Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function

N Engl J Med. 2008 Apr 17;358(16):1682-91. doi: 10.1056/NEJMoa0708801. Epub 2008 Apr 9.

Abstract

Background: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function.

Methods: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls.

Results: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4)).

Conclusions: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipokines
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Asthma / blood
  • Asthma / genetics*
  • Biomarkers / blood
  • Bronchial Hyperreactivity / blood
  • Bronchial Hyperreactivity / genetics*
  • Case-Control Studies
  • Child
  • Chitinase-3-Like Protein 1
  • Female
  • Founder Effect
  • Genetic Predisposition to Disease
  • Genotype
  • Glycoproteins / blood*
  • Glycoproteins / genetics*
  • Humans
  • Lectins
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Pulmonary Ventilation / genetics

Substances

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