Clinical significance of chronic bronchitis in different racial groups.

BACKGROUNDS: Limited data are available on racial differences in the clinical features of chronic bronchitis (CB) patients with chronic obstructive pulmonary disease (COPD). In this study, we aimed to compare clinical features among CB patients of different races. We also analyzed the clinical significance of CB, defined classically and based on the COPD Assessment Test (CAT), to validate the CAT-based definition. METHODS: We analyzed patient data extracted from the Korean COPD Subgroup Study (KOCOSS) cohort (2012-2021) and US Genetic Epidemiology of COPD (COPDGene) study (2008-2011). We compared clinical characteristics among CB and non-CB patients of three different races using two CB definitions. RESULTS: In this study, 3,462 patients were non-Hispanic white (NHW), 1,018 were African American (AA), and 1,793 were Asian. The proportions of NHW, AA, and Asian patients with CB according to the classic definition were 27.4%, 20.9%, and 10.7%, compared with 25.2%, 30.9%, and 23.0% according to the CAT-based definition, respectively. The risk of CB prevalence was highest in NHW and lowest in Asian COPD patients. Among all races, CB patients were more likely to be current smokers, have worse respiratory symptoms and poorer health-related quality of life (HrQoL), and to have decreased lung function and exercise capacity. Most of these characteristics showed similar associations with the outcomes between the two definitions of CB. A binominal regression model revealed that CB patients of all races had an increased risk of future exacerbations according to both CB definitions, except for Asian patients with classically defined CB. CONCLUSIONS: The presence of CB was associated with worse respiratory symptoms, HrQoL, exercise capacity and lung function, and more exacerbations, regardless of race or CB definition. The CAT-based definition may be more useful for assessing the risk of future exacerbations in Asian COPD patients.

Examining neighbourhood-level disparities in Black, Latina/o, Asian, and White physical health, mental health, chronic conditions, and social disadvantage in California.

Racial/ethnic minority individuals in the U.S. experience numerous health disparities versus Whites, often due to differences in social determinants. Yet, limited large-scale research has examined these differences at the neighbourhood level. We merged 2021 PLACES Project and 2020 American Community Survey data across 3,211 census tracts (neighbourhoods) defined as majority (>50%) Black, Latina/o, Asian or White. T-tests and hierarchical linear regressions were used to examine differences and associations between neighbourhoods on key health (general health, mental health, obesity, diabetes, cancer, coronary heart disease, chronic obstructive pulmonary disease, stroke), and social outcomes (income, unemployment, age, population density). Results indicated that minority neighbourhoods in California exhibited stark health and social disparities versus White neighbourhoods, displaying worse outcomes on nearly every social and health variable/condition examined; particularly for Black and Latina/o neighbourhoods. Moreover, regression findings revealed that, after considering income, unemployment, and population density, (1) fair/poor mental health and higher percentages of Black, Latina/o and Asian residents in neighbourhoods independently associated with greater neighbourhood fair/poor physical health, and (2) fair/poor mental health significantly associated with greater prevalence of obesity and COPD. This study thus underscores the need to address the profound health and social disparities experienced by minority neighbourhoods for more equitable neighbourhoods.

Ethnic differences in respiratory disease for Native Hawaiians and Pacific Islanders: Analysis of mediation processes in two community samples.

