Research papers published

Snoring and nocturnal reflux: association with lung function decline and respiratory symptoms

Emilsson ÖI, Hägg SA, Lindberg E, Franklin KA, Toren K, Benediktsdottir B, Aspelund T, Gómez Real F, Leynaert B, Demoly P, Sigsgaard T, Perret J, Malinovschi A, Jarvis D, Garcia-Aymerich J, Gislason T, Janson C

ERJ Open Res. DOI: 10.1183/23120541.00010-2019

The study aim was to examine the association of snoring and nocturnal gastro-oesophageal reflux (nGOR) with respiratory symptoms and lung function, and if snoring and/or nGOR associated with a steeper decline in lung function.

Data from the third visit of the European Community Respiratory Health Survey (ECRHS) was used for cross-sectional analysis. Pre- and post-bronchodilator spirometry was performed, and information on sleep, nGOR and respiratory symptoms was collected (n=5715). Habitual snoring and nGOR were assessed by questionnaire reports. Pre-bronchodilator spirometry from ECRHS I, II and III (20 years follow-up) were used to analyse lung function changes by multivariate regression analysis.

Snoring and nGOR were independently associated with a higher prevalence of wheeze, chest tightness, breathlessness, cough and phlegm. The prevalence of any respiratory symptom was 79% in subjects with both snoring and nGOR versus 56% in those with neither (p<0.001). Subjects with both snoring and nGOR had more frequent exacerbations (adjusted prevalence 32% versus 19% among "no snoring, no nGOR", p=0.003). Snoring but not nGOR was associated with a steeper decline in forced expiratory volume in 1 s over 10 years after adjusting for confounding factors (change in % predicted -5.53, versus -4.58 among "no snoring", p=0.04) and forced vital capacity (change in % predicted -1.94, versus -0.99 among "no snoring", p=0.03).

Adults reporting both habitual snoring and nGOR had more respiratory symptoms and more frequent exacerbations of these symptoms. Habitual snoring was associated with a steeper decline in lung function over time.

Epigenome-wide association study of lung function level and its change

Imboden M, Wielscher M, Rezwan FI, Amaral AFS, Schaffner E, Jeong A, Beckmeyer-Borowko A, Harris SE, Starr JM, Deary IJ, Flexeder C, Waldenberger M, Peters A, Schulz H, Chen S, Sunny SK, Karmaus WJJ, Jiang Y, Erhart G, Kronenberg F, Arathimos R, Sharp GC, Henderson AJ, Fu Y, Piirilä P, Pietiläinen KH, Ollikainen M, Johansson A, Gyllensten U, de Vries M, van der Plaat DA, de Jong K, Boezen HM, Hall IP, Tobin MD, Jarvelin MR, Holloway JW, Jarvis D, Probst-Hensch NM

Eur Respir J. DOI: 10.1183/13993003.00457-2019.

Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults. In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalised absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers. EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96×10-21 and Pcombined=7.22×10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.

Occupational exposure to solvents and lung function decline: A population based study 

Alif SM, Dharmage S, Benke G, Dennekamp M, Burgess J, Perret JL, Lodge C, Morrison S, Johns DP, Giles G, Gurrin L, Thomas PS, Hopper JL, Wood-Baker R, Thompson B, Feather I, Vermeulen R, Kromhout H, Jarvis D, Garcia Aymerich J, Walters EH, Abramson MJ, Matheson MC

Thorax. DOI: 10.1136/thoraxjnl-2018-212267

While cross-sectional studies have shown associations between certain occupational exposures and lower levels of lung function, there was little evidence from population-based studies with repeated lung function measurements.

We aimed to investigate the associations between occupational exposures and longitudinal lung function decline in the population-based Tasmanian Longitudinal Health Study.

Lung function decline between ages 45 years and 50 years was assessed using data from 767 participants. Using lifetime work history calendars completed at age 45 years, exposures were assigned according to the ALOHA plus Job Exposure Matrix. Occupational exposures were defined as ever exposed and cumulative exposure -unit- years. We investigated effect modification by sex, smoking and asthma status.

Compared with those without exposure, ever exposures to aromatic solvents and metals were associated with a greater decline in FEV1 (aromatic solvents 15.5 mL/year (95% CI -24.8 to 6.3); metals 11.3 mL/year (95% CI -21.9 to - 0.7)) and FVC (aromatic solvents 14.1 mL/year 95% CI -28.8 to - 0.7; metals 17.5 mL/year (95% CI -34.3 to - 0.8)). Cumulative exposure (unit years) to aromatic solvents was also associated with greater decline in FEV1 and FVC. Women had lower cumulative exposure years to aromatic solvents than men (mean (SD) 9.6 (15.5) vs 16.6 (14.6)), but greater lung function decline than men. We also found association between ever exposures to gases/fumes or mineral dust and greater decline in lung function.

Exposures to aromatic solvents and metals were associated with greater lung function decline. The effect of aromatic solvents was strongest in women. Preventive strategies should be implemented to reduce these exposures in the workplace

DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non-Atopic Asthma

Jeong A, Imboden M, Ghantous A, Novoloaca A, Carsin AE, Kogevinas M, Schindler C, Lovison G, Herceg Z, Cuenin C, Vermeulen R, Jarvis D, Amaral AFS, Kronenberg F, Vineis P, Probst-Hensch N

Int J Environ Res Public Health.  DOI: 10.3390/ijerph16040600

A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthmalink. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-κB signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.

