Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life

Abstract

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.

Keywords: CC16; asthma; birth cohorts.

Figure 1.

Longitudinal association of a 1-SD decrease in circulating club cell secretory protein concentrations with the presence of (A) active asthma, (B) asthma with infrequent symptoms, and (C) asthma with frequent symptoms. The no active asthma group was used as the reference group. Models were adjusted for survey year, sex, race or ethnicity, parental asthma, and childhood atopy (assessed by skin prick test at Year 6 in TCRS [Tucson Children’s Respiratory Study] and Year 5 in MAAS [UK Manchester Asthma and Allergy Study] and by Phadiatop test at Year 8 in BAMSE [Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey]). In MAAS, only active asthma was evaluated at Year 18 because of incomplete information on symptom frequency. Totals of 113 TCRS, 596 BAMSE, and 73 MAAS participants had missing information for race or ethnicity, parental asthma, or childhood atopy and were excluded from the analyses. CI = confidence interval; n = number of participants; N = total number of observations; OR = odds ratio; RRR = relative risk ratio.

Figure 2.

Geometric means of circulating club cell secretory protein concentrations by rs3741240 genotypes. Number of participants = 463, 2,023, and 671; number of observations = 2,179, 2,833, and 1,692 for TCRS (Tucson Children’s Respiratory Study), BAMSE (Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey), and MAAS (UK Manchester Asthma and Allergy Study), respectively. P values were derived from random effects models, adjusted for survey year. CI = confidence interval.

Figure 3.

Association of baseline circulating club cell secretory protein with (A) persistence of symptoms and (B) persistence of frequent symptoms up to adult life among children with asthma at the first survey. n = number of participants. Results were derived from logistic regression (unadjusted). Persistence of frequent symptoms was evaluated only in TCRS (Tucson Children’s Respiratory Study) and BAMSE (Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey) because of incomplete information on symptom frequency at Year 18 in MAAS (UK Manchester Asthma and Allergy Study). CI = confidence interval.