OBJECTIVE: The prevalence of asthma and chronic obstructive pulmonary disorder (COPD) is elevated for Native Hawaiians but the basis for this differential is not well understood. We analyze data on asthma and COPD in two samples including Native Hawaiians Pacific Islanders, and Filipinos to determine how ethnicity is related to respiratory disease outcomes. METHODS: We analyzed the 2016 and 2018 Behavioral Risk Factor Surveillance Survey (BRFSS), a telephone survey of participants ages 18 and over in the State of Hawaii. Criterion variables were a diagnosis of asthma or COPD by a health professional. Structural equation modeling tested how five hypothesized risk factors (cigarette smoking, e-cigarette use, second-hand smoke exposure, obesity, and financial stress) mediated the ethnic differential in the likelihood of disease. Age, sex, and education were included as covariates. RESULTS: Structural modeling with 2016 data showed that Native Hawaiian ethnicity was related to higher levels of the five risk factors and each risk factor was related to a higher likelihood of respiratory disease. Indirect effects were statistically significant in almost all cases, with direct effects to asthma and COPD also observed. Mediation effects through comparable pathways were also noted for Pacific Islanders and Filipinos. These findings were replicated with data from the 2018 survey. CONCLUSIONS: Native Hawaiian and Pacific Islander ethnicity is associated with greater exposure to five risk factors and this accounts in part for the ethnic differential in respiratory disease outcomes. The results support a social-ecological model of health disparities in this population. Implications of the findings for preventive interventions are discussed.

Asthma and Chronic Obstructive Pulmonary Disease.

In the United States, asthma and chronic obstructive pulmonary disease (COPD) disproportionately affect African Americans, Puerto Ricans, and other minority groups. Compared with non-Hispanic whites, minorities have been marginalized and more frequently exposed to environmental risk factors such as tobacco smoke and outdoor and indoor pollutants. Such divergent environmental exposures, alone or interacting with heredity, lead to disparities in the prevalence, morbidity, and mortality of asthma and COPD, which are worsened by lack of access to health care. In this article, we review the burden and risk factors for racial or ethnic disparities in asthma and COPD and discuss future directions in this field.

Effect of PRDX6 gene polymorphism on susceptibility to chronic obstructive pulmonary disease in the Chinese Han population.

BACKGROUND: To explore the relationship of peroxiredoxin6 (PRDX6) tag-single nucleotide polymorphisms (SNPs) with susceptibility to chronic obstructive pulmonary disease (COPD) in the Chinese Han population. METHODS: A total of 502 patients with COPD and 481 healthy controls from nine hospitals in China were enrolled in this study. The PRDX6 tag-SNPs were identified by linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between identified tag-SNPs and COPD risk were further evaluated. RESULTS: Four PRDX6 tag-SNPs, including rs7314, rs34619706, rs33951697, and rs4382766, were identified in 30 healthy controls. Moreover, in the allele model, there was no statistical difference in locus in PRDX6 between patients with COPD and healthy controls (P > 0.05). However, in the recessive model, rs33951697 locus in PRDX6 gene carrier with T/T had an increased risk of COPD (odds ratio [OR] = 2.59, 95% CI = 1.06-6.33, P = 0.028). Furthermore, in the relevance analysis between genetic polymorphisms and smoking behavior and lung function indexes, we found that the number of smoked cigarettes per day and FEV1/FVC differed among different genotypes of PRDX6, rs4382766, and rs7314 (P < 0.05). CONCLUSION: PRDX6 gene polymorphism with smoking status may contribute to the etiology of COPD in the Chinese Han population.