Exogenous female sex steroids may reduce lung ageing after menopause: A 20-year follow-up study of a general population sample (ECRHS)

Triebner K, Accordini S, Calciano L, Johannessen A, Benediktsdóttir B, Bifulco E, Demoly P, Dharmage SC, Franklin KA, Garcia-Aymerich J, Gullón Blanco JA, Heinrich J, Holm M, Jarvis D, Jõgi R, Lindberg E, Martínez-Moratalla J, Muniozguren Agirre N, Pin I, Probst-Hensch N, Raherison C, Sánchez-Ramos JL, Schlünssen V, Svanes C, Hustad S, Leynaert B, Gómez Real F

Maturitas. DOI: 10.1016/j.maturitas.2018.11.007

Menopause involves hypoestrogenism, which is associated with numerous detrimental effects, including on respiratory health. Hormone replacement therapy (HRT) is often used to improve symptoms of menopause. The effects of HRT on lung function decline, hence lung ageing, have not yet been investigated despite the recognized effects of HRT on other health outcomes.

The population-based multi-centre European Community Respiratory Health Survey provided complete data for 275 oral HRT users at two time points, who were matched with 383 nonusers and analysed with a two-level linear mixed effects regression model.

We studied whether HRT use was associated with the annual decline in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).

Lung function of women using oral HRT for more than five years declined less rapidly than that of nonusers. The adjusted difference in FVC decline was 5.6 mL/y (95%CI: 1.8 to 9.3, p = 0.01) for women who had taken HRT for six to ten years and 8.9 mL/y (3.5 to 14.2, p = 0.003) for those who had taken it for more than ten years. The adjusted difference in FEV1 decline was 4.4 mL/y (0.9 to 8.0, p = 0.02) with treatment from six to ten years and 5.3 mL/y (0.4 to 10.2, p = 0.048) with treatment for over ten years.

In this longitudinal population-based study, the decline in lung function was less rapid in women who used HRT, following a dose-response pattern, and consistent when adjusting for potential confounding factors. This may signify that female sex hormones are of importance for lung ageing.

Time and age trends in smoking cessation in Europe

Pesce G, Marcon A, Calciano L, Perret JL, Abramson MJ, Bono R, Bousquet J, Fois AG, Janson C, Jarvis D, Jõgi R, Leynaert B, Nowak D, Schlünssen V, Urrutia-Landa I, Verlato G, Villani S, Zuberbier T, Minelli C, Accordini S

PLoS One. DOI: 10.1371/journal.pone.0211976

Smoking is the main risk factor for most of the leading causes of death. Cessation is the single most important step that smokers can take to improve their health. With the aim of informing policy makers about decisions on future tobacco control strategies, we estimated time and age trends in smoking cessation in Europe between 1980 and 2010.
Data on the smoking history of 50,228 lifetime smokers from 17 European countries were obtained from six large population-based studies included in the Ageing Lungs in European Cohorts (ALEC) consortium. Smoking cessation rates were assessed retrospectively, and age trends were estimated for three decades (1980-1989, 1990-1999, 2000-2010). The analyses were stratified by sex and region (North, East, South, West Europe).
Overall, 21,735 subjects (43.3%) quit smoking over a total time-at-risk of 803,031 years. Cessation rates increased between 1980 and 2010 in young adults (16-40 years), especially females, from all the regions, and in older adults (41-60 years) from North Europe, while they were stable in older adults from East, South and West Europe. In the 2000s, the cessation rates for men and women combined were highest in North Europe (49.9 per 1,000/year) compared to the other regions (range: 26.5-32.7 per 1,000/year). A sharp peak in rates was observed for women around the age of 30, possibly as a consequence of pregnancy-related smoking cessation. In most regions, subjects who started smoking before the age of 16 were less likely to quit than those who started later.
Our findings suggest an increasing awareness on the detrimental effects of smoking across Europe. However, East, South and West European countries are lagging behind North Europe, suggesting the need to intensify tobacco control strategies in these regions. Additional efforts should be made to keep young adolescents away from taking up smoking, as early initiation could make quitting more challenging during later life.

Restrictive spirometry pattern is associated with low physical activity levels. A population based international study

Carsin AE, Fuertes E, Schaffner E, Jarvis D, Antó JM, Heinrich J, Bellisario V, Svanes C, Keidel D, Imboden M, Weyler J, Nowak D, Martinez-Moratalla J, Gullón JA, Sanchez Ramos JL, Caviezel S, Beckmeyer-Borowko A, Raherison C, Pin I, Demoly P, Cerveri I, Accordini S, Gislason T, Toren K, Forsberg B, Janson C, Jogi R, Emtner M, Gómez Real F, Raza W, Leynaert B, Pascual S, Guerra S, Dharmage SC, Probst-Hensch N, Garcia-Aymerich J

