Jenny Hallberg

MMP12, lung function, and COPD in high-risk populations.

BACKGROUND Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. METHODS We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. RESULTS The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [-82A-->G]) was positively associated with FEV(1) in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2x10(-6)). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P=0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.005) and among participants in a family-based study of early-onset COPD (P=0.006). CONCLUSIONS The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.

Traffic-related air pollution and childhood respiratory symptoms, function and allergies.

Background: Urban air pollution can trigger asthma symptoms in children, but there is conflicting evidence on effects of long-term exposure on lung function, onset of airway disease and allergic sensitization. Methods: The spatial distribution of nitrogen oxides from traffic (traffic-NOx) and inhalable particulate matter from traffic (traffic-PM10) in the study area was assessed with emission databases and dispersion modeling. Estimated levels were used to assign first-year exposure levels for children in a prospective birth cohort (n = 4089), by linking to geocoded home addresses. Parents in 4 Swedish municipalities provided questionnaire data on symptoms and exposures when the children were 2 months and 1, 2, and 4-year-old. At 4 years, 73% of the children underwent clinical examination including peak expiratory flow and specific IgE measurements. Results: Exposure to air pollution from traffic during the first year of life was associated with an excess risk of persistent wheezing (odds ratio [OR] for 44 &mgr;g/m3 [5th–95th percentile] difference in traffic-NOx = 1.60; 95% confidence interval [CI] = 1.09–2.36). Similar results were found for sensitization (measured as specific IgE) to inhalant allergens, especially pollen (OR for traffic-NOx = 1.67; 95% CI = 1.10–2.53), at the age of 4 years. Traffic-related air pollution exposure during the first year of life was also associated with lower lung function at 4 years of age. Results were similar using traffic-NOx and traffic-PM10 as indicators. Conclusions: Exposure to moderate levels of locally emitted air pollution from traffic early in life appears to influence the development of airway disease and sensitization in preschool children.

Breast-feeding in relation to asthma, lung function, and sensitization in young schoolchildren

BACKGROUND The evidence from previous studies on beneficial effects of breast-feeding in relation to development of asthma is conflicting. OBJECTIVE To investigate the relation between breast-feeding and asthma and/or sensitization during the first 8 years of life. METHOD In a birth cohort, children were followed up to 8 years by questionnaires at ages 2 months and 1, 2, 4, and 8 years to collect information on exposures and health effects. Determination of serum IgE antibodies to common inhalant and food allergens was performed at 4 and 8 years. Longitudinal analyses were applied by using general estimated equations. The study population consisted of 3825 children (93% of the original cohort), of whom 2370 gave blood and 2564 performed lung function measurements at 8 years. RESULTS Children exclusively breast-fed 4 months or more had a reduced risk of asthma during the first 8 years of life (adjusted odds ratio [OR], 0.63; 95% CI, 0.50-0.78) compared with children breast-fed less than 4 months. At 8 years, reduced risks of sensitization (adjusted OR, 0.79; 95% CI, 0.64-0.99) and asthma in combination with sensitization (adjusted OR, 0.59; 95% CI, 0.37-0.93) were seen among children exclusively breast-fed 4 months or more. This group also had a significantly better lung function measured with peak expiratory flow. CONCLUSION Breast-feeding for 4 months or more seems to reduce the risk of asthma up to 8 years. At this age, a reduced risk was observed particularly for asthma combined with sensitization. Furthermore, breast-feeding seems to have a beneficial effect on lung function.

Interactions between Glutathione S-Transferase P1, Tumor Necrosis Factor, and Traffic-Related Air Pollution for Development of Childhood Allergic Disease

Background Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers. Objective Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the β2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease. Methods In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NOx) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping. Results Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NOx exposure during the first year of life (pnominal < 0.001–0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NOx (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0–5.3). In children with TNF-308 GA/AA genotypes, the GSTP1–NOx interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2. Conclusion The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy.