The Relationship Between Chemokine and Chemokine Receptor Genes Polymorphisms and Chronic Obstructive Pulmonary Disease Susceptibility in Tatar Population from Russia: A Case Control Study.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease affecting primarily distal respiratory pathways and lung parenchyma. This study aimed to determine possible genetic association of chemokine and chemokine receptor genes polymorphisms with COPD in a Tatar population from Russia. SNPs of CCL20, CCR6, CXCL8, CXCR1, CXCR2, CCL8, CCL23, CCR2, and CX3CL1 genes and their gene-gene interactions were analyzed for association with COPD in cohort of 601 patients and 617 controls. As a result statistically significant associations with COPD in the study group under the biologically plausible assumption of additive genetic model were identified in CCL20 (rs6749704) (P = 0.00001, OR 1.55), CCR6 (rs3093024) (P = 0.0003, OR 0.74), CCL8 (rs3138035) (P = 0.0001, OR 0.67), CX3CL1 (rs170364) (P = 0.023, OR 1.21), CXCL8 (rs4073) (P = 0.007, OR 1.23), CXCR2 (rs2230054) (P = 0.0002, OR 1.32). Following SNPs CCL20 (rs6749704), CX3CL1 (rs170364), CCL8 (rs3138035), CXCL8 (rs4073), CXCR2 (rs2230054) showed statistically significant association with COPD only in smokers. The association of CCR6 (rs3093024) with COPD was confirmed both in smokers and in non-smokers. A relationship between smoking index and CCL20 (rs6749704) (P = 0.04), CCR6 (rs3093024) (P = 0.007), CCL8 (rs3138035) (P = 0.0043), and CX3CL1 (rs170364) (P = 0.04) was revealed. A significant genotype-dependent variation of Forced Vital Capacity was observed for CCL23 (rs854655) (P = 0.04). Forced Expiratory Volume in 1 s / Forced Vital Capacity ratio was affected by CCL23 (rs854655) (P = 0.05) and CXCR2 (rs1126579) (P = 0.02). Using the APSampler algorithm, we obtained nine gene-gene combinations that remained significantly associated with COPD; loci CCR2 (rs1799864) and CCL8 (rs3138035) were involved in the largest number of the combinations. Our results indicate that CCL20 (rs6749704), CCR6 (rs3093024), CCR2 (rs1799864), CCL8 (rs3138035), CXCL8 (rs4073), CXCR1 (rs2234671), CXCR2 (rs2230054), and CX3CL1 (rs170364) polymorphisms are strongly associated with COPD in Tatar population from Russia, alone and in combinations. For the first time combination of the corresponding SNPs were considered and as a result 8 SNP patterns were associated with increased risk of COPD.

Determinants of Lung Fissure Completeness.

Rationale: New advanced bronchoscopic treatment options for patients with severe chronic obstructive pulmonary disease (COPD) have led to increased interest for COPD phenotyping, including fissure completeness. Objectives: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD. Methods: We used data from 9,926 participants of the COPDGene study who underwent chest computed tomographic (CT) scans. Fissure completeness was calculated from CT scans after quantitative CT analysis at baseline and 5-year follow-up. Clinical and environmental factors, including sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD, were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic White subjects and African American subjects. Measurements and Main Results: African American subjects had significantly higher fissure completeness than non-Hispanic White subjects for all three fissures (P < 0.001). There was no change in fissure completeness between baseline and 5-year follow-up. For all fissures, no clinically relevant differences in fissure completeness were found for other clinical or environmental factors, including COPD severity. Rs2173623, rs264866, rs2407284, rs7310342, rs4904145, rs6504172, and rs7209556 showed genome-wide significant associations with fissure completeness in non-Hispanic White subjects. In African American subjects, rs264866, rs4904145 and rs6504172 were identified as significant associations. Rs2173623, rs6504172, and rs7209556 lead to WNT5A and HOXB antisense RNA expression, which play an important role during embryogenesis. Conclusions: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD (including exacerbation frequency), maternal smoking during pregnancy, or maternal COPD.

Racial Segregation and Respiratory Outcomes among Urban Black Residents with and at Risk of Chronic Obstructive Pulmonary Disease.

Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with chronic obstructive pulmonary disease (COPD) morbidity has not been established.Objectives: To investigate whether racial residential segregation is associated with COPD morbidity among urban Black adults with or at risk of COPD.Methods: Racial residential segregation was assessed using isolation index, based on 2010 decennial census and baseline address, for Black former and current smokers in the multicenter SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), a study of adults with or at risk for COPD. We tested the association between isolation index and respiratory symptoms, physiologic outcomes, imaging parameters, and exacerbation risk among urban Black residents, adjusting for established COPD risk factors, including smoking. Additional mediation analyses were conducted for factors that could lie on the pathway between segregation and COPD outcomes, including individual and neighborhood socioeconomic status, comorbidity burden, depression/anxiety, and ambient pollution.Measurements and Main Results: Among 515 Black participants, those residing in segregated neighborhoods (i.e., isolation index ⩾0.6) had worse COPD Assessment Test score (ß = 2.4; 95% confidence interval [CI], 0.7 to 4.0), dyspnea (modified Medical Research Council scale; ß = 0.29; 95% CI, 0.10 to 0.47), quality of life (St. George's Respiratory Questionnaire; ß = 6.1; 95% CI, 2.3 to 9.9), and cough and sputum (ß = 0.8; 95% CI, 0.1 to 1.5); lower FEV1% predicted (ß = -7.3; 95% CI, -10.9 to -3.6); higher rate of any and severe exacerbations; and higher percentage emphysema (ß = 2.3; 95% CI, 0.7 to 3.9) and air trapping (ß = 3.8; 95% CI, 0.6 to 7.1). Adverse associations attenuated with adjustment for potential mediators but remained robust for several outcomes, including dyspnea, FEV1% predicted, percentage emphysema, and air trapping.Conclusions: Racial residential segregation was adversely associated with COPD morbidity among urban Black participants and supports the hypothesis that racial segregation plays a role in explaining health inequities affecting Black communities.

Genetic variants in MIR2113 and MIR129-LEP are associated with the susceptibility of COPD in the Chinese Han population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the result of interaction between genetic and environmental factors. In this study, we aimed to explore whether MIR2113 and MIR129-LEP polymorphisms confer susceptibility to COPD. METHODS: We selected five polymorphisms of two genes (MIR2113: rs2505059 and rs9320913; MIR129-LEP: rs7778167, rs791595 and rs4731420) based on previous studies and genotyped 629 samples, which included 315 COPD patients and 314 controls with Agena MassARRAY platform. The association of MIR2113 and MIR129-LEP polymorphisms with COPD risk was conducted with logistic regression by calculating odd ratios (OR) and 95% confidence intervals (CI). RESULTS: MIR2113 rs2505059 was remarkably linked with a decreased susceptibility of COPD in five genetic models, whereas MIR2113 rs9320913, MIR129-LEP rs791595 and MIR129-LEP rs4731420 could enhance the susceptibility of COPD in the Chinese Han population (P < 0.05). Stratified analysis revealed that the influences of genetic variants on COPD risk were dependent on age, sex, Body mass index or smoking status (P < 0.05). Haplotype analysis showed that Ars791595Crs4731420 haplotype significant increased the susceptibility of COPD. CONCLUSION: It suggested that polymorphisms of MIR2113 and MIR129-LEP might be linked with the susceptibility of COPD among the Chinese Han population.

The effect of CYP3A4 genetic variants on the susceptibility to chronic obstructive pulmonary disease in the Hainan Han population.

PURPOSE: Genetic polymorphisms act a crucial role in chronic obstructive pulmonary disease (COPD) progression. This study aimed to investigate the correlation between CYP3A4 variants and COPD risk. METHODS: We carried out a case-control study of 821 individuals (313 patients and 508 healthy subjects) to identify the correlation of CYP3A4 SNPs with COPD risk in the Hainan Han population. The association was evaluated by Odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Our study showed that rs4646437 polymorphism was related to a significantly increased susceptibility to COPD (OR 1.45, 95% CI = 1.10-1.90, p = 0.008). Stratified analyses indicated that rs4646437 polymorphism was significantly related to an increased risk of COPD in males (OR 1.95, 95% CI = 1.19-3.20, p = 0.008). However, rs4646440 played a protective role in females (OR 0.54, 95% CI = 0.31-0.93, p = 0.024). Rs4646437 was found to significantly improve the risk of COPD in smokers (OR 1.67, 95% CI = 1.12-2.48, p = 0.011). While rs4646440 had a significantly lower susceptibility to COPD in non-smokers (OR 0.64, 95% CI = 0.45-0.90, p = 0.010). Haplotype analysis revealed that Ars4646440Trs35564277 haplotype of CYP3A4 was found to increase the risk of COPD in non-smokers (OR 1.71, 95% CI = 1.04-2.82, p = 0.034). CONCLUSION: Our result gives a new understanding of the association between CYP3A4 gene and COPD in the Hainan Han population.

