Lung Function and Gene Expression of Pathogen Recognition Pathway Receptors: the Cardia Lung Study.
ABSTRACT: Activation of toll-like receptors (TLR1, TLR5, TLR6) and downstream markers (CCR1, MAPK14, ICAM1) leads to increased systemic inflammation. Our objective was to study the association between the gene expression levels of these six genes and lung function (Forced Expiratory Volume in one second (FEV1), Forced Vital Capacity (FVC) and FEV1/FVC). We studied gene expression levels and lung function in the Coronary Artery Risk Development in Young Adults study. Spirometry testing was used to measure lung function and gene expression levels were measured using the Nanostring platform. Multivariate linear regression models were used to study the association between lung function measured at year 30, 10-year decline from year 20 to year 30, and gene expression levels (highest quartile divided into two levels - 75th to 95th and>95th to 100th percentile) adjusting for center, smoking and BMI, measured at year 25. Year 30 FEV1 and FVC were lower in the highest level of TLR5 compared to the lowest quartile with difference of 4.00% (p for trend: 0.04) and 3.90% (p for trend: 0.05), respectively. The 10-year decline of FEV1 was faster in the highest level of CCR1 as compared to the lowest quartile with a difference of 1.69% (p for trend: 0.01). There was no association between gene expression and FEV1/FVC. Higher gene expression levels in TLR5 and CCR1 are associated with lower lung function and faster decline in FEV1 over 10 years, in a threshold manner, providing new insights into the role of inflammation in lung function.
Project description:Systemic inflammation has been associated with reduced lung function. Adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and P-selectin, figure importantly in initiating the inflammatory response. We studied the association between ICAM-1 and P-selectin concentrations and lung function in the Coronary Artery Risk Development in Young Adults study.Spirometry testing was conducted at years 5, 10, and 20. ICAM-1 and P-selectin were assayed at year 15.Complete data were obtained from 2,455 participants. We first predicted year-20 lung function from year-15 ICAM-1 concentration data. After controlling for race, gender, height, age, physical activity, smoking status, alcohol intake, BMI, and asthma status, all taken at year 15, the year-20 FVC was 164 mL higher (p < 0.0001) and FEV(1) was 164 mL higher (p = 0.0003) in the lowest ICAM-1 concentration quartile than the highest ICAM-1 quartile, whereas the FEV(1)/FVC ratio showed no association (p = 0.25). We then predicted the year-15 ICAM-1 concentration from year-5 lung function and change in lung function (year 10 - year 5). The year-15 ICAM-1 concentration was about 13 ng/mL higher in the lowest vs highest quartile of either the year-5 FVC (p = 0.01) or year-5 FEV(1) (p = 0.005). Year-15 ICAM-1 concentration was unrelated to year-5 FEV(1)/FVC ratio. Greater loss in FVC and FEV(1) (year 10 - year 5) also was associated with higher year-15 ICAM-1 concentrations. Associations between P-selectin and lung function followed a similar but weaker pattern to that observed for ICAM-1.These data suggest a bidirectional association between circulating adhesion molecules, such as ICAM-1 and P-selectin, and pattern of lung function change in adults.
