Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40.

Abstract

BACKGROUND:

Single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) promoter, the gene encoding YKL-40, are associated with circulating YKL-40 levels and asthma prevalence. However, the effects of gene polymorphisms on asthma severity and airway expression of YKL-40 have not been examined.

OBJECTIVE:

We sought to determine the effect of genetic variation in CHI3L1 on asthma severity and YKL-40 expression in subjects from the Yale Center for Asthma and Airways Disease and the Severe Asthma Research Program.

METHODS:

SNPs spanning the CHI3L1 gene were genotyped in 259 Yale Center for Asthma and Airways Disease and 919 Severe Asthma Research Program subjects. Association and haplotype analyses were conducted to identify effects on airflow obstruction, YKL-40 levels, and asthma severity.

RESULTS:

Fifteen SNPs in CHI3L1 were associated with FEV1, serum YKL-40 levels, or both. rs12141494 (intron 6) was the only SNP in subjects of European ancestry in both cohorts that was associated with serum YKL-40 levels and postbronchodilator FEV1. Conditional analysis demonstrated that the effect on lung function was independent of the promoter SNP rs4950928, and haplotype analysis demonstrated that G alleles at rs12141494 and rs4950928 are associated with lower YKL-40 expression and higher FEV1 percent predicted values. In asthmatic subjects the risk allele A at rs12141494 was associated with severe asthma and higher YKL-40 expression in the airway (P ≤ .05).

CONCLUSION:

In contrast to the promoter SNP rs4950928, the intronic SNP rs12141494 in CHI3L1 is associated with asthma severity, lung function, and YKL-40 expression in the blood and airway. These data suggest that SNP rs12141494 modulates YKL-40 expression in the airway and contributes to airway remodeling and asthma severity.

• Authors: Jose L Gomez, Gina M Crisafi, Carole T Holm, Deborah A Meyers, Gregory A Hawkins, Eugene R Bleecker, Nizar Jarjour, Severe Asthma Research Program (SARP) Investigators, Lauren Cohn, Geoffrey L Chupp
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 136 Issue 1 Pg. 51-58.e10 (Jul 2015) ISSN: 1097-6825 [Electronic] United States
• PMID: 25592985 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adipokines
• CHI3L1 protein, human
• Chitinase-3-Like Protein 1
• Lectins

Topics

• Adipokines (genetics)
• Adult
• Aged
• Airway Remodeling
• Asthma (genetics)
• Chitinase-3-Like Protein 1
• DNA Mutational Analysis
• Disease Progression
• Female
• Gene Expression Regulation (genetics)
• Genetic Association Studies
• Genotype
• Humans
• Lectins (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide