Elevated plasma TGF-β1 levels in patients with chronic obstructive pulmonary disease

SummaryBackgroundTransforming growth factor-β1 (TGF-β1), a multifunctional cytokine, has been implicated to be responsible for the increased deposition of extracellular matrix in the airways, and increased submucosal collagen expression in chronic obstructive pulmonary disease (COPD). We determined plasma TGF-β1 levels in patients with COPD and explored its association with common functional polymorphisms of TGF-β1 gene at C-509T and T869C in the development of COPD in a case–control study.MethodsStable COPD patients who were ever smokers, and age and pack-years smoked matched healthy controls (n = 205 in each group) were recruited for measurement of plasma TGF-β1 levels using commercially available ELISA kit, and genotyped at C-509T and T869C functional polymorphisms of TGF-β1 gene using polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP).ResultsCOPD patients had significantly elevated plasma TGF-β1 levels in comparison to healthy controls irrespective of the genotypes. Allele frequencies and genotype distributions at both polymorphic sites were not different among COPD patients or controls. TGF-β1 levels were inversely correlated (Pearson's correlation analysis) with FEV1 (% predicted) (p < 0.001) and FVC (% predicted) (p < 0.001).ConclusionThe findings of elevated plasma TGF-β1 levels in patients with COPD suggest that TGF-β1 may play a role in COPD pathogenesis. The C-509T and T869C functional polymorphisms of TGF-β1 gene do not represent a genetic predisposition to COPD susceptibility in Hong Kong Chinese patients

Prevalence of sleep disordered breathing in a population of Canadian grainworkers