Respir Med. DOI: 10.1016/j.rmed.2018.11.017

Restrictive spirometry pattern is an under-recognised disorder with a poor morbidity and mortality prognosis. We compared physical activity levels between adults with a restrictive spirometry pattern and with normal spirometry.
Restrictive spirometry pattern was defined as a having post-bronchodilator FEV1/FVC ≥ Lower Limit of Normal and a FVC<80% predicted in two population-based studies (ECRHS-III and SAPALDIA3). Physical activity was measured using the International Physical Activity Questionnaire. The odds of having low physical activity (<1st study-specific tertile) was evaluated using adjusted logistic regression models.
Subjects with a restrictive spirometry pattern (n = 280/4721 in ECRHS, n = 143/3570 in SAPALDIA) reported lower levels of physical activity than those with normal spirometry (median of 1770 vs 2253 MET·min/week in ECRHS, and 3519 vs 3945 MET·min/week in SAPALDIA). Subjects with a restrictive spirometry pattern were more likely to report low physical activity (meta-analysis odds ratio: 1.41 [95%CI 1.07-1.86]) than those with a normal spirometry. Obesity, respiratory symptoms, co-morbidities and previous physical activity levels did not fully explain this finding.
Adults with a restrictive spirometry pattern were more likely to report low levels of physical activity than those with normal spirometry. These results highlight the need to identify and act on this understudied but prevalent condition

Childhood Body Composition Trajectories and Adolescent Lung Function: Findings from the ALSPAC Study

Peralta GP, Fuertes E, Granell R, Mahmoud O, Roda C, Serra I, Jarvis D, Henderson J, Garcia-Aymerich J

Am J Respir Crit Care Med. DOI: 10.1164/rccm.201806-1168OC

Body composition changes throughout life may explain the inconsistent associations reported between body mass index (BMI) and lung function in children.

To assess the associations of body weight and composition trajectories from 7 to 15 years with lung function at 15 years and lung function growth between 8 and 15 years.

Sex-specific BMI, lean body mass index (LBMI) and fat mass index (FMI) trajectories were developed using Group-Based Trajectory Modeling on data collected at least twice between 7 and 15 years from 6,964 children (49% boys) in the UK Avon Longitudinal Study of Parents and Children birth cohort. Associations of these trajectories with post-bronchodilation lung function parameters at 15 years and with lung function growth rates from 8 to 15 years were assessed using multivariable linear regression models, stratified by sex, in a subgroup with lung function data (n=3,575).

For all body mass measures we identified parallel trajectories that increased with age. There was no consistent evidence of an association between the BMI trajectories and lung function measures. Higher LBMI trajectories were associated with higher levels and growth rates of FVC, FEV1, and FEF25-75 in both sexes (e.g. boys in the highest LBMI trajectory had on average a 0.62L [95%CI: 0.44; 0.79, p-trend<0.0001] higher FVC at 15 years than boys in the lowest trajectory). Increasing FMI trajectories were associated with lower levels and growth rates of FEV1 and FEF25-75 only in boys and lower levels of FEV1/FVC in both sexes.

Higher lean body mass during childhood and adolescence is consistently associated with higher lung function at 15 years in both sexes, whereas higher fat mass is associated with lower levels of only some lung function parameters.

SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts

Beckmeyer-Borowko A, Imboden M, Rezwan FI, Wielscher M, Amaral AFS, Jeong A, Schaffner E, Auvinen J, Sebert S, Karhunen V, Bettschart R, Turk A, Pons M, Stolz D, Kronenberg F, Arathimos R, Sharp GC, Relton C, Henderson AJ, Jarvelin MR, Jarvis D, Holloway JW, Probst-Hensch NM

Respiratory Research DOI: 10.1186/s12931-018-0850-8

The pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort.

DNA methylation and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. 

Methylation at cg08257009 in the SERPINA gene cluster, was associated with FEV1/FVC in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing.

The results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.

Childhood Respiratory Risk Factor Profiles and Middle-Age Lung Function: A Prospective Cohort Study from the First to Sixth Decade

Bui DS, Walters HE, Burgess JA, Perret JL, Bui MQ, Bowatte G, Lowe AJ, Russell MA, Thompson BR, Hamilton GS, James AL, Giles GG, Thomas PS, Jarvis D, Svanes C, Garcia-Aymerich J, Erbas B, Frith PA, Allen KJ, Abramson MJ, Lodge CJ, Dharmage SC.

Annals ATS DOI: 10.1513/AnnalsATS.201806-374OC  

Childhood risk factors for long-term lung health often coexist and their specific patterns may affect subsequent lung function differently.  In this study we identified childhood risk factor profiles and their influence on lung function and chronic obstructive pulmonary disease (COPD) in middle age, and potential pathways.

Profiles of 11 childhood respiratory risk factors, documented at age 7, were identified in 8,352 participants from the Tasmanian Longitudinal Health. Associations between risk profiles and post-bronchodilator lung function and COPD at age 53, mediation by childhood lung function and adult asthma, and interaction with personal smoking were investigated.

We found that profiles of childhood respiratory risk factors predict middle-age lung function levels and COPD risk. Specifically, children with frequent asthma attacks and allergies, especially if they also become adult smokers, are the most vulnerable group. Targeting active asthma in adulthood (i.e., a dominant mediator) and smoking (i.e., an effect modifier) may block causal pathways and lessen the effect of such established early-life exposures.

