Alu and LINE-1 methylation and lung function in the normative ageing study.
ABSTRACT: To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.Cohort study.Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA.Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white.Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws.In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV(1)) (?=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (?=27 ml, p=0.06) and lower FEV(1)/FVC (?=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV(1) (?=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (?=9.6 ml/year, p=0.002).In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures.
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:Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N?=?50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA?=?)5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA?=?)4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA?=?)1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Project description:Vitamin D has immunomodulatory and antiinflammatory effects that may be modified by cigarette smoke and may affect lung function.To examine the effect of vitamin D deficiency and smoking on lung function and lung function decline.A total of 626 men from the Normative Aging Study had 25-hydroxyvitamin D levels measured at three different times between 1984 and 2003 with concurrent spirometry. Vitamin D deficiency was defined as serum level ? 20 ng/ml. Statistical analysis was performed using multivariable linear regression and mixed effects models.In the overall cohort, there was no significant effect of vitamin D deficiency on lung function or on lung function decline. In both cross-sectional and longitudinal multivariable models, there was effect modification by vitamin D status on the association between smoking and lung function. Cross-sectional analysis revealed lower lung function in current smokers with vitamin D deficiency (FEV(1), FVC, and FEV(1)/FVC; P ? 0.0002), and longitudinal analysis showed more rapid rates of decline in FEV(1) (P = 0.023) per pack-year of smoking in subjects with vitamin D deficiency as compared with subjects who were vitamin D sufficient.Vitamin D deficiency was associated with lower lung function and more rapid lung function decline in smokers over 20 years in this longitudinal cohort of elderly men. This suggests that vitamin D sufficiency may have a protective effect against the damaging effects of smoking on lung function. Future studies should seek to confirm this finding in the context of smoking and other exposures that affect lung function.
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:RATIONALE:A 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. OBJECTIVES:To 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. METHODS:Data 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. MEASUREMENTS AND MAIN RESULTS:GOLD-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. CONCLUSIONS:Subjects 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).
Project description:A study was undertaken to determine if quantitative CT estimates of lung parenchymal overinflation and airway dimensions in smokers with a normal forced expiratory volume in 1 s (FEV(1)) can predict the rapid decline in FEV(1) that leads to chronic obstructive pulmonary disease (COPD).Study participants (n = 143; age 45-72 years; 54% male) were part of a lung cancer screening trial, had a smoking history of >30 pack years and a normal FEV(1) and FEV(1)/forced vital capacity (FVC) at baseline (mean (SD) FEV(1) 99.4 (12.8)%, range 80.2-140.7%; mean (SD) FEV(1)/FVC 77.9 (4.4), range 70.0-88.0%). An inspiratory multislice CT scan was acquired for each subject at baseline. Custom software was used to measure airway lumen and wall dimensions; the percentage of the lung inflated beyond a predicted maximal lung inflation, the low attenuation lung area with an x ray attenuation lower than -950 HU and the size distribution of the overinflated lung areas and the low attenuation area were described using a cluster analysis. Multiple regression analysis was used to test the hypothesis that these CT measurements combined with other baseline characteristics might identify those who would develop an excessive annual decline in FEV(1).The mean (SD) annual change in FEV(1) was -2.3 (4.7)% predicted (range -23.0% to +8.3%). Multiple regression analysis revealed that the annual change in FEV(1)%predicted was significantly associated with baseline percentage overinflated lung area measured on quantitative CT, FEV(1)% predicted, FEV(1)/FVC and gender.Quantitative CT scan evidence of overinflation of the lung predicts a rapid annual decline in FEV(1) in smokers with normal FEV(1).
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:Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans.We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV?) per pack-year of smoking (-5.7 ml FEV?/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV?/ smoking pack-year) (interaction P value ?=?0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV(1) decline in Health ABC and independently replicated in CARDIA.African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.
Project description:<h4>Background</h4>Emphysema in asymptomatic heavy smokers can be detected during CT-scan screening for lung cancer. Metalloproteinases (MMPs) have been found to play a role in the pathogenesis of chronic obstructive pulmonary disease and to possibly serve as biomarkers for emphysema.<h4>Methods</h4>The NYU Lung Cancer Biomarker Center enrolled study subjects over 50?years of age with lung cancer risk factors from January 1, 2010, to December 31, 2015. These subjects received chest multi-detector computed tomography, spirometry, and provided serum for immunoassays for metalloproteinases (MMP) -1,?-2,?-7,?-9, -10 and tissue inhibitor of metalloproteinases (TIMP) -1 and -2.<h4>Results</h4>Three hundred sixteen study subjects were enrolled. Of the 222 patients who met the inclusion criteria, 46% had emphysema. Smokers with emphysema had increased pack-years of smoking compared to smokers without emphysema (51?±?24 pack-years (mean?±?sd) versus 37?±?20; p?<?0.0001). Smokers with emphysema also had lower FEV<sub>1</sub>/FVC percent compared to smokers without emphysema (68?±?11 (mean?±?sd) versus 75?±?8; p?<?0.0001). Increased age and pack-years of smoking were associated with increased odds of emphysema. None of the metalloproteinases or tissue inhibitors of metalloproteinases were useful to predict the presence of emphysema in smokers.<h4>Conclusion</h4>Emphysema was detected by CT in almost half of heavy urban smokers. Serum MMP levels provided minimal additional information to improve the detection of mild emphysema among smokers given their clinical characteristics (age, pack-years, and FEV<sub>1</sub>/FVC ratio).
Project description:BACKGROUND:Prior studies have shown that AHRR (cg05575921) hypomethylation may be a marker of smoking, lung cancer risk and potentially lung cancer survival (in some lung cancer subtypes). It is unknown if AHRR (cg05575921) hypomethylation is associated with reduced survival among lung cancer patients. METHODS:In bisulfite treated leukocyte DNA from 465 lung cancer patients from the Copenhagen prospective lung cancer study, we measured AHRR (cg05575921) methylation. 380 died during max follow-up of 4.4 years. Cox proportional hazard models were used to analyze survival as a function of AHRR (cg05575921) methylation. RESULTS:We observed the expected inverse correlation between cumulative smoking and AHRR methylation, as methylation (%) decreased (Coefficient -0.03; 95% confidence interval, -0.04- -0.02, p = 8.6x10-15) for every pack-year. Cumulative smoking > 60 pack-years was associated with reduced survival (hazard ratio and 95% confidence interval 1.48; 1.05-2.09), however, AHRR (cg05575921) methylation was not associated with survival when adjusted for sex, body mass index, smoking status, ethnicity, performance status, TNM Classification, and histology type of lung cancer. CONCLUSION:AHRR (cg05575921) methylation is linked to smoking but does not provide independent prognostic information in lung cancer patients.