, exhaled nitric oxide, and serum IgE, may help in selecting appropriate therapies for ACO. In this review, we provide an overview of available treatments for both asthma and COPD and explore their potential role in the treatment of patients with ACO.
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http://dx.doi.org/10.1016/j.chest.2018.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688980PMC
January 2019

Asthma Is a Risk Factor for Respiratory Exacerbations Without Increased Rate of Lung Function Decline: Five-Year Follow-up in Adult Smokers From the COPDGene Study.

Chest 2018 02 15;153(2):368-377. Epub 2017 Dec 15.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA.

Background: Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions.

Methods: Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at < 16 years. Childhood asthma was defined as self-reported asthma diagnosed by a health professional at < 16 years. ACO was defined as subjects with COPD who self-reported asthma diagnosed by a health-professional at ≤ 40 years. Smokers with and those without these early-life respiratory diseases were compared on measures of disease progression.

Results: Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P < .001; ACO, P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans.

Conclusions: Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period.

Trial Registry: ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2017.11.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815872PMC
February 2018

What's New with the St George's Respiratory Questionnaire and Why Do We Care?

Chronic Obstr Pulm Dis 2017 Apr 3;4(2):83-86. Epub 2017 Apr 3.

Clinical Discovery Unit, Early Clinical Discovery, AstraZeneca, Cambridge, United Kingdom.

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http://dx.doi.org/10.15326/jcopdf.4.2.2017.0139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559106PMC
April 2017

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

Am J Respir Cell Mol Biol 2017 07;57(1):35-46

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

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10) and PPP4R4/SERPINA1 (P = 1.01 × 10) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.
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http://dx.doi.org/10.1165/rcmb.2016-0331OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516277PMC
July 2017

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Nat Genet 2017 Mar 6;49(3):426-432. Epub 2017 Feb 6.

Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
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http://dx.doi.org/10.1038/ng.3752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381275PMC
March 2017

Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1.

J Cachexia Sarcopenia Muscle 2017 Jun 2;8(3):428-436. Epub 2017 Jan 2.

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

Background: There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.

Methods: A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years of age with three consecutive BMI time points (n = 4162). Four GWAS of ΔBMI using generalized estimating equations were performed among 1085 participants with a cancer diagnosis, 204 with gastrointestinal (GI) cancer, 112 with lung cancer, and 237 with COPD to test for association with 418 365 single-nucleotide polymorphisms (SNPs).

Results: Two SNPs reached a level of genome-wide significance (P < 5 × 10 ) with ΔBMI: (i) rs41526344 within the CNTN4 gene, among COPD cases (β = 0.13, P = 4.3 × 10 ); and (ii) rs4751240 in the gene Dedicator of Cytokinesis 1 (DOCK1) among GI cancer cases (β = 0.10, P = 1.9 × 10 ). The DOCK1 SNP association replicated in the ΔBMI GWAS among COPD cases (β  = 0.10, P  = 9.3 × 10 ). The DOCK1 gene codes for the dedicator of cytokinesis 1 protein, which has a role in myoblast fusion.

Conclusions: In sum, one statistically significant common variant in the DOCK1 gene was associated with ΔBMI in GI cancer and COPD cases providing support for at least partially shared aetiology of ΔBMI in complex diseases.
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http://dx.doi.org/10.1002/jcsm.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476850PMC
June 2017

Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women.

Am J Respir Cell Mol Biol 2017 03;56(3):332-341

1 Channing Division of Network Medicine and.

Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.
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http://dx.doi.org/10.1165/rcmb.2016-0172OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359539PMC
March 2017

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

Genet Epidemiol 2016 09 21;40(6):475-85. Epub 2016 Jun 21.

Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.
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http://dx.doi.org/10.1002/gepi.21979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981534PMC
September 2016

Analysis of Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome Defined on the Basis of Bronchodilator Response and Degree of Emphysema.

Ann Am Thorac Soc 2016 09;13(9):1483-9

1 Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.

Rationale: Despite the increasing recognition of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) as a clinical entity, it remains poorly characterized due to a lack of agreement on its definition and diagnostic criteria.

Objectives: The aim of this study was to use spirometry and computed tomography (CT) to help better define ACOS as well as to classify subjects with ACOS based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) letter grade.

Methods: We analyzed 10,192 subjects enrolled in the COPDGene Study. Subjects were non-Hispanic white or African American current or former smokers aged 45-80 years with at least a 10-pack-year smoking history. Subjects were categorized as having either ACOS with a bronchodilator response or chronic obstructive pulmonary disease with emphysema on the basis of spirometry, high-resolution CT, and a history of asthma or hay fever.