Residential air pollution does not modify the positive association between physical activity and lung function in current smokers in the ECRHS study

Elaine Fuertes, Iana Markevych, Deborah Jarvis, Danielle Vienneau, Kees de Hoogh, Josep Maria Antó, Gayan Bowatt, Roberto Bono, Angelo G. Corsico, Margareta Emtner, Thorarinn Gislason, José Antonio Gullón, Joachim Heinrich, John Henderson, Mathias Holm, Ane Johannessen, Bénédicte Leynaert, Alessandro Marcon, Pierpaolo Marchetti, Jesús Martínez Moratalla, Silvia Pascuala, Nicole Probst-Hensch, José Luis Sánchez-Ramosa, Valerie Sirouxa, Johan Sommara, Joost Weyler, Nino Kuenzli, Bénédicte Jacquemin, Judith Garcia-Aymerich

Environment International DOI: 10.1016/j.envint.2018.07.032

This study assessed whether annual average residential concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) and < 10 μm (PM10) modify the effect of physical activity on lung function among never- (N = 2801) and current (N = 1719) smokers in the multi-centre European Community Respiratory Health Survey.

Associations between repeated assessments (at 27–57 and 39–67 years) of being physically active(physical activity: ≥2 times and ≥1 h per week) and forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) were evaluated.

Among current smokers, physical activity and lung function were positively associated regardless of air pollution levels. Among never-smokers, physical activity was associated with lung function in areas with low/medium NO2, PM2.5 mass and PM10 mass concentrations (e.g. mean difference in FVC between active and non-active subjects was 43.0 mL , 49.5 mL and 49.7 mL  respectively), but these associations were attenuated in high air pollution areas.

Physical activity has beneficial effects on adult lung function in current smokers, irrespective of residential air pollution levels in Western Europe. Trends among never-smokers living in high air pollution areas are less clear.

Age at puberty and risk of asthma: A Mendelian randomisation study

Minelli C, van der Plaat DA, Leynaert B, Granell R, Amaral AFS, Pereira M, Mahmoud O, Potts J, Sheehan NA, Bowden J, Thompson J, Jarvis D, Davey Smith G, Henderson J

PLoS Med. DOI: 10.1371/journal.pmed.100263

Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.

MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.

This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.

Body silhouettes as a tool to reflect obesity in the past

Lønnebotn M, Svanes C, Igland J, Franklin KA, Accordini S, Benediktsdóttir B, Bentouhami H, Blanco JAG, Bono R, Corsico A, Demoly P, Dharmage S, Dorado Arenas S, Garcia J, Heinrich J, Holm M, Janson C, Jarvis D, Leynaert B, Martinez-Moratalla J, Nowak D, Pin I, Raherison-Semjen C, Sánchez-Ramos JL, Schlünssen V, Skulstad SM, Dratva J, Gómez Real F

PLoS One. DOI: 10.1371/journal.pone.0195697

Life course data on obesity may enrich the quality of epidemiologic studies analysing health consequences of obesity. However, achieving such data may require substantial resources. We investigated the use of body silhouettes in adults as a tool to reflect obesity in the past. We used large population-based samples to analyse to what extent self-reported body silhouettes correlated with the previously measured (9-23 years) body mass index (BMI) from both measured (European Community Respiratory Health Survey, N = 3 041) and self-reported (Respiratory Health In Northern Europe study, N = 3 410) height and weight. We calculated Spearman correlation between BMI and body silhouettes and ROC-curve analyses for identifying obesity (BMI ≥30) at ages 30 and 45 years. Spearman correlations between measured BMI age 30 (±2y) or 45 (±2y) and body silhouettes in women and men were between 0.62-0.66 and correlations for self-reported BMI were between 0.58-0.70. The area under the curve for identification of obesity at age 30 using body silhouettes vs previously measured BMI at age 30 (±2y) was 0.92 (95% CI 0.87, 0.97) and 0.85 (95% CI 0.75, 0.95) in women and men, respectively; for previously self-reported BMI, 0.92 (95% CI 0.88, 0.95) and 0.90 (95% CI 0.85, 0.96). Our study suggests that body silhouettes are a useful epidemiological tool, enabling retrospective differentiation of obesity and non-obesity in adult women and men.

Transgenerational and intergenerational epigenetic inheritance in allergic diseases

Mørkve Knudsen T, Rezwan FI, Jiang Y, Karmaus W, Svanes C, Holloway JW

J Allergy Clin Immunol. DOI: 10.1016/j.jaci.2018.07.007

It has become clear that early life (including in utero exposures) is a key window of vulnerability during which environmental exposures can alter developmental trajectories and initiate allergic disease development. However, recent evidence suggests that there might be additional windows of vulnerability to environmental exposures in the parental generation before conception or even in previous generations. There is evidence suggesting that information of prior exposures can be transferred across generations, and experimental animal models suggest that such transmission can be conveyed through epigenetic mechanisms. Although the molecular mechanisms of intergenerational and transgenerationational epigenetic transmission have yet to be determined, the realization that environment before conception can alter the risks of allergic diseases has profound implications for the development of public health interventions to prevent disease. Future research in both experimental models and in multigenerational human cohorts is needed to better understand the role of intergenerational and transgenerational effects in patients with asthma and allergic disease. This will provide the knowledge basis for a new approach to efficient intervention strategies aimed at reducing the major public health challenge of these conditions.

Trends in smoking initiation in Europe over 40 years: A retrospective cohort study

Alessandro Marcon , Giancarlo Pesce, Lucia Calciano, Valeria Bellisario, Shyamali C. Dharmage, Judith Garcia-Aymerich, Thorarinn Gislasson, Joachim Heinrich, Mathias Holm, Christer Janson, Deborah Jarvis, Bénédicte Leynaert, Melanie C. Matheson, Pietro Pirina, Cecilie Svanes, Simona Villani, Torsten Zuberbier, Cosetta Minelli , Simone Accordini , on behalf of the Ageing Lungs In European Cohorts study
PLOS One DOI:/10.1371/journal.pone.0201881


Tobacco consumption is the largest avoidable health risk. Understanding changes of smoking over time and across populations is crucial to implementing health policies. We evaluated trends in smoking initiation between 1970 and 2009 in random samples of European populations.

We pooled data from six multi centre studies involved in the Ageing Lungs in European Cohorts consortium, including overall 119,104 subjects from 17 countries (range of median ages across studies: 33–52 years). We estimated retrospectively trends in the rates of smoking initiation (uptake of regular smoking) by age group, and tested birth cohort effects using Age-Period-Cohort (APC) modelling. We stratified all analyses by sex and region (North, East, South, West Europe).

Smoking initiation during late adolescence (16–20 years) declined for both sexes and in all regions (except for South Europe, where decline levelled off after 1990). By the late 2000s, rates of initiation during late adolescence were still high (40–80 per 1000/year) in East, South, and West Europe compared to North Europe (20 per 1000/year). Smoking initiation rates during early adolescence (11–15 years) showed a marked increase after 1990 in all regions (except for North European males) but especially in West Europe, where they reached 40 per 1000/year around 2005. APC models supported birth cohort effects in the youngest cohorts.

Smoking initiation is still unacceptably high among European adolescents, and increasing rates among those aged 15 or less deserve attention. Reducing initiation in adolescents is fundamental, since youngsters are particularly vulnerable to nicotine addiction and tobacco adverse effects.

Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life

Bui DS, Walters HE, Burgess JA, Perret JL, Bui MQ, Bowatte G, Lowe AJ, Russell MA, Thompson BR, Hamilton GS, James AL, Giles GG, Thomas PS, Jarvis D, Svanes C, Garcia-Aymerich J, Erbas B, Frith PA, Allen KJ, Abramson MJ, Lodge CJ, Dharmage SC

Lancet Respir Med DOI:10.1016/S2213-2600(18)30100-0

Lifetime lung function is related to quality of life and longevity. Over the lifespan, individuals follow different lung function trajectories.  We used six waves of the Tasmanian Longitudinal Health Study (TAHS) to model lung function trajectories measured at 7, 13, 18, 45, 50, and 53 years.  

We identified six trajectories. The three early life below average trajectories had increased risk of COPD at age 53 years compared with the average group.  Early-life predictors of the below average trajectories included childhood asthma, bronchitis, pneumonia, allergic rhinitis, eczema, parental asthma, and maternal smoking. Personal smoking and active adult asthma increased the impact of maternal smoking and childhood asthma, respectively, on the early below average, accelerated decline trajectory.

The three below average trajectories contributed 75% of COPD burden and were associated with modifiable early-life exposures whose impact was aggravated by adult factors. We postulate that reducing maternal smoking, encouraging immunisation, and avoiding personal smoking, especially in those with smoking parents or low childhood lung function, might minimise COPD risk. Clinicians and patients with asthma should be made aware of the potential long-term implications of non-optimal asthma control for lung function trajectory throughout life, and the role and benefit of optimal asthma control on improving lung function should be investigated in future intervention trials

Association of Height Growth in Puberty with Lung Function: A Longitudinal Study

Osama Mahmoud, Raquel Granell, Kate Tilling, Cosetta Minelli,  Judith Garcia-Aymerich, John W. Holloway, Adnan Custovic, Deborah Jarvis,  Jonathan Sterne and John Henderson

American Journal of Respiratory and Critical Care Medicine DOI: 10.1164/rccm.201802-0274OC

Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear.

To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated Super Imposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders.

Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC.

Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.

Prediction models for the development of COPD: a systematic review.

Matheson, MC.; Bowatte, G.; Perret, JL.; Lowe, AJ.; Senaratna, C.; Hall, GL.; de Klerk, N.; Keogh L.; McDonald, CF.; Waidyatillake, NT.; Sly, PD.; Jarvis, D.; Abramson, MJ.; Lodge, CJ.; Dharmage, SC.

International Journal of COPD. DOI: 10.2147/COPD.S155675

Early detection of people who are at risk of developing Chronic Obstructive Pulmonary Disease (COPD) is crucial to implement preventive strategies. In this article, we reviewed performance of previously developed COPD risk prediction tools and discussed their ability to predict risk of development of COPD.  To date only four such COPD risk prediction models have been published in people who did not have the disease at baseline. The models have used numerous variables to predict risk of developing COPD; smoking, sex and age were the common variables used in models. We concluded that overall the models were neither useful in accurately predicting future risk of COPD nor good at ruling out future risk of COPD. We recommended that further studies are needed to develop new prediction models and robustly validate them in external cohorts.

This project has received funding from European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study under grant agreement no 633212) as well  as from National Health Medical Research Council (NHMRC) Australia under the NHMRC EU collaborative grants scheme grant scheme (App ID1101313)

Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study.

