John E. Hokanson

Genetic Epidemiology of COPD (COPDGene) Study Design

ABSTRACT Background: COPDGene is a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes. Methods/Results: COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out. Conclusions: COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.

Variants in FAM13A are associated with chronic obstructive pulmonary disease

We performed a genome-wide association study for chronic obstructive pulmonary disease (COPD) in three population cohorts, including 2,940 cases and 1,380 controls who were current or former smokers with normal lung function. We identified a new susceptibility locus at 4q22.1 in FAM13A and replicated this association in one case-control group (n = 1,006) and two family-based cohorts (n = 3,808) (rs7671167, combined P = 1.2 × 10−11, combined odds ratio in case-control studies 0.76, 95% confidence interval 0.69–0.83).

Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes

PURPOSEnTo test the hypothesis-given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)-that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease.nnnMATERIALS AND METHODSnThis research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a -950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements.nnnRESULTSnIn a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047).nnnCONCLUSIONnGreater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes.

The Chronic Bronchitic Phenotype of COPD: An Analysis of the COPDGene Study

BACKGROUNDnChronic bronchitis (CB) in patients with COPD is associated with an accelerated lung function decline and an increased risk of respiratory infections. Despite its clinical significance, the chronic bronchitic phenotype in COPD remains poorly defined.nnnMETHODSnWe analyzed data from subjects enrolled in the Genetic Epidemiology of COPD (COPDGene) Study. A total of 1,061 subjects with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II to IV were divided into two groups: CB (CB+) if subjects noted chronic cough and phlegm production for ≥ 3 mo/y for 2 consecutive years, and no CB (CB-) if they did not.nnnRESULTSnThere were 290 and 771 subjects in the CB+ and CB- groups, respectively. Despite similar lung function, the CB+ group was younger (62.8 ± 8.4 vs 64.6 ± 8.4 years, P = .002), smoked more (57 ± 30 vs 52 ± 25 pack-years, P = .006), and had more current smokers (48% vs 27%, P < .0001). A greater percentage of the CB+ group reported nasal and ocular symptoms, wheezing, and nocturnal awakenings secondary to cough and dyspnea. History of exacerbations was higher in the CB+ group (1.21 ± 1.62 vs 0.63 ± 1.12 per patient, P < .027), and more patients in the CB+ group reported a history of severe exacerbations (26.6% vs 20.0%, P = .024). There was no difference in percent emphysema or percent gas trapping, but the CB+ group had a higher mean percent segmental airway wall area (63.2% ± 2.9% vs 62.6% ± 3.1%, P = .013).nnnCONCLUSIONSnCB in patients with COPD is associated with worse respiratory symptoms and higher risk of exacerbations. This group may need more directed therapy targeting chronic mucus production and smoking cessation not only to improve symptoms but also to reduce risk, improve quality of life, and improve outcomes.nnnTRIAL REGISTRYnClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Coronary artery and thoracic calcium on noncontrast thoracic CT scans: Comparison of ungated and gated examinations in patients from the COPD Gene cohort

OBJECTIVEnCoronary artery calcification (CAC) and thoracic aortic calcification, (TAC) are frequently detected on ungated multidetector computed tomography (MDCT) performed for lung evaluations. We sought to evaluate concordance of CAC and TAC scores on ungated (thoracic) and electrocardiogaphically (ECG)-gated (cardiac) MDCT scans.nnnMETHODSnFifty patients, enrolled in the Genetic Epidemiology of COPD study (COPDGene), were recruited to undergo gated CAC scans with 64-detector row CT, in addition to the ungated thoracic studies already being obtained as part of their study evaluation. Coronary and thoracic calcium were measured similarly (Agatston score, requiring 3 contiguous voxels of >130 Hounsfield units) with low-dose ungated studies and ECG-gated MDCT performed at the same scanning session. Intertechnique scoring variability and concordance were calculated.nnnRESULTSnCorrelations between gated and ungated CAC and TAC were excellent (r = 0.96). The relative differences (median variability) measured by ECG-gated versus ungated MDCT were relatively high for CAC (44%) but not for TAC (8%). Prevalence of depicted CAC (n = 33; 66%) and TAC (n = 21; 42%) were coincident between ECG-gated and ungated MDCT, respectively (intertechnique concordance, 100%). Bland-Altman plots for CAC showed mean differences of 354 (confidence interval, 169-538) and 16.1 (confidence interval, -89 to 121).nnnCONCLUSIONnLow-dose ungated MDCT is reliable for prediction of the presence of CAC and assessment of Agatston score. Concordance between methods and between TAC and CAC is high. This technique should allow for atherosclerotic disease risk stratification among patients undergoing ungated lung CT evaluation without requiring additional scanning. Measurement of TAC is almost as accurate from gated CT, and CAC scores are highly concordant.