Project description:BACKGROUND:Systemic inflammation is associated with reduced lung function in both healthy individuals and those with chronic obstructive pulmonary disease (COPD). Whether systemic inflammation in healthy young adults is associated with future impairment in lung health is uncertain. METHODOLOGY/PRINCIPAL FINDINGS:We evaluated the association between plasma fibrinogen and C-reactive protein (CRP) in young adults and lung function in the Coronary Artery Risk Development in Young Adults cohort study. Higher year 7 fibrinogen was associated with greater loss of forced vital capacity (FVC) between years 5 and 20 (439 mL in quartile 4 vs. 398 mL in quartile 1, P<0.001) and forced expiratory volume in 1 second (FEV(1)) (487 mL in quartile 4 vs. 446 mL in quartile 1, P<0.001) independent of cigarette smoking, body habitus, baseline lung function and demographic factors. Higher year 7 CRP was also associated with both greater loss of FVC (455 mL in quartile 4 vs. 390 mL in quartile 1, P<0.001) and FEV(1) (491 mL in quartile 4 vs. 442 mL in quartile 1, P = 0.001). Higher year 7 fibrinogen and CRP were associated with abnormal FVC at year 20 (odds ratio (OR) per standard deviation 1.51 (95% confidence interval (CI): 1.30-1.75) for fibrinogen and 1.35 (95% CI: 1.14-1.59) for CRP). Higher year 5 fibrinogen was additionally associated with abnormal FEV(1). A positive interaction was observed between pack-years cigarette smoking and year 7 CRP for the COPD endpoint, and among participants with greater than 10 pack-years of cigarette exposure, year 7 CRP was associated with greater odds of COPD at year 20 (OR per standard deviation 1.53 (95% CI: 1.08-2.16). CONCLUSION/SIGNIFICANCE:Systemic inflammation in young adults is associated with abnormal lung function in middle age. In particular, elevated CRP may identify vulnerability to COPD among individuals who smoke. TRIAL REGISTRATION:ClinicalTrials.gov NCT00005130.
Project description:<h4>Background</h4>The potential effects of pulmonary dysfunction on cardiovascular diseases (CVD) are receiving attention. We aimed to investigate and quantify the cross-sectional and longitudinal associations between lung function and overall cardiovascular risk among Chinese general population.<h4>Methods</h4>We studied 4019 participants from the Wuhan-Zhuhai cohort, with a follow-up of 3 years. A multivariable risk algorithm generated from the Framingham study was used to calculate individuals' overall cardiovascular risk i.e. 10-Year CVD Risk, which was further classified into 2 categories: low (<?10%) and high (?10%) CVD risk. General linear model and logistic regression model were separately used to assess the associations of lung function with continuous and dichotomous 10-Year CVD Risk.<h4>Results</h4>Cross-sectionally, each 5% decrease in FEV<sub>1</sub>/FVC was associated with a 0.47% increase in 10-Year CVD Risk (P?<?0.001). The adjusted odds ratio (OR) (95% confidence interval [CI]) for the prevalence of high CVD risk (10-Year CVD Risk?10%) was 1.12 (1.07, 1.17) corresponding to each 5% decrease in FEV<sub>1</sub>/FVC. The OR (95% CI) for high CVD risk in the lowest group of FEV<sub>1</sub>/FVC (<?70% i.e. chronic obstructive pulmonary disease [COPD]) was 2.37 (1.43, 3.91) when compared with the highest group. Longitudinally, the adjusted risk ratio (RR) (95% CI) for the incidence of high CVD risk was 1.14 (1.03, 1.25) with each 5% decrease in baseline FEV<sub>1</sub>/FVC. Compared with the highest group of FEV<sub>1</sub>/FVC, the RR (95% CI) for high CVD risk in the lowest group (COPD) was 4.06 (1.46, 11.26). Analyses of 10-Year CVD Risk with FVC or FEV<sub>1</sub> showed similar trends and significant associations (all P?<?0.05).<h4>Conclusion</h4>Reduced lung function was cross-sectionally and longitudinally associated with increased cardiovascular risk in Chinese general population.
Project description:RATIONALE:The course of lung function decline for smokers with early airflow obstruction remains undefined. It is also unclear which early spirometric characteristics identify individuals at risk for rapid decline and increased mortality. OBJECTIVES:To determine the association between spirometric measures and 5-year decline in FEV(1) and 12-year mortality. METHODS:We analyzed longitudinal data from the Lung Health Study, a clinical trial of intensive smoking cessation intervention with or without bronchodilator therapy in 5,887 smokers with mild to moderate airflow obstruction. Participants were stratified into bins of baseline FEV(1) to FVC ratio, using bins of 5%, and separately into bins of Z-score (difference between actual and predicted FEV(1)/FVC, normalized to SD of predicted FEV(1)/FVC). Associations between spirometric measures and FEV(1) decline and mortality were determined after adjusting for baseline characteristics and time-varying smoking status. MEASUREMENTS AND MAIN RESULTS:The cohort was approximately two-thirds male, predominantly of white race (96%), and with mean age of 49 ± 7 years. In general, individuals with lower lung function by any metric had more rapid adjusted FEV(1) decline. A threshold for differential decline was present at FEV(1)/FVC less than 0.65 (P < 0.001) and Z-score less than -2 (2.3 percentile) (P < 0.001). At year 12, 575 (7.2%) of the cohort had died. Lower thresholds of each spirometric metric were associated with increasing adjusted hazard of death. CONCLUSIONS:Smokers at risk or with mild to moderate chronic obstructive pulmonary disease have accelerated lung function decline. Individuals with lower baseline FEV(1)/FVC have more rapid decline and worse mortality.
