Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

Chitinases are family enzymes generated from innate cellular sources, such as macrophages, neutrophils, and eosinophils which can modulate and amplify airway inflammation/ remodeling in asthma. 28, 29 Of the chitinases studied in asthma, CHI3L1, also known as YKL-40 and AMCase, have SNPs linked to asthma, whereas CHIT1 has not been linked to asthma. 29 SNPs in the CHI3L1 promoter influence YKL-40 serum levels and these SNPs are associated with asthma, AHR and decreased lung function. 29 CHI3L1 genetic polymorphisms are associated with decreased lung function. For example, the CHI3L1 SNP rs4950928 C allele was significantly associated with lower FEV1% (P = 0.046), FEV1/FVC (P = 0.002) and presence of AHR (P = 0.002) in a study of 632 Hutterites. 30 In a study of Danish adults, CHI3L1 SNPs rs10399931 and rs4950930 were associated with FEV1/FVC. 31 The CHI3L1 SNP rs12141494 A allele was significantly associated with higher serum YKL-40 levels and decreased post-bronchodilator FEV1% in the Severe Asthma Research Program cohort. 32 The same associations were replicated in Japanese asthmatics, in whom the CHI3L1 SNP rs12141494 AA genotype was associated with decreased FEV1%. 33 Furthermore, the CHI3L1 SNP rs12141494 A allele was associated with higher levels of YKL-40 in the asthmatic airway as measured in both sputum (P ≤ 0.05) 32 and bronchoalveolar lavage (BAL) (P < 0.05, 770.8 pg/mL for AA vs. 179.3 pg/mL for GG). 33 These findings suggested that CHI3L1 genetic polymorphism modulated expression of YKL-40 in the airway and contributed to lung function in asthma. However, longitudinal studies are needed to determine whether SNPs in CHI3L1 are linked to decline in lung function in asthma over time.