Early-Onset Chronic Obstructive Pulmonary Disease Is Associated with Female Sex, Maternal Factors, and African American Race in the COPDGene Study

RATIONALEnThe characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.nnnMETHODSnWe analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n=70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n =306, age >64 yr, FEV1 <50% predicted).nnnMEASUREMENTS AND MAIN RESULTSnSubjects with severe, early-onset COPD were predominantly females (66%), P =0.0004. Proportionally,early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P <0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P =0.008). Maternal smoking (70 vs. 44%, P=0.0001) and maternal COPD (23 vs.12%, P=0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P ¼=0.0007); maternal COPD, OR, 4.7 (95% CI,1.3–17; P=0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P=0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P ¼ 0.03).nnnCONCLUSIONSnThese observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10−5 for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Clinical and Radiographic Predictors of GOLD–Unclassified Smokers in the COPDGene Study

RATIONALEnA significant proportion of smokers have lung function impairment characterized by a reduced FEV(1) with a preserved FEV(1)/FVC ratio. These smokers are a poorly characterized group due to their systematic exclusion from chronic obstructive pulmonary disease (COPD) studies.nnnOBJECTIVESnTo characterize the clinical, functional, and radiographic features of Global Initiative for Chronic Obstructive Lung Disease (GOLD)-Unclassified (FEV(1)/FVC ≥ 0.7 and FEV(1) < 80% predicted) and lower limits of normal (LLN)-unclassified (FEV(1)/FVC ≥ LLN and FEV(1) < LLN) subjects compared to smokers with normal lung function and subjects with COPD.nnnMETHODSnData from the first 2,500 subjects enrolled in the COPDGene study were analyzed. All subjects had 10 or more pack-years of smoking and were between the ages of 45 and 80 years. Multivariate regression models were constructed to determine the clinical and radiological variables associated with GOLD-Unclassified (GOLD-U) and LLN-Unclassified status. Separate multivariate regressions were performed in the subgroups of subjects with complete radiologic measurement variables available.nnnMEASUREMENTS AND MAIN RESULTSnGOLD-U smokers account for 9% of smokers in COPDGene and have increased body mass index (BMI), a disproportionately reduced total lung capacity, and a higher proportion of nonwhite subjects and subjects with diabetes. GOLD-U subjects exhibit increased airway wall thickness compared to smoking control subjects and decreased gas trapping and bronchodilator responsiveness compared to subjects with COPD. When LLN criteria were used to define the unclassified group, African American subjects were no longer overrepresented. Both GOLD-U and LLN-Unclassified subjects demonstrated a wide range of lung function impairment, BMI, and percentage of total lung emphysema.nnnCONCLUSIONSnSubjects with reduced FEV(1) and a preserved FEV(1)/FVC ratio are a heterogeneous group with significant symptoms and functional limitation who likely have a variety of underlying etiologies beyond increased BMI. Clinical trial registered with www.clinicaltrials.gov (NCT000608764).

The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility

Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

Adults with type 1 diabetes eat a high-fat atherogenic diet that is associated with coronary artery calcium

Aims/hypothesisCoronary heart disease is the leading cause of mortality among people with type 1 diabetes. Diet is an important lifestyle factor that relates to risk of CHD. The aim of this study was to examine how diet and adherence to dietary guidelines differ between adults with and without type 1 diabetes, and their correlation with CHD risk factors and coronary artery calcium (CAC).MethodsThe study involved 571 people with type 1 diabetes and 696 controls, aged 19 to 56xa0years, who were asymptomatic for CHD. CAC was measured by electron-beam computed tomography.ResultsCompared with the controls, adults with type 1 diabetes reported a diet higher in fat, saturated fat and protein but lower in carbohydrates. Fewer than half of those with type 1 diabetes met dietary guidelines for fat and carbohydrate intake, and only 16% restricted saturated fat to less than 10% of daily energy intake. Adults with type 1 diabetes were significantly less likely to meet dietary guidelines than controls. Fat and saturated fat intakes were positively correlated, but carbohydrate intake was negatively correlated with CHD risk factors and HbA1c. A high-fat diet and higher intake of protein were associated with greater odds of CAC, while higher carbohydrate intake was associated with reduced odds of CAC.Conclusions/interpretationAdults with type 1 diabetes reported consuming higher than recommended levels of fat and saturated fat. High fat intake was associated with increased CHD risk factors, worse glycaemic control and CAC. An atherogenic diet may contribute to the risk of CHD in adults with type 1 diabetes.