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. 2022 Sep;21(5):811-820.
doi: 10.1016/j.jcf.2022.03.007. Epub 2022 Mar 31.

Club cell secretory protein and lung function in children with cystic fibrosis

Jing Zhai  1 , Mary J Emond  2 , Amber Spangenberg  1 , Debra A Stern  1 , Monica M Vasquez  1 , Elizabeth E Blue  3 , Kati J Buckingham  4 , Duane L Sherrill  1 , Marilyn Halonen  1 , Ronald L Gibson  5 , Margaret Rosenfeld  5 , Scott D Sagel  6 , Michael J Bamshad  7 , Wayne J Morgan  8 , Stefano Guerra  9
Affiliations

Club cell secretory protein and lung function in children with cystic fibrosis

Jing Zhai et al. J Cyst Fibros. 2022 Sep.

Abstract

Background: Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF).

Methods: We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7-16 using mixed models.

Results: Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV1/FVC and, marginally, FEV1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations).

Conclusions: Serum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF.

Keywords: Club cell secretory protein; Cystic fibrosis; Lung function.

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Conflict of interest statement

Declaration of Competing Interest MJE, EEB, KJB, MH, RLG, MR, SDS, MJB, WJM, and SG report receiving grant support through their institution for the present work. SDS reports receiving honoraria from DKBMed. WJM reports receiving consulting fees from the Cystic Fibrosis Foundation, receiving speaker honoraria from the American College of Chest Physicians, and participating on the CFF DSMB.

Figures

Figure 1a.
Figure 1a.
Study design pQTL: protein quantitative trait loci N obs for Biomarker Studies/pQTL analyses = number of samples analyzed for biomarkers N obs for Genetic Associations with Lung Function = number of prospective lung function measurements
Figure 1b.
Figure 1b.
Consort diagram for the different components of the current study.
Figure 2a.
Figure 2a.
Categorization of participants into 5 groups based on tertiles of CC16 and tertiles of the PCA component of inflammatory biomarkers in adolescence. The 5 groups are defined as: - Group 1 (Dark Green, N=30): participants in the highest CC16 tertile and lowest inflammatory tertile - Group 2 (Light Green, N=57): other participants with CC16 tertile higher than inflammatory tertile - Group 3 (Gray, N=81): participants with CC16 tertile equal to inflammatory tertile - Group 4 (Orange, N=56): participants with CC16 tertile lower than inflammatory tertile (excluding participants in Group 5) - Group 5 (Red, N=31): participants in the lowest CC16 tertile and highest inflammatory tertile
Figure 2b.
Figure 2b.
ORs for being in the Low Lung Function (LLF) group in adolescence across the five groups generated by the combination of CC16 and inflammatory tertiles. Group 1 (High CC16 tertile, Low inflammatory tertile) is the reference. Group 5 includes participants in the highest inflammatory and lowest CC16 tertiles. ORs adjusted for sex, age at serum collection, CFTR genotype risk group, maternal smoking during pregnancy, and annual household income. P values for the comparison of Group 5 with Group 1 (p<0.0001), Group 2 (p<0.0001), Group 3 (p=0.001), and Group 4 (p=0.002)
Figure 3.
Figure 3.
FEV1 measurements between ages 7–16 years among the 130 participants in the Low Lung Function (LLF) and 130 participants in the High Lung Function (HLF) groups selected for biomarker studies. The solid lines represent locally weighted scatterplot smoothing (loess) lines. Loess is a non-parametric strategy for fitting smooth curves to data points without assuming a data distribution shape. When tested in mixed models, LLF participants had a significantly steeper decline of FEV1 % predicted between ages 7–16 years than HLF participants (p<0.0001).
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