Project description:Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD); however, more than 25% of COPD patients are non-smokers, and gene-by-smoking interactions are expected to affect COPD onset. We aimed to identify the common genetic variants interacting with pack-years of smoking on FEV<sub>1</sub>/FVC ratios in individuals with normal lung function. A genome-wide interaction study (GWIS) on FEV<sub>1</sub>/FVC was performed for individuals with FEV<sub>1</sub>/FVC ratio???70 in the Korea Associated Resource cohort data, and significant SNPs were validated using data from two other Korean cohorts. The GWIS revealed that rs10947231 and rs8192575 met genome-wide significant levels; For [Formula: see text] the likelihood ratio (LR) test was conducted, and its P values, P<sub>LR</sub>, for rs10947231 and rs8192575 were 2.23?×?10<sup>-12</sup> and 1.18?×?10<sup>-8</sup>, respectively. Interaction between rs8192575 and smoking is significantly replicated with two additional data (P<sub>INT</sub>?=?0.0454, 0.0131). Expression quantitative trait loci, topologically associated domains, and PrediXcan analyses revealed that rs8192575 is significantly associated with AGER expression. SNPs on the 6p21 region are associated with FEV<sub>1</sub>/FVC, and the effect of smoking on FEV<sub>1</sub>/FVC differs among the associated genotypes.
Project description:<h4>Background</h4>Chronic lung allograft dysfunction (CLAD), a complication affecting the survival of lung transplanted patients, includes two clinical phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Everolimus is used in CLAD because of its antiproliferative mechanism. In lung transplant patients treated with everolimus, the clinical course of renal and lung function has not yet been assessed systematically in CLAD, BOS and RAS patients for more than 6?months.<h4>Methods</h4>We retrospectively evaluated the 12-month follow-up of renal and lung function of lung-transplanted patients switched to everolimus and evaluated the reduction in immunosuppressant dosage (ISD) and mortality. Subgroups were based on indication for everolimus treatment: CLAD and non-CLAD patients, BOS and RAS among CLAD patients.<h4>Results</h4>We included 26 patients, 17 with CLAD (10 BOS, seven RAS). After 1?year from the everolimus switch, we observed renal function improvement (serum creatinine -17%, estimated glomerular filtration rate +24%) and stable pulmonary function [forced expiratory volume in the first second (FEV<sub>1</sub>) -0.5%, forced vital capacity (FVC) +0.05%]. RAS patients had progressive functional loss, whereas BOS patients had FEV<sub>1</sub> improvement and FVC stability. All-cause mortality was higher in the CLAD <i>versus</i> non-CLAD group (41% <i>versus</i> 11%), without differences between BOS and RAS patients (<i>p</i>?>?0.05). All patients had significant and persistent ISD reduction.<h4>Conclusion</h4>Lung transplant patients treated with everolimus had improvements in renal function and reduced ISD. We observed sustained improvements in lung function for CLAD related to BOS subgroup results, whereas RAS confirmed the 1-year worsening functional trend. Data seem to suggest one more piece of the puzzle in CLAD phenotyping.