Measurements And Main Results: Subjects with ACOS were younger (60.6 vs. 65.9 years old; P < 0.0001), more likely to be African American (26.8% vs. 14.4%; P < 0.0001), had a higher body mass index (29.6 vs. 25.1 kg/m(2); P < 0.0001), and were more likely to be current smokers (50.9% vs. 20.7%; P < 0.0001). The majority of subjects with ACOS were categorized as GOLD grade B. Despite less severe spirometry and CT findings in subjects with ACOS, there was no significant difference in severe or frequent exacerbations.

Conclusions: Bronchodilator responsiveness and degree of emphysema can help define ACOS. When defined on the basis of bronchodilator responsiveness and degree of emphysema, patients with ACOS represent a unique and high-risk group with distinct clinical features.
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http://dx.doi.org/10.1513/AnnalsATS.201511-761OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614769PMC
September 2016

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2016 07;194(1):48-57

21 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.

Objectives: To identify coding variants associated with COPD.

Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.

Measurements And Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.

Conclusions: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
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http://dx.doi.org/10.1164/rccm.201510-2053OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960630PMC
July 2016

Sex-specific features of emphysema among current and former smokers with COPD.

Eur Respir J 2016 Jan 5;47(1):104-12. Epub 2015 Nov 5.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Recent studies suggest that males with chronic obstructive pulmonary disease (COPD) have more emphysema than females. It is not known if these differences persist across degrees of COPD severity. Our aim was to identify sex-specific differences in quantitative emphysema within COPD subgroups based on COPD severity.We included non-Hispanic white and African-American subjects from the COPDGene study with at least 10 pack-years of smoking and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry grade II or greater. We examined sex-specific differences in log-transformed emphysema (log per cent low-attenuation area (%LAA)) by GOLD spirometry grade among subjects with early-onset COPD (<55 years old) and advanced emphysema (>25% emphysema).Compared with females, males had higher log %LAA: overall (1.97±1.4 versus 1.69±1.6, β=0.32 (0.04), p=1.34×10(-14)), and among non-Hispanic white (p=8.37×10(-14)) and African-American subjects (p=0.002). Females with early-onset COPD, severe emphysema and GOLD grade IV COPD had similar emphysema as males, but markedly fewer pack-years smoking (early-onset, p=0.01; severe emphysema and GOLD grade IV, p<0.001).This study identifies subsets of female smokers with COPD who are particularly susceptible to parenchymal destruction.
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http://dx.doi.org/10.1183/13993003.00996-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374719PMC
January 2016

Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction.

Ann Am Thorac Soc 2014 Nov;11(9):1371-8

1 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Rationale And Objectives: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma.

Methods: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models.

Measurements And Main Results: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models.

Conclusion: In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
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http://dx.doi.org/10.1513/AnnalsATS.201403-095OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298990PMC
November 2014

Radiological correlates and clinical implications of the paradoxical lung function response to β₂ agonists: an observational study.

Lancet Respir Med 2014 Nov 9;2(11):911-918. Epub 2014 Sep 9.

Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama, Birmingham, AL, USA; Lung Health Center, University of Alabama, Birmingham, AL, USA.

Background: Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to β₂ agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with β₂ agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications.

Methods: Non-Hispanic white and African-American patients (aged 45-80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV₁) or forced vital capacity (FVC), or both, after administration of a shortacting β₂ agonist (180 μg salbutamol).

Findings: Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10,364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50-2·39; p<0·0001), less emphysema (0·96, 0·92-0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01-1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted β for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (-45·8 [-78·5 to -13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00-1·81; p=0·048).

Interpretation: Paradoxical response to β₂ agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of β2agonists in some patients.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-2600(14)70185-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306040PMC
November 2014

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

Respir Med 2014 Oct 11;108(10):1469-80. Epub 2014 Aug 11.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Background: Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1).

Methods: Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects.

Results: K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects.

Conclusions: Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity.
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http://dx.doi.org/10.1016/j.rmed.2014.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253548PMC
October 2014

The clinical and genetic features of COPD-asthma overlap syndrome.

Eur Respir J 2014 Aug 29;44(2):341-50. Epub 2014 May 29.

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

Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African-Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African-American populations, and combined these results in a meta-analysis. More females and African-Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57 × 10(-6)) and SOX5 (rs59569785, p=1.61 × 10(-6)) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18 × 10(-7)) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management.
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http://dx.doi.org/10.1183/09031936.00216013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154588PMC
August 2014

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future.

Chronic Obstr Pulm Dis 2014 May 6;1(1):33-46. Epub 2014 May 6.