Marcon A, Locatelli F, Keidel D, Beckmeyer-Borowko AB, Cerveri I, Dharmage SC, Fuertes E, Garcia-Aymerich J, Heinrich J, Imboden M, Janson C, Johannessen A, Leynaert B, Pascual Erquicia S, Pesce G, Schaffner E, Svanes C, Urrutia I, Jarvis D, Probst-Hensch NM, Accordini S; Ageing Lungs in European Cohorts (ALEC) study.

Thorax. DOI: 10.1136/thoraxjnl-2017-211289

Chronic Obstructive Pulmonary disease (COPD) is a serious respiratory condition mainly caused by cigarette smoking. It is characterised by a persistent and progressive limitation of the airflow through the airways that causes dyspnoea and breathlessness.

Airway responsiveness is the ability of the airways to narrow when breathing cold air, or inhaling airborne allergens or other noxious particles. In clinical practice it is usually assessed by measuring the volume of air exhaled during a forced expiration following the inhalation of a medicine inducing some bronchoconstriction. Measurements of airway responsiveness are useful in diagnosing asthma, since most patients with asthma have an abnormal reaction to airways irritants. However, the contribution of airway responsiveness to the development of COPD is still unclear.

In this study, we analysed data from 4205 subjects who participated in two large international studies, and we investigated whether a high degree of airway responsiveness is a risk factor for COPD. We found that young adults with a high responsiveness had a greater risk of developing COPD twenty years later compared with less responsive individuals. This was observed both in smokers and in non-smokers. Importantly, a high responsiveness was a risk factor for COPD even in subjects without a history of asthma, suggesting that airway responsiveness may be related to asthma and COPD through different pathways.

This study gives some clues to better understand the mechanisms and causes of COPD. Future  research should clarify whether early pharmacological treatment in patients with high responsiveness can slow down the progression of the disease.

This project has received funding from European Union’s Horizon 2020 research and innovation programme, Ageing Lungs in European Cohorts (ALEC) Study, under grant agreement no 633212.

Occupational exposures and 20-year incidence of COPD: the European Community Respiratory Health Survey.

 Lytras T, Kogevinas M, Kromhout H, Carsin AE, Antó JM, Bentouhami H, Weyler J, Heinrich J, Nowak D, Urrutia I, Martinez-Moratalla J, Gullón JA, Pereira-Vega A, Raherison-Semjen C, Pin I, Demoly P, Leynaert B, Villani S, Gislason T, Svanes C, Holm M, Forsberg B, Norbäck D, Mehta AJ, Probst-Hensch N, Benke G, Jogi R, Torén K, Sigsgaard T, Schlünssen V, Olivieri M, Blanc PD, Vermeulen R, Garcia-Aymerich J, Jarvis D, Zock JP.

 Thorax. doi: 10.1136/thoraxjnl-2017-211158


In this paper, 3343 adults participating in the European Community Respiratory Health Survey (ECRHS) were followed-up for 20 years. Full job histories were obtained for this period, and a range of occupational exposures for each participant was estimated using a Job-Exposure Matrix. Exposure to biological dusts, gases, fumes and pesticides was associated with a higher incidence of Chronic Obstructive Pulmonary Disease (COPD) at the end of follow-up. These occupational exposures were associated with 21% of all COPD cases observed in this cohort, highlighting the large potential for prevention. The results of this study substantially strengthen the evidence base for occupation as a major risk factor for COPD. An open question for future research is whether the effects of these occupational exposures are modified by smoking, since the number of incident COPD cases among non-smokers in this cohort was low.

A three-generation study on the association of tobacco smoking with asthma.

Accordini S, Calciano L, Johannessen A, Portas L, Benediktsdóttir B, Bertelsen RJ, Bråbäck L, Carsin AE, Dharmage SC, Dratva J, Forsberg B, Gomez Real F, Heinrich J, Holloway JW, Holm M, Janson C, Jögi R, Leynaert B, Malinovschi A, Marcon A, Martínez-Moratalla Rovira J, Raherison C, Sánchez-Ramos JL, Schlünssen V, Bono R, Corsico AG, Demoly P, Dorado Arenas S, Nowak D, Pin I, Weyler J, Jarvis D, Svanes C; Ageing Lungs in European Cohorts (ALEC) Study.

International Journal of Epidemiology DOI: 10.1093/ije/dyy031

Mothers’ smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers’ smoking may have a similar effect, and biological plausibility that fathers’ smoking during adolescence may influence offspring’s health through transmittable epigenetic changes in sperm precursor cells. In this study, we evaluated the three-generation associations of tobacco smoking with asthma. Between 2010-2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged  <=51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents’ (grandparents) and their own asthma, education, and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Fathers’ smoking before they were 15 and mothers’ smoking during pregnancy were associated with asthma without nasal allergies in their offspring. Grandmothers’ smoking during pregnancy was associated with asthma in their daughters and with asthma with nasal allergies in their grandchildren within the maternal line. This study has shown that fathers’ smoking during early adolescence, and grandmothers’ and mothers’ smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study) under grant agreement no 633212.

Leisure-time vigorous physical activity is associated with better lung function: the prospective ECRHS study.

