Iris Lavi

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.

Serum levels of Clara cell secretory protein, asthma, and lung function in the adult general population

a Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain b Inserm U1018, CESP Centre for Research in Epidemiology and Population Health, Respiratory and Environmental Epidemiology Team, Villejuif, France c Universite Paris Sud 11, Villejuif, France d IMIM (Hospital del Mar Research Institute), Barcelona, Spain e CIBER Epidemiologia y Salud Publica (CIBERESP), Spain f Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), Hospital del Mar-IMIM, Parc de Recerca Biomedica de Barcelona (PRBB), Barcelona, and Centro de Investigacion en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Bunyola, Majorca, Balearic Islands, Spain g Hospital General de Almansa, Complejo Hospitalario Universitario de Albacete, Spain, and the Unit of Epidemiology and Health Information, Public Health of Bizkaia, Bizkaia, Spain h Department of Health, Basque Government, Bilbao, Basque Country, Spain i Unit of Epidemiology and Medical Statistics, Department of Public Health and Community Medicine, University of Verona, Verona, Italy j Universitat Pompeu Fabra, Barcelona, Spain k Arizona Respiratory Center, University of Arizona, Tucson, Ariz

The relation of circulating YKL-40 to levels and decline of lung function in adult life

BACKGROUND YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers. AIM To determine the longitudinal relation of circulating YKL-40 to levels and decline of lung function in the general population. METHODS We used longitudinal data from up to 13 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972 and 1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function. RESULTS Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p = 0.05) faster than subjects in the third quartile, 5 ml/yr (p = 0.02) faster than subjects in the second quartile, and 10 ml/yr (p < 0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined, the top YKL-40 quartile was associated with a 9 ml/yr (p = 0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p = 0.35). CONCLUSIONS Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking.

Persistent organic pollutants and children's respiratory health: the role of cytokines and inflammatory biomarkers.

Evidence of adverse effects of persistent organic pollutants (POPs) on the developmental respiratory and immune systems in children is still limited, and the biological mechanisms behind such effects are not fully understood. The aim of the present study is to evaluate the effects of prenatal DDE, HCB and ΣPCB exposure on childrens respiratory health from birth to 14 years and to evaluate the role of immune biomarkers in these associations. We measured prenatal DDE, HCB and ΣPCB levels in 405 participants of the INMA-Menorca birth cohort (Spain) and collected information on wheeze, chest infections, atopy and asthma from birth until the age of 14 years. At age 4 years, 275 children provided serum samples and IL6, IL8, IL10, TNFα and C-reactive protein were measured. We applied linear and logistic regression models and generalized estimating equations. Prenatal DDE was associated with wheeze at age 4 years [RR (95% CI) per doubling of concentration=1.35 (1.07, 1.71)], but not thereafter. Prenatal HCB was associated with wheeze [1.58 (1.04, 2.41)] and chest infections [1.89 (1.10, 3.25)] at age 10years. No associations were found with ΣPCBs. IL10 levels increased with increasing POP concentration, with HCB showing the strongest association [β (95% CI)=0.22 (0.02, 0.41)]. IL8, IL10 and TNFα were associated with wheeze and/or chest infections and IL10 was associated with asthma. Prenatal DDE and HCB exposure was associated with respiratory health of children at different ages. This study further suggests a possible role of IL10, but not of the other immune biomarkers examined, as an early marker of chronic immune-related health effects of POPs.

Genetic and epigenetic regulation of YKL-40 in childhood

Background: Circulating levels of the chitinase‐like protein YKL‐40 are influenced by genetic variation in its encoding gene (chitinase 3–like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL‐40 early in life is unknown. Objective: We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL‐40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL‐40 levels) are associated with asthma in early childhood. Methods: We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole‐blood DNA, and circulating YKL‐40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression. Results: YKL‐40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL‐40 levels were associated with higher methylation levels. Participants with high YKL‐40 levels (defined as the highest YKL‐40 tertile) had increased odds for asthma compared with subjects with low YKL‐40 levels (meta‐analyzed adjusted odds ratio, 1.90 [95% CI, 1.08–3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. Conclusions: The effects of CHI3L1 genetic variation on circulating YKL‐40 levels are partly mediated by methylation profiles. In our study YKL‐40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma.

Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma

Interleukin-1 receptor–like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma. Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10−16) and serum IL1RL1-a levels (p=2.8×10−56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma. In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma. Interleukin-1 receptor-like 1 (IL1RL1) SNPs regulate IL1RL1-methylation and serum IL1RL1-a levels, yet these effects are not related to asthma http://ow.ly/AStC30hSvGy