BRIP1 rs10744996C>A variant increases the risk of chronic obstructive pulmonary disease in the Mongolian population of northern China.

NEW FINDINGS: What is the central question of this study? What is the role of breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) polymorphism in chronic obstructive pulmonary disease (COPD)? What is the main finding and its importance? Variant rs10744996C>A of BRIP1 increases the susceptibility of the Mongolian population to COPD. The expression of BRIP1 was significantly reduced in cigarette smoke extract-treated airway epithelial cells. ABSTRACT: Cigarette smoke is a major environmental pollutant that can induce DNA damage in humans. The development and progression of chronic obstructive pulmonary disease (COPD) are known to be related to the impairment of DNA repair. Breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) plays an important role in DNA interstrand crosslink repair and double-strand break repair. However, the role of BRIP1 polymorphisms in COPD has not been previously described. In this study, whole genome sequencing was used to identify mutations, and single nucleotide polymorphism (SNP) genotyping was used to verify the selected SNPs. In addition the BRIP1 expression levels in 16HBE and A549 airway epithelial cells treated with or without cigarette smoke extract (CSE) were measured using western blotting and RT-qPCR. Rs10744996C>A in the 3'-untranslated region (3'UTR) of BRIP1 was then genotyped in 1296 COPD cases and 988 healthy control subjects from a Mongolian population in northern China. Significant differences in the distribution of rs10744996C>A variants between COPD and control groups (P = 0.001) were identified. Rs10744996C>A was found to be associated with significantly increased COPD risk (adjusted odds ratio = 1.60, 95% CI = 1.30-1.98, P < 0.0001). Additionally, rs10744996A genotype was found to interact with a family history of cancer and a history of x-ray exposure (P = 0.028 and 0.009, respectively). BRIP1 expression levels in 16HBE and A549 cells treated with CSE were significantly lower compared to the control treated cells. The rs10744996C>A variant of BRIP1 increased the COPD susceptibility of the Mongolian population cohort. BRIP1 mRNA and protein expression levels were significantly reduced in conjunction with CSE-induced DNA damage in 16HBE and A549 cells.

"Bayis Ilh Tus - a strong breath" a community-based research project to estimate the prevalence of chronic obstructive pulmonary disease in remote and rural first nations communities in Canada: research protocol.

BACKGROUND: Respiratory health conditions appear to be more common among First Nations people versus non-First Nations people in Canada. However, the prevalence of chronic obstructive pulmonary disease (COPD) and its associated risk factors in First Nations communities are unknown. This project aims to estimate the prevalence of COPD in several First Nations communities in British Columbia, Canada and to characterize respiratory symptoms, COPD risk factors, and healthcare utilization. METHODS: This project is approved by both the University of British Columbia and Carrier Sekani Family Services Research Ethics Boards. We will randomly sample 220 adults, 30 years and older, from 11 participating First Nations. Each participant will complete pre- and post-bronchodilator spirometry tests and the adapted American Thoracic Society Epidemiological Questionnaire with items about smoking history, respiratory symptoms, co-morbidities, and exposures, in order to identify the presence of COPD and its associated individual, occupational, and community risk factors. Homes will be assessed for air quality measures including particulate matter, carbon monoxide and carbon dioxide, and humidity. Health care utilization will be abstracted from the electronic medical record. DISCUSSION: This is the first project in Canada to estimate the prevalence of COPD in First Nations communities using a random-sampling approach to recruitment. Additionally, although this study will collect detailed information on smoking history, we will also characterize past and current risk factors beyond cigarette smoking. Finally, our methodology ensures that the benefits to the communities are realized during the study period. Individual results will be shared with individuals and health providers to facilitate care. Air quality results will be sent to each Nation's governing council to facilitate remediation where necessary. TRIAL REGISTRATION: The study has been retrospectively registered at clinicaltrials.gov ( NCT04105088 ).