Fuertes E, Carsin AE, Antó JM, Bono R, Corsico AG, Demoly P, Gislason T, Gullón JA, Janson C, Jarvis D, Heinrich J, Holm M, Leynaert B, Marcon A, Martinez-Moratalla J, Nowak D, Pascual Erquicia S, Probst-Hensch NM, Raherison C, Raza W, Gómez Real F, Russell M, Sánchez-Ramos JL, Weyler J, Garcia Aymerich J

Thorax DOI: 10.1136/thoraxjnl-2017-210947

Using data from 3912 adults participating in the European Community Respiratory Health Survey (ECRHS) cohort, this paper found that regular vigorous physical activity (during leisure-time) is associated with better lung function among current smokers. The fact that this association was only apparent among current smokers supports the existence of an inflammation-related biological mechanism and highlights the importance of physical activity in this group at higher risk (due to smoking) for poor lung function. The paper also found that participants who were active at the last examination (either by becoming or remaining active) had significantly higher lung function than those consistently inactive over a ten-year period.  However, any associations between the physical activity indicators we considered and lung function decline over a ten-year period, a result that requires further investigation by studies with additional follow-ups and objective measures of various types and intensities of physical activity. Overall, the results of this study inform and support public health messages that promote increasing and maintaining regular physical activity as a method of preserving respiratory health in middle-age adults.

This project has received funding from European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study under grant agreement no 633212) and the Marie Skłodowska-Curie Individual Fellowship scheme (Elaine Fuertes, H2020- MSCA-F-2015; proposal number 704268).

Zoonotic helminth exposure and risk of allergic diseases: A study of two generations in Norway.

Jogi NO & Svanes C (shared first authorship), Siiak SP, Logan E, Holloway JW, Igland J, Johannessen A, Levin M, Real FG, Schlussen V, Horsnell WGC & Bertelsen RJ (shared last authorship).

Clin Exp Allergy DOI: 10.1111/cea.13055 


Countries with a high prevalence of helminth infection (parasitic worms) have been shown to have lower rates of allergies. However, zoonotic helminth infections, where humans are not the primary hosts, have been associated with increased risk of allergies.  
In this article we investigated two generations in Bergen, Norway, and found that IgG4 antibodies towards Ascaris and Toxocara spp. were frequently detected in these cohorts (among 29% of parents investigated in ECRHS, and 10% of  offspring investigated in RHINESSA). Young people with these parasitic worm antibodies were four times more likely to have asthma and allergies than their peers without such antibodies. However, in the parents antibodies to Ascaris and Toxocara spp. were not related to allergies in the parents themselves, but did predict increased allergy risk in their offspring. Exploring the difference in response to helminths across generations may lead to a better understanding of the rise in allergies.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study) under grant agreement no 633212, and from the World Universities Network (WUN) Research Development Fund.

Dietary antioxidants and 10-year lung function decline in adults from the ECRHS survey.

Garcia-Larsen V, Potts JF, Omenaas E, Heinrich J, Svanes C, Garcia-Aymerich J, Burney PG, Jarvis DL  on behalf of the ALEC study

European Respiratory Journal DOI: 10.1183/13993003.02286-2016


This paper found that adults who on average ate more than two tomatoes or more than three portions of fresh fruit a day had a slower decline in lung function compared to those who ate less than one tomato or less than one portion of fruit a day, respectively.   The protective effect was only observed in fresh fruit and vegetables rather than other dietary sources and processed foods containing fruits and vegetables—such as tomato sauce.

For the study, the research team assessed the diet and lung function of more than 650 adults in 2002, then repeated lung function tests on the same group of participants 10 years later. Participants from Germany, Norway, and the United Kingdom completed questionnaires assessing their diets and overall nutritional intake. The study controlled for factors such as age, height, sex, body mass index, socio-economic status, physical activity, and total energy intake.

Among former smokers, the connection between diet and lung function was even more striking. Ex-smokers who ate a diet high in tomatoes and fruits had slower decline over the 10-year period. This suggests that nutrients in their diets are helping to repair damage done by smoking.

Systematic review of lung function and COPD with peripheral blood DNA methylation in population based studies.

Machin M, Amaral AFS, Wielscher M, Rezwan F, Imboden M, Jarvelin MJR Adcock I Probst-Hensch N, Holloway J, Jarvis D  on behalf of the ALEC study

BMC Pulmonary Medicine  DOI: 10.1186/s12890-017-0397-3


This paper is a systematic review of published studies that examined peripheral blood DNA methylation patterns in people with and without COPD. It concluded that DNA methylation patterns in peripheral blood from individuals with reduced lung function or COPD may be different to those in people with normal lung function. However, the review could not find any consistent associations of lung function or COPD with differentially methylated CpG sites. Larger studies with a longitudinal design to address reverse causality may prove a more fruitful area of research.

Respiratory symptoms are more common among short sleepers independent of obesity

Björnsdóttir E, Janson C, Lindberg E, Arnardottir ES, Benediktsdóttir B, Garcia-Aymerich J, Carsin AE, Real FG, Torén K, Heinrich J, Nowak D, Sánchez-Ramos JL, Demoly P, Arenas SD, Navarro RC, Schlünssen V, Raherison C, Jarvis DL, Gislason T. 

