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

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.

Figure 1. Single-Nucleotide Polymorphisms (SNPs) in CHI3L1 and Its Upstream Region on Chromosome 1q32.1

Part A shows the structure of the CHI3L1 gene. Coding exons are indicated by black rectangles, and untranslated regions are shown as gray rectangles; the arrow indicates the direction of transcription. The gene spans from 201,414,557 bp to 201,422,504 bp. Part B shows the linkage disequilibrium (r²) among SNPs in HapMap CEPH samples (of persons of European ancestry collected by the Centre d’Etude du Polymorphisme Humain) from 201,416,807 bp to 201,436,499 bp (Haploview). SNPs typed in the Hutterites and the SNP typed in the case and control populations (−131C→G) are indicated by black rectangles. SNPs in the linkage-disequilibrium plot are equally spaced across the region (and thus are not to physical scale). The linkage-disequilibrium pattern in the Hutterites and in the European CEPH sample is shown in Figure S3 in the Supplementary Appendix.

Figure 2. Serum YKL-40 Level, Asthma Prevalence, and Lung-Function Measures in Hutterites, According to −131C→G Genotype (rs4950928)

All measures differed significantly among the three genotypes. Panel A shows the mean natural-log–transformed serum YKL-40 levels (P = 1.1×10⁻¹³ by the general two-allele model). Panel B shows asthma prevalences among 554 Hutterites (P = 0.047 by the case–control quasi-likelihood test). Panel C shows the mean percent of the predicted forced expiratory volume in 1 second (FEV₁) (P = 0.046 by the general two-allele model). Panel D shows the mean ratio of FEV₁ to forced vital capacity (FVC) (P = 0.002 by the general two-allele model).

Figure 3. Mean Serum YKL-40 Levels in the Childhood Origins of Asthma Cohort, According to Age and −131C→G Genotype (rs4950928)

P values were calculated for the differences in mean natural-log–transformed serum YKL-40 levels among the three genotype groupings by means of an analysis of variance. Vertical bars indicate standard errors.