OBJECTIVES: To determine the prevalence of sleep disordered breathing (SDB) in a Canadian population of industrial workers (grainworkers). To determine the clinical features that are predictive of SDB and the validity of self-reported snoring. DESIGN: Cross-sectional, interviewer-administered questionnaire with selective recruitment of subjects for home sleep monitoring. SETTING: Community setting, Vancouver, British Columbia. PARTICIPANTS: All male grainworkers at grain elevators in Vancouver were approached for completion of a questionnaire. Eighty-three per cent of 524 subjects completed the questionnaire and were divided by presumed risk for SDB into four groups. All subjects in the highest risk group (group 1-frequent snoring and witnessed apneas) and a random sample of 40 subjects in the other three groups (group 2 -frequent snoring without witnessed apneas; group 3 -infrequent snoring rare; group 4 -nonsnoring) were approached for home sleep monitoring and 42% consented. INTERVENTIONS: Interviewer-administered questionnaire and home sleep monitoring. RESULTS: The overall prevalence of SDB in this relatively overweight group was estimated to be 25%, with a stepwise increase from group 4 to group 1 (7%, 29%, 40%, 60%). Presence of snoring and witnessed apneas, a greater body-mass index and a larger neck circumference were associated with SDB. Self-reported snoring was not found to be predictive. CONCLUSIONS: This first study of the prevalence of SDB in Canada suggests that SDB is at least as prevalent in Canada as in other industrialized nations and may actually be more common than previously thought. Further studies are required to determine the morbidity, mortality and economic loss associated with SDB in industrial workers. Key Words: Home monitoring, Obstructive sleep apnea, Screening, Self-reported snoring, Sleep disordered breathing Prévalence des troubles respiratoires du sommeil dans une population de travailleurs du grain OBJECTIFS : Déterminer la prévalence des troubles respiratoires du sommeil dans une population canadienne de travailleurs de l&apos;industrie du grain. Déterminer les caractéristiques cliniques prédictives des troubles respiratoires du sommeil et la validité du ronflement signalé par les sujets eux-mêmes. MODÈLE : Questionnaire transversal rempli par un intervieweur et recrutement sélectif de sujets pour mener des études du sommeil à domicile. CONTEXTE : Dans la communauté de Vancouver en Colombie-Britannique. PARTICIPANTS : On a demandé à tous les sujets de sexe masculin travaillant dans les silos à grains de répondre à un questionnaire. Quatre-vingt-trois pour cent des 524 sujets ont complété le questionnaire ; ils étaient divisés en quatre groupes selon le risque présumé de troubles respiratoires du sommeil. On a demandé à tous les sujets du groupe à risque le plus élevé (groupe 1 -ronflement fréquent et apnées observées) et un échantillon aléatoire de 40 sujets dans les trois autres groupes (groupe 2 -ronflement fréquent sans apnées observées ; groupe 3 -rare ronflement occasionnel ; groupe 4 -aucun ronflement) de subir des études de sommeil à domicile. Quarante-deux pour cent des sujets ont consenti à subir de telles études. INTERVENTIONS : Questionnaire rempli par un intervieweur et études du sommeil à domicile. RÉSULTATS : La prévalence globale des troubles respiratoires du sommeil dans cette population relativement obèse a été estimée à 25 %, avec une augmentation par paliers du groupe 4 jusqu&apos;au groupe 1 (7 %, 29 %, 40 %, 60 %). Le ronflement et les apnées observées, un index de masse corporelle plus élevé et un tour du cou plus grand étaient associés à des troubles respiratoires du sommeil. voir page suivante S leep disordered breathing (SDB), including obstructive sleep apnea and obstructive sleep hypopnea, is associated with significant mortality (1,2) and morbidity (3). SDB is most common in middle-aged men, but its true prevalence in this group is still being determined. While early studies estimated the prevalence of SDB to be 0.9% and 1.3%, (4,5) more recent studies from the United States and Australia (6-8) have reported prevalence rates of SDB in middle-aged men to be in the range of 10% to 15%. To date there have been no published studies of the prevalence of SDB in Canada. The main objective of this study was to obtain an estimate of the prevalence of SDB in industrial workers, using a population of men working at grain elevators in Vancouver, British Columbia as a model. To achieve this objective we studied subjects with all levels of risk for SDB. A secondary objective was to determine which clinical features and anthropometric data were predictive of SDB. We also examined the relationship between self-reported snoring and recorded snoring. PATIENTS AND METHODS Subjects: The target population was men working in grain terminals. The sample frame, for the purpose of this study, consisted of men working at the grain terminals in the Vancouver area. Questionnaire administration: Subjects completed a questionnaire administered by trained interviewers that included questions concerning demographic data, sleep disturbance (snoring, witnessed apneas, daytime sleepiness), smoking history and included the American Thoracic Society Respiratory Disease Questionnaire (9). All subjects had their height, weight, blood pressure and neck circumference measured. The subjects were divided into four groups based on the reported presence of snoring and witnessed apneas: group 1, frequent snoring and witnessed apneas; group 2, frequent snoring without witnessed apneas; group 3, infrequent snoring or rare; group 4, nonsnoring. All subjects in group 1 and a random sample of 40 subjects in groups 2 to 4 were approached about overnight home sleep monitoring. Subjects who consented formed the sample population for determining SDB prevalence. Home sleep monitoring: Home sleep was monitored using the Mesam 4 (Madaus Medizin Elektronik, Freiburg, Germany) (10). The Mesam 4 is a four-channel digital recording device. The Mesam system has been validated in two previous studies (10,11). A polysomnographic technologist, trained in the use of the Mesam 4, set up the device at the subject&apos;s home on the study night and retrieved it the next morning. Heart rate was monitored through a single-lead electrocardiogram (modified V2) and R-R intervals were measured in milliseconds. Snoring sounds were monitored through an electric subminiature microphone, type MCE 2,000 (frequency range, 30 to 20,000 cycles/s ± 2dB, sensitivity 0.6 mV/microbar at 1000 cycles/s ± 4 dB; Conrad Electronics, Hirschau, Germany), taped above the larynx. Arterial oxygen saturation was measured continuously with a finger probe. The body position sensor, a flat cylinder 18 mm high with a diameter of 50 mm, was placed on the lower part of the sternum. Automated scoring software is available with the Mesam that provides a respiratory disturbance index. However, previous research has shown that hand scoring provides results that are more closely related to the results of simultaneous polysomnography than the automated analysis results (11). The Mesam recordings were therefore hand scored in 5 min epochs. This was done independently and in a blinded fashion by two physicians trained in SDB and familiar with the Mesam 4. Interobserver variability was determined using the Kappa statistic (12). Snoring was scored as absent, present during less than 50% of the recording, or present during 50% or more of the recording. A respiratory event was scored if at least two of the following three parameters were present: pauses in snoring of at least 10 s; heart rate deceleration and acceleration of at least 10 beats/min; and an associated arterial oxygen desaturation of at least 2%. If recurrent episodes were present during the majority of a 5 min epoch, the epoch was defined as positive for SDB. The subjects&apos; records were then classified based on the following criteria: normalevents less than 10% of the recording; possible SDB -events 10% to 30% of the recording; definite SDB -events greater than 30% of the recording. The Mesam 4 does not record sleep; therefore, the total study time is not equivalent to a total sleep time. Using a total study time rather than a total sleep time tends to underestimate the degree of SDB. This approach was adopted to avoid concerns that the prevalence of SDB would be overestimated in this population. Calculation of prevalence: The prevalence of both suspected and definite SDB was calculated but the conservative latter definition was used for the primary analysis. The prevalence of SDB was calculated in each sample group by the equation: Prevalence = (number of subjects with definite SDB × 100%)/ total number of subjects To estimate the overall prevalence of definite SDB in the entire group of grainworkers the prevalence obtained from each sample groups was projected to their respective total groups. Overall prevalence = [(sample group 1)(number of subjects in total group 1) + (sample group 2)(number of subjects in total group 2) + (sample group 3)(number of subjects in total group 3) + (sample group 4)(number of subjects in total group 4)] × 100%/total number of grainworkers Can Respir J Vol 5 No 3 May/June 1998 185 Prevalence of SDB in grainworkers Le ronflement signalé par les sujets eux-mêmes ne représentait pas un facteur prédictif. CONCLUSIONS : Cette première étude sur la prévalence des troubles respiratoires du sommeil au Canada permet de croire qu&apos;ils sont aussi fréquents dans ce pays que dans les autres pays industrialisés mais aussi que leur incidence serait en fait plus importante que celle présumée antérieurement. D&apos;autres études sont nécessaires pour déterminer la morbidité, la mortalité et la perte économique associées aux troubles respiratoires du sommeil chez les travailleurs industriels. where sample group refers to the prevalance of SDB in the sample group specificed. Before this calculation, subjects approached for home sleep monitoring who did not participate (refused or could not be contacted) were compared with their respective total groups in terms of age, body mass index (BMI) and neck circumference. If no significant difference was found between the sample group and total group, then the previously described formula was used to calculate prevalence. If a significant difference was found between a sample group and either those who did not participate or the group as a whole then the above formula was modified such that the respective group prevalence was multiplied by only the number of subjects in the sample group and not by the entire total group. Statistics: One-way ANOVA was used to to compare the anthropometric data and a c 2 test was used to compare the questionnaire data (categorical) among the four total groups and among the three home sleep monitoring derived diagnostic groups (normal, possible SDB, definite SDB). The sample groups and the total groups were compared by an unpaired Student&apos;s t test. Prevalence was calculated as described above, and the interobserver variability was calculated using the Kappa statistic (a Kappa score greater than 0.7 is indicative of minimal interobserver variability). RESULTS Questionnaire data: Four hundred and thirty-seven men of the 524 men approached completed the questionnaire and had a limited physical examination (83% response rate). Nineteen (4.3%) admitted to snoring often and had a history of witnessed apneas (group 1), 98 (22.3%) snored often without witnessed apneas (group 2), 185 (42.3%) snored sometimes or rarely (group 3) and 135 (31.1%) were nonsnorers (group 4). These groups differed significantly in the distribution of neck circumference (P&lt;0.0001), BMI (P&lt;0.0001) and age (P&lt;0.05) ( The distribution of diagnoses from home sleep monitoring differed among the four groups By projecting the prevalence of definite SDB found in the four sample groups to their respective total group the overall prevalence of SDB was estimated to be 25% in this group of grainworkers: In group 1 the prevalence of the sample group was multiplied by the number of subjects in the sample group rather than the total group. There was a significant difference in BMI between those studied (heavier) and those who were not studied (P&lt;0.02, Table 2), although those who were studied were similar to the total group. There were no significant differences between those subjects studied and those that did not participate in sample groups 2 to 4 (P&gt;0.05, Figure 1) Prevalence of definite sleep disordered breathing in the sample groups and the total population There were no differences among the total groups and their respective sample groups in age, BMI or neck circumference. The two physicians scoring the Mesam studies agreed on categorization of the studies 85% of the