BMJ Open Respir Res. DOI: 10.1136/bmjresp-2017-000206

Sleep is a daily activity and the health impacts of poor sleep are yet under studied. In this article we found that subjects who sleep less than six hours a day have a higher prevalence of respiratory symptoms such as cough, wheezing or waking up due to shortness of breath. This association was seen in an analysis of information from more than 5000 adults from 10 different European countries, which have different sleeping patterns. Importantly, the association was not explained by a higher proportion of subjects with obesity among those with symptoms. The cross-sectional nature of the study prevents us from knowing for certain whether shorter sleep causes an increase in respiratory symptoms or more respiratory symptoms prevent longer sleep. Longitudinal studies are needed but this report highlights the importance of considering sleep as another important lifestyle parameter, such as smoking, diet and physical activity, that influences our respiratory health.


This project has received funding from European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study under grant agreement no 633212)

Age at menarche and lung function: a Mendelian randomization study.

Gill D, Sheehan NA, Wielscher M, Shrine N, Amaral AFS, Thompson JR, Granell R, Leynaert B, Real FG, Hall IP, Tobin MD, Auvinen J, Ring SM, Jarvelin MR, Wain LV, Henderson J, Jarvis D, Minelli C

European Journal of Epidemiology DOI: 10.1007/s10654-017-0272-9

This paper, which uses information from the ALEC cohort studies and from the UK Biobank, shows that early menarche in girls is associated with worse lung function, in particular a low forced vital capacity (FVC), in later adult life. This difference cannot be seen in children or young adolescents who are going through or have recently experienced menarche, suggesting that early menarche is associated with failure to achieve maximal lung function or more rapid lung function decline.  Results from a secondary analysis conducted in boys suggest a role for pubertal timing in general rather than menarche specifically. This analysis has used a technique called Mendelian Randomisation to investigate associations. Although becoming more widespread,  Mendelian Randomisation is not widely used in the scientific literature. Briefly,  it uses genetic information as a proxy for the exposure (in this analysis, menarche) – and has the advantage of not being influenced by confounding or by reverse causation (two common problems in epidemiology). When associations are observed using this technique it strengthens the causal inference that can be made. Therefore this paper provides compelling evidence that early puberty (in girls, indicated by early menarche) is associated with poorer lung health in adult life (low FVC). No associations with airway obstruction were observed.

Childhood lung function predicts adult COPD and asthma-COPD overlap syndrome (ACOS)

Bui DS, Burgess JA, Lowe AJ, Perret JL, Lodge CJ, Bui M, Morrison S, Thompson BR, Thomas PS, Giles GG, Garcia-Aymerich J, Jarvis D, Abramson MJ, Walters HE, Matheson MC, Dharmage SC.

Am J Respir Crit Care Med. DOI: 10.1164/rccm.201606-1272OC  

Using data from Tasmanian Longitudinal Health Study (TAHS), this paper found that children in the lowest quartile for lung function at age 7 had increased risk of developing COPD and asthma-COPD overlap syndrome (ACOS) by middle age, compared to those in the highest quartile for lung function. This study provides further evidence on the early life origins of these diseases, and suggests that screening of lung function in school-age children may provide an opportunity to detect children who are likely to have ongoing poorer lung health. Multi-faceted intervention strategies could then be implemented to reduce the burden of COPD and ACOS in adulthood. Further research is needed to better understand the risk factors for lower lung function in children and adult risk factors that may interact with lower lung function to increase the risk of rapid lung function decline.

This project has received funding from European Union’s Horizon 2020 research and innovation programme (Ageing Lungs in European Cohorts (ALEC) Study under grant agreement no 633212) as well  as from National Health Medical Research Council (NHMRC) Australia under the NHMRC EU collaborative grants scheme grant scheme (App ID1101313)

Clinical markers of asthma and IgE assessed in parents before conception predict asthma and hayfever in the offspring.

Bertelsen, RJ. ; Rava, M.; Carsin, AE.; Accordini, S.; Benediktsdottir, B.; Dratva, J.; Franklin, KA.; Heinrich, J.; Holm, M.; Janson, C.; Johannessen, A.; Jarvis, DL.; Jogi, R.; Leyneart, B.; Norback, D.; Omenaas, ER.; Raherison, C.; Sánchez-Ramos, JL.; Schlunssen, V.; Sigsgaard, T.; Dharmage, SC.; Svanes, C. Parental asthmatic and allergic activity before conception predicts asthma and allergy in the offspring.

Clin Exp Allergy. DOI: 10.1111/cea.12906

Selected Editor’s choice: Editor-in-Chief’s Editorial DOI: 10.1111/cea.12932

Information from animal models suggest that the immunological profiles of the parents may be transferred to the offspring, possible through epigenetic mechanisms.  In this study, we assessed the association between parental asthma severity, bronchial hyperresponsiveness (BHR) and total and specific IgEs, measured before conception and after birth of the child, with offspring asthma and hayfever. Using data from 4293 participants from the ECRHS and their 9100 offspring, we found that parental BHR and specific IgE positivity were associated with offspring asthma and hayfever, with the strongest association observed for parental clinical assessment measured before conception as compared to after birth of the child.


These results reflect the authors' view and the EU Commission is not responsible for any use that may be made of the results.

  • Twitter Clean

© 2015 by

ALEC Study.

Proudly created with


Emmanuel Kaye Building

Manresa Road

London SW3 6LR



T: 020 7594 7944