Traffic-related air pollution and lung function in children at 8 years of age: a birth cohort study

RATIONALE Long-term exposure to air pollution has been related to lung function decrements in children, but the role of timing of exposure remains unknown. OBJECTIVES To assess the role of long-term exposure to air pollution on lung function in school-age children. METHODS More than 1,900 children in the Swedish birth cohort BAMSE were followed with repeated questionnaires, dynamic spirometry, and IgE measurements until 8 years of age. Outdoor concentrations of particulate matter with an aerodynamic diameter less than 10 μm (PM(10)) from road traffic were estimated for residential, day care, and school addresses from birth and onward using dispersion modeling. The relationship between time-weighted average exposure during different time windows and FEV at 8 years was analyzed by linear regression, adjusting for potential confounding factors, including short-term exposure to air pollution. MEASUREMENTS AND MAIN RESULTS A 5th to 95th percentile difference in time-weighted average particulate matter less than 10 μm in aerodynamic diameter exposure during the first year of life was associated with a reduced FEV(1) of -59.3 ml (95% confidence interval, -113 to -5.6) at 8 years of age. The negative association was particularly pronounced in children concomitantly sensitized to common inhalant or food allergens (-136.9 ml; 95% confidence interval, -224.1 to -49.7). Exposure after the first year of life seemed to have less impact on lung function at 8 years. CONCLUSIONS Our results indicate that exposure to traffic-related air pollution during infancy affects lung function in children up to 8 years of age and particularly in those sensitized to common inhalant or food allergens.

Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study

BACKGROUND Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population. METHODS We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Childrens Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function. FINDINGS After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001). INTERPRETATION Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. FUNDING National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.

Phenotyping asthma, rhinitis and eczema in MeDALL population-based birth cohorts: an allergic comorbidity cluster

Asthma, rhinitis and eczema often co‐occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co‐occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques.

Early-Life Exposure to Traffic-related Air Pollution and Lung Function in Adolescence

RATIONALE Exposure to air pollution during infancy has been related to lung function decrements in 8-year-old children, but whether the negative effects remain into adolescence is unknown. OBJECTIVES To investigate the relationship between long-term air pollution exposure and lung function up to age 16 years. METHODS A total of 2,278 children from the Swedish birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) performed spirometry at age 16 years. Levels of outdoor air pollution from local road traffic were estimated (nitrogen oxides [NOx] and particulate matter with an aerodynamic diameter of <10 μm [PM10]) for residential, daycare, and school addresses during the lifetime using dispersion modeling. Associations between exposure in different time windows and spirometry indexes were analyzed by linear regression and mixed effect models. MEASUREMENTS AND MAIN RESULTS Exposure to traffic-related air pollution during the first year of life was associated with FEV1 at age 16 years of -15.8 ml (95% confidence interval [CI], -33.6 to 2.0 for a 10 μg/m(3) difference in NOx), predominately in males (-30.4 ml; 95% CI, -59.1 to -1.7), and in subjects not exposed to maternal smoking during pregnancy or infancy. Later exposures appeared to have had an additional negative effect. High exposure during the first year of life was also associated with odds ratios for FEV1 and FVC less than the lower limit of normal (LLN) (defined as a z-score < -1.64 SD) of 3.8 (95% CI, 1.3-10.9) and of 4.3 (95% CI, 1.2-15.0), respectively. The results for PM10 were similar to those for NOx. CONCLUSIONS Exposure to traffic-related air pollution in infancy is negatively associated with FEV1 at age 16 years, leading to increased risk of clinically important deficits.

Genetic and environmental influence on lung function impairment in Swedish twins

BackgroundThe understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms.MethodsThe current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms.ResultsFully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men.ConclusionDifferences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.

Lung function at 6 and 18 months after preterm birth in relation to severity of bronchopulmonary dysplasia

Many preterm infants with bronchopulmonary dysplasia (BPD) demonstrate impaired lung function and respiratory symptoms during infancy. The relationships between initial BPD severity, lung function and respiratory morbidity are not fully understood. We aimed to investigate the association between BPD severity and subsequent lung function and whether lung function impairment is related to respiratory morbidity.