time. In the studies in which there was not complete agreement, the two physicians were never more than one category removed. The interobserver variability, as calculated by the Kappa statistic, was 0.7. Factors associated with SDB: Among grainworkers who underwent home sleep monitoring, the presence of snoring (P&lt;0.005) and witnessed apneas (P&lt;0.04), a greater BMI (P&lt;0.040) and a larger neck circumference (P&lt;0.02) were found to be predictive of definite SDB. However, the presence of daytime sleepiness, history of hypertension (patient reported) and smoking history were not associated with the presence of SDB. There was no difference in measured blood pressure between the patients with and those without SDB. The relatively small sample size in each group may limit the power to detect true differences among the groups. Validity of self-reported snoring: Fifty-eight subjects underwent home sleep monitoring. Fourteen of these subjects denied snoring but home sleep monitoring revealed that five did not snore, five snored for less than 50% of the night and four snored for more than 50% of the night DISCUSSION In this first study of the prevalence of SDB in Canada, we found that 25% of a population of male grainworkers had SDB. The known risk factors of male sex and higher than average BMI in the study population are probably responsible for a higher prevalence of SDB than previously reported. A history of snoring and witnessed apneas as well as greater BMI and larger neck circumference were found to be useful predictors of SDB, a finding consistent with previous studies (6,13-15). Smoking was more common in subjects who re- ported snoring (with or without witnessed apneas) but we did not find a previously reported association between smoking history and SDB (7). Furthermore, self-reported snoring was not found to be a reliable guide to the presence of recorded snoring. A number of factors could have contributed to our finding of a greater prevalence of SDB in our study than that reported by others. Certain assumptions were made in previous prevalence studies, the most common of which is that self-reported snoring and daytime sleepiness were reliable symptoms of SDB The recognition of obstructive breathing associated with neurological arousal without accompanying arterial oxygen desaturation has expanded the definition of SDB. It is now apparent that there is a continuum of SDB associated with progressively more clinical consequences, from chronic snoring to obstructive sleep hypopnea to severe obstructive sleep apnea. The diagnostic threshold to define SDB within this continuum directly affects the measured prevalence. For example, the initial study by Lavie (4) used a diagnostic threshold of an apnea index greater than 10/h; however, if one uses an apnea index more than five/h the prevalence moves from 1% to nearly 16% in a group of male industrial workers. The use of home oximetry to define cases of SDB, a less sensitive monitoring system than conventional overnight, in-hospital polysomnography, has also contributed to the underestimation of prevalence rates. Stradling and Crosby (17) studied 893 men with overnight oximetry and found that 45 (5%) had more than five desaturations of 4% per hour. Thirty-one of these men had overnight polysomnography, and three had severe, nonpositional SDB (0.3%) and 18 had mild to moderate, positional apnea (2.4%). Men with clinically significant SDB with apneas and hypopneas without associated desaturations of 4% would have been missed using this methodology. More recent studies conducted in the United States and Australia using expanded definitions of SDB have found prevalence rates similar to our study (10% to 20%). In a recent study from the United States, 40% of middle-aged men and 30% of middle-aged women were found to be habitual snorers (6). Significant SDB was defined as the presence of an apnea-hypopnea index (AHI) greater than five/h (from polysomnography) and symptoms of excessive daytime sleepiness. About 4% of middle-aged men and 2% of middle-aged women met these criteria. When they defined SDB based only on AHI, 24% of middle-aged men had an AHI greater than five/h, 15% had an AHI greater than 10 per hour, and 9% had an AHI greater than 15/h. These prevalence rates are similar to those found in our study. Bearpark and colleagues Obesity is a significant risk factor for SDB. We examined a relatively healthy, nonhypertensive population of middleaged, working men who had a higher average BMI (29±5 kg/m

Associations between the 17q21 region and allergic rhinitis in 5 birth cohorts

Non peer reviewe

The Role of Circulating Serotonin in the Development of Chronic Obstructive Pulmonary Disease

BACKGROUND: Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age. METHODS: The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA). RESULTS: The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = -0.149, p = 0.108). CONCLUSION: Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.published_or_final_versio

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

Background: Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE. Objective: To identify the genetic predictors of serum total IgE levels. Methods: We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals. Results: We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis. Conclusion: This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

BACKGROUND: Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE. OBJECTIVE: To identify the genetic predictors of serum total IgE levels. METHODS: We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals. RESULTS: We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10(−6)) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10(−7), respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis. CONCLUSION: This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals

Occupational Asthma -- The Last 50 Years

It was indeed a great honour for me to be this year's Christie Memorial Lecturer. Although I have not been fortunate enough to have had personal contact with Professor Christie, one of the greatest lung physiologists of our time, I have had the opportunity over the years of interacting with and learning from the group working in the laboratory named after him - the Meakins-Christie Laboratories - as a member of the Respiratory Health Network of Centres of Excellence, Canada