CC16: A Treatable Trait in Asthma?

The club cell secretory protein (CC16) gene, found on chromosome 11q12.3, is highly expressed in the airways and encodes the pneumoprotein CC16. This protein is so richly secreted by bronchiolar club cells and other epithelial cells that it is one of the most abundant proteins in respiratory secretions (1). CC16 is reported to have several protective functions, including antiinflammatory, immunomodulatory, and antioxidant effects (2). It has also been implicated as a biomarker for several lung states and conditions, including lung function decline, airway hyperresponsiveness, acute lung injury, cystic fibrosis, and chronic obstructive pulmonary disease (3–7).

In asthma, depletion of circulating CC16 has been associated with both childhood and adult asthma, but only in cross-sectional studies (8, 9). Interestingly, low CC16 mRNA expression in bronchial epithelial cells was associated with asthma severity, as well as type 2 inflammation (10). Although showing potential as a novel biomarker for asthma, this still left many questions, including, Does CC16 provide more information than our traditional biomarkers of type 2 inflammation? and, Can CC16 predict the natural course of asthma? Up to one-third of children with symptoms at 7 years old will continue to experience them in adult life (11, 12). Although some parameters, such as childhood obstructive spirometry and particular genetic factors, correlate with persistence into adult life, there are currently no applicable predictive models (11).

In this issue of the Journal, Voraphani and colleagues (pp. 758–769) sought to investigate the longitudinal relationship of circulating CC16 from childhood to adult life and its association with symptom persistence into adulthood (13). To undertake this task, they used three well-characterized, population-based birth cohorts, from the United States (TCRS [Tucson Children’s Respiratory Study]), Sweden (BAMSE [Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey]), and the United Kingdom (MAAS [Manchester Asthma and Allergy Study]). They measured circulating CC16 concentrations in 3,124 children and analyzed genotype data for the SNP rs3741240, the strongest protein quantitative trait locus for serum CC16.

Reassuringly, circulating CC16 effects were consistent across the three cohorts, including the sex reversal effect of lower concentrations in boys during childhood but lower concentrations in women during adulthood. Circulating CC16 deficits, by 1 SD, were associated with a 20% increased odds of asthma, even after accounting for potential confounders such as sex, ethnicity, early-life respiratory illnesses, and atopy. Furthermore, there appeared to be a dose effect, as more frequent symptoms were more strongly associated with low CC16 (40% increased odds) than less frequent symptoms. Interestingly, the phenotype of atopic or nonatopic asthma did not modify the association between CC16 deficits and asthma.

To investigate the role of lung function as a mediator of the association between circulating CC16 and asthma, the authors applied four mutually exclusive groups on the basis of symptom frequency and normal or low lung function. Frequent asthma symptoms and low lung function were both independently associated with low CC16, but low lung function was not a prerequisite for the association with symptoms, indicating that there is a direct association between CC16 and asthma, alongside the likely indirect association through lung function impairment.

In the genetic analysis, to achieve sufficient sample size, the authors also used UK Biobank and Trans-National Asthma Genetic Consortium genotype data and found an important, albeit small (2%), significant association with the SNP rs3741240 and asthma, strengthening the evidence of a causal association. Other genetic analyses, a Mendelian randomization study, demonstrated a causal association between CC16 and accelerated lung function decline and chronic obstructive pulmonary disease (14). Put together, these findings together imply that CC16 is critical to lung development, perhaps in part by protecting the airway epithelium through regulation of inflammation via the nuclear factor-κB pathway and the regulation of prostaglandin and leukotriene synthesis (15). In their final analysis, including 233 children with at least 1 year of follow-up data in adulthood (TCRS, 8–36 yr; BAMSE, 12–24 yr; and MAAS, 8–18 yr), those children with the lowest tertile of CC16 had twice the odds of having persistent symptoms into adulthood, with 3.5 times the odds in the children with frequent symptoms, even after adjusting for potential confounders.

Certain genetic or environmental factors may inhibit CC16 production and increase susceptibility to airway inflammation and/or abnormal airway function, resulting in the development and progression of asthma. Circulating CC16 could therefore contribute meaningfully to predicting the course of childhood asthma, even across different endotypes. However, there is still much work to do in testing this theory, including developing a prognostic predictive model applicable in clinical practice and, most critically, externally validating it in a large independent cohort. More detailed examination of the functional consequence of reduced CC16 in primary airway structural and immune cells will provide plausibility for CC16 as a direct driver of asthma progression and symptoms.

Limitations of the study included the small sample size for some aspects of the analyses; reliance on reporting of symptoms as a marker of asthma development, severity, and progression; and the need to examine CC16 in additional ethnic groups. Such population-based surveys are at risk of recall and selection bias, and we should consider that remission of symptoms may not reflect the resolution of pathology. Additional data that were not available in this study but could have been edifying include information on type 2 inflammation and asthma medication.

Voraphani and colleagues have further added to the weight of evidence implying that low CC16 has exciting potential as a biomarker of asthma progression and severity. In addition, CC16 alone or as a combination of CC16 with current T2 biomarkers may provide better stratification of patients with asthma for future targeted therapeutic intervention.