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

Chronic obstructive pulmonary disease (COPD) affects over 10 million Americans. This complex disorder demonstrates many different presentations in a wide variety of patients, and results from a combination of environmental exposures and genetic risk factors. Smoking alone does not result in COPD: not all smokers develop COPD and lung function decline among smokers is highly variable. There is growing evidence for genetic risk factors for COPD: early familial aggregation and linkage analysis studies strongly suggested genetic contributions to COPD, and recent genome-wide association studies have identified several genomic regions that are clearly related to COPD susceptibility. However, despite recent advances in COPD genetics, much of the heritability of COPD remains unexplained, and functional studies are only beginning to elucidate a role for the genetic associations that have been identified. Despite this, the future is bright for understanding the genetics of COPD. Improvements in COPD phenotyping, collaborations among COPD study cohorts, and novel integrative approaches to identifying genetic markers all promise to unravel much of this missing heritability and ultimately lead to improvements in our understanding of COPD susceptibility and treatment.
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http://dx.doi.org/10.15326/jcopdf.1.1.2014.0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559139PMC
May 2014

CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland.

Am J Respir Cell Mol Biol 2012 Aug 29;47(2):203-8. Epub 2012 Mar 29.

Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA.

We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P < 0.01), with more pack-years of smoking (45 versus 33 pack-years, P < 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P = 7.4 × 10(-7)), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P = 3.4 × 10(-3)), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P = 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P = 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).
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http://dx.doi.org/10.1165/rcmb.2012-0011OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423462PMC
August 2012

Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP.

Hum Mol Genet 2012 Mar 2;21(6):1325-35. Epub 2011 Dec 2.

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.

Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.
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http://dx.doi.org/10.1093/hmg/ddr569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284120PMC
March 2012

The clinical features of the overlap between COPD and asthma.

Respir Res 2011 Sep 27;12:127. Epub 2011 Sep 27.

Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.

Methods: We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.

Results: 119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p=0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p=0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p<0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p<0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.

Conclusion: Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.

Trial Registration: ClinicalTrials.gov: NCT00608764.
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http://dx.doi.org/10.1186/1465-9921-12-127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204243PMC
September 2011

Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men.

Diabetes Care 2005 Jul;28(7):1636-42

Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

Objective: The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men.

Research Design And Methods: A total of 60 men (mean age 60.5 +/- 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (V(O2max)) and expression of oxidative phosphorylation genes in skeletal muscle.

Results: A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m(2) and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone-binding globulin but not BMI. Testosterone levels also correlated with V(O2max) (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001).

Conclusions: These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.
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http://dx.doi.org/10.2337/diacare.28.7.1636DOI Listing
July 2005

Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men.

J Clin Endocrinol Metab 2005 May 15;90(5):2636-41. Epub 2005 Feb 15.

Reproductive Endocrine Unit, BHX 511, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

Insulin resistance is associated with low testosterone (T) levels in men, the mechanism of which is unclear. Thus, the aim of this study was to evaluate the hypothalamic-pituitary-gonadal axis in men with a spectrum of insulin sensitivity. Twenty-one men (aged 25-65 yr) had a glucose tolerance test and assessment of insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Insulin sensitivity, expressed as the M value (milligrams per kilograms(-1) per minute(-1)), was calculated from the glucose disposal rate during the final 30 min of the clamp. Eighteen subjects had blood sampling every 10 min for 12 h to assess LH pulsatility. Hypogonadism was then induced with a GnRH antagonist, followed by sequential stimulation testing with GnRH (750 ng/kg, iv) and human chorionic gonadotropin (hCG; 1000 IU, im) to assess pituitary and testicular responsiveness, respectively. Nine subjects had normal glucose tolerance, nine had impaired glucose tolerance, and three had diabetes mellitus. There was a positive relationship between M and T levels (r = 0.46; P < 0.05). No relationship was seen between M and parameters of LH secretion, including mean LH levels, LH pulse amplitude, LH pulse frequency, and LH response to exogenous GnRH administration. In contrast, a strong correlation was observed between M and the T response to hCG (r = 0.73; P < 0.005). Baseline T levels correlated with the increase in T after hCG administration (r = 0.47; P < 0.05). During the clamp, T levels increased from a baseline level of 367 +/- 30 to 419 +/- 38 ng/dl during the last 30 min (P < 0.05). From these data we conclude that insulin resistance is associated with a decrease in Leydig cell T secretion in men. Additional studies are required to determine the mechanism of this effect.
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http://dx.doi.org/10.1210/jc.2004-2190DOI Listing
May 2005