Increased Chitotriosidase Is Associated With Aspergillus and Frequent Exacerbations in South-East Asian Patients With Bronchiectasis.

BACKGROUND: Chitinase activity is an important innate immune defence mechanism against infection that includes fungi. The 2 human chitinases: chitotriosidase (CHIT1) and acidic mammalian chitinase are associated to allergy, asthma, and COPD; however, their role in bronchiectasis and bronchiectasis-COPD overlap (BCO) is unknown. RESEARCH QUESTION: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap? STUDY DESIGN AND METHODS: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles. RESULTS: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations. INTERPRETATION: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. METHODS: Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®. RESULTS: The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. CONCLUSIONS: All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Association between Tumor Necrosis Factor-308 G/A Polymorphism and Chronic Obstructive Pulmonary Disease Risk in Chinese Population: Evidence from a Meta-Analysis.

BACKGROUND: Association studies of tumor necrosis factor (TNF)-308 G/A (rs1800629) polymorphism and chronic obstructive pulmonary disease (COPD) have shown inconsistent and contradictory results among different populations. In the present study, a meta-analysis was performed to evaluate the association between TNF-308 G/A polymorphism and COPD susceptibility in Chinese population. MATERIALS AND METHODS: Systemic assessment was performed for the published studies from PubMed, Embase, Web of Science, the Cochrane Library, Wanfang Data, and CNKI prior to July 2018. Odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled using STATA software. RESULTS: A total of eighteen studies comprising 1,817 COPD cases and 2,056 controls were included in this meta-analysis. Overall, significant results were obtained between TNF-308 G/A polymorphism and COPD risk in Chinese population (A vs. G, OR = 2.45, 95% CI: 1.93 - 3.11; AA vs. GG, OR = 4.53, 95% CI: 2.67 - 7.68; AA vs. GA + GG, OR = 3.74, 95% CI: 2.21 - 6.33; AA + GA vs. GG, OR = 2.53, 95% CI: 1.97 - 3.26) under allele and homozygote models as well as recessive and dominant models. In the subgroup analyses, TNF-308 G/A polymorphism was significantly associated with increased COPD risk both in North China and South China, as well as in population-based studies. CONCLUSIONS: This meta-analysis indicates that TNF-308A/G polymorphism may contribute to individual suscepti-bility to COPD in Chinese population.

CYP2B6 genetic polymorphisms influence chronic obstructive pulmonary disease susceptibility in the Hainan population.

Introduction: Chronic obstructive pulmonary disease (COPD) is a lung disease closely related to exposure to exogenous substances. CYP2B6 can activate many exogenous substances, which in turn affect lung cells. The aim of this study was to assess the association of single-nucleotide polymorphisms (SNPs) in CYP2B6 with COPD risk in a Chinese Han population. Materials and methods: Genotypes of the five candidate SNPs in CYP2B6 were identified among 318 cases and 508 healthy controls with an Agena MassARRAY method. The association between CYP2B6 polymorphisms and COPD risk was evaluated using genetic models and haplotype analyses. Results: In allele model, we observed that rs4803420 G and rs1038376 A were related to COPD risk. And rs4803420 G/T and G/T-T/T were related to a decreased COPD risk compared to GG genotype in the co-dominant and dominant models, respectively. When comparing with the AA genotype, rs1038376 A/T and A/T-T/T were associated with an increased COPD risk in the co-dominant and dominant models, respectively. Further gender stratification co-dominant and dominant models analysis showed that genotype G/T and G/T-T/T of rs4803420, and genotype A/T and A/T-T/T of rs1038376 were significantly associated with COPD risk compared to the wide type in males and females, while allele C of rs12979270 was only associated with COPD risk in females. Smoking status stratification analysis showed that rs12979270 C was significantly associated with an increased COPD risk under the allele model compared with allele A in the smoking subgroup. Haplotype analysis showed that haplotype GTA and TAA were related to COPD risk. Conclusion: Our data is the first to demonstrate that CYP2B6 polymorphisms may exert effects on COPD susceptibility in the Chinese Han population.