Project description:Impaired lung function has been linked to obesity and systemic inflammation. Pericardial fat has been shown to be associated with anomalies in cardiac structure, function, and atherosclerosis. We hypothesized that pericardial fat may have a similar role in the impairment of lung function.Cross-sectional associations of pericardial fat volumes, quantified by multidetector CT scan, with FEV(1) and FVC assessed by spirometry, were investigated in 1,293 participants (54.5 ± 10.8 years; 66.4% women) in the Jackson Heart Study. We also examined whether these associations were independent of visceral adipose tissue (VAT).Pericardial fat was associated with impaired lung function after multivariable adjustment, but these associations generally did not remain after adjustment for VAT. An exception was the FEV(1)/FVC ratio. Higher pericardial fat volumes were associated with higher odds of a restrictive lung pattern and lower odds of airway obstruction. Participants in the highest quartile had the highest odds of a restrictive lung pattern (OR, 1.85; 95% CI, 1.22-2.79, compared with quartile 1), even after adjustment for VAT. The odds of obstruction decreased across increasing quartiles of pericardial fat. These relationships were generally graded, suggesting dose-response trends.Pericardial fat is generally associated with lower lung function and independently associated with a restrictive lung pattern in middle-aged and elderly adults. Further research is needed to fully understand the mechanisms through which pericardial fat contributes to pulmonary anomalies.
Project description:<b>Background:</b>Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma.<br><br><b>Methods:</b>WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes.<br><br><b>Results:</b>A genome-wide significant association was identified between baseline FEV<sub>1</sub>/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10<sup>-8</sup> in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10<sup>-6</sup>). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV<sub>1</sub> (P = 3.3 × 10<sup>-3</sup>), postbronchodilator (PB) FEV<sub>1</sub> (7.3 × 10<sup>-3</sup>), and PB FEV<sub>1</sub>/FVC ratio (P = 2.7 × 10<sup>-3</sup>). The identified baseline FEV<sub>1</sub>/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR.<br><br><b>Conclusions:</b>These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
Project description:Antioxidant enzymes play an important role in the defense against oxidative stress in the lung and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Sequence variation in genes encoding antioxidant enzymes may alter susceptibility to COPD by affecting longitudinal change in lung function in adults. We genotyped 384 sequence variants in 56 candidate genes in 1281 African American and 1794 European American elderly adults in the Health, Aging, and Body Composition study. Single-marker associations and gene-by-smoking interactions with rate of change in FEV? and FEV?/FVC were evaluated using linear mixed-effects models, stratified by race/ethnicity. In European Americans, rs17883901 in GCLC was statistically significantly associated with rate of change in FEV?/FVC; the recessive genotype (TT) was associated with a 0.9% per year steeper decline (P = 4.50 × 10(-5)). Statistically significant gene-by-smoking interactions were observed for variants in two genes in European Americans: the minor allele of rs2297765 in mGST3 attenuated the accelerated decline in FEV?/FVC in smokers by 0.45% per year (P = 1.13 × 10(-4)); for participants with greater baseline smoking pack-years, the minor allele of rs2073192 in IDH3B was associated with an accelerated decline in FEV?/FVC (P = 2.10 × 10(-4)). For both genes, nominally significant interactions (P < 0.01) were observed at the gene level in African Americans (P = 0.007 and 4.60 × 10(-4), respectively). Nominally significant evidence of association was observed for variants in SOD3 and GLRX2 in multiple analyses. This study identifies two novel genes associated with longitudinal lung function phenotypes in both African and European Americans and confirms a prior finding for GCLC. These findings suggest novel mechanisms and molecular targets for future research and advance the understanding of genetic determinants of lung function and COPD risk.
Project description:Bronchodilator (BD) drugs are commonly prescribed for treatment and management of obstructive lung function present with diseases such as asthma. Administration of BD medication can partially or fully restore lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken before BD medication have been extensively studied, and the genetics of the BD response itself have received some attention. However, few studies have focused on the genetics of post-BD lung function. To address this gap, we analyzed lung function phenotypes in 1103 subjects from the Study of African Americans, Asthma, Genes, and Environment, a pediatric asthma case-control cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results with an admixture mapping scan of three pulmonary function tests (forced expiratory volume in 1?s [FEV<sub>1</sub> ], forced vital capacity [FVC], and FEV<sub>1</sub> /FVC) taken before and after albuterol BD administration on the same subjects, yielding six traits. We identified 18 GWAS loci, and five additional loci from admixture mapping, spanning several known and novel lung function candidate genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel potential genetic drivers of pre- and post-BD lung function: ADAMTS1, RAD54B, and EGLN3.