A functional variant alters binding of activating protein 1 regulating expression of FGF7 gene associated with chronic obstructive pulmonary disease.

BACKGROUND: Genome-wide association studies (GWASs) of a large cohort of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified multiple risk genes, including fibroblast growth factor 7 (FGF7). However, the underlying molecular mechanism influencing function of FGF7 and risk of COPD remains further study. METHODS: In this study, we replicated the genetic association of variants near the FGF7 gene in 258 Chinese Han patients with COPD and 311 healthy controls. Additionally, we functionally evaluated a candidate causal variant upstream of the FGF7 gene. RESULTS: The most significant association was observed at rs12905203 (P = 5.9 × 10- 3, odd ratio, OR = 1.516) that explains associations of previously reported variants at the FGF7 locus. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays showed that the risk allele of the variant was bound to activator protein 1 transcription factors (c-Fos and c-Jun) with a significantly reduced affinity and associated with decreased mRNA expression of FGF7 in fibroblast cells at both resting and PMA/Ionomycin-stimulated conditions. Overexpression of c-Fos and c-Jun proteins or stimulation with PMA/Ionomycin significantly increases mRNA expression of FGF7 in fibroblast cells. Bioinformatic analysis showed that the variant overlaps with multiple genetic regulatory marks, suggesting the regulatory DNA element might function as an enhancer for the FGF7 gene. Luciferase enhancer activity assays demonstrated that the DNA sequences carrying the variant produce enhancer activity while the risk allele of the variant reduces its activity. CONCLUSIONS: In this study, we demonstrated a consistent association of the FGF7 gene with COPD and mechanistically characterized a candidate functional variant upstream of the FGF7 gene. These data highlighted the important role of the risk variant and the FGF7 gene in influencing risk for COPD.

Genome-Wide Association Analysis of Single-Breath DlCO.

DlCO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DlCO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DlCO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for DlCO in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and DlCO. We estimated the SNP-based heritability of DlCO in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with DlCO: variants near TGFB2, CHRNA3, and PDE11A loci (P < 5 × 10-8). In addition, 12 loci were suggestively associated with DlCO in European ancestry white (P < 1 × 10-5 in the combined analysis and P < 0.05 in both COPDGene and GenKOLS), including variants near NEGR1, CADM2, PCDH7, RETREG1, DACT2, NRG1, ANKRD18A, KRT86, NTN4, ARHGAP28, INSR, and PCBP3. Some DlCO-associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DlCO (P < 0.001). We identified several genetic loci that were significantly associated with DlCO and characterized effects of known COPD-associated loci on DlCO. These results could lead to better understanding of the heterogeneous nature of COPD.

Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.

Genome-wide association studies have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome, as compared with genotyping arrays or exome sequencing. We hypothesized that WGS in subjects with severe COPD and smoking control subjects with normal pulmonary function would allow us to identify novel genetic determinants of COPD. We sequenced 821 patients with severe COPD and 973 control subjects from the COPDGene and Boston Early-Onset COPD studies, including both non-Hispanic white and African American individuals. We performed single-variant and grouped-variant analyses, and in addition, we assessed the overlap of variants between sequencing- and array-based imputation. Our most significantly associated variant was in a known region near HHIP (combined P = 1.6 × 10-9); additional variants approaching genome-wide significance included previously described regions in CHRNA5, TNS1, and SERPINA6/SERPINA1 (the latter in African American individuals). None of our associations were clearly driven by rare variants, and we found minimal evidence of replication of genes identified by previously reported smaller sequencing studies. With WGS, we identified more than 20 million new variants, not seen with imputation, including more than 10,000 of potential importance in previously identified COPD genome-wide association study regions. WGS in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1. Larger sample sizes will be needed to identify associated variants in novel regions of the genome.