Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function.
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.
Ober
Carole
C
University of Chicago, Chicago, IL 60637, USA. c-ober@genetics.uchicago.edu
Tan
Zheng
Z
Sun
Ying
Y
Possick
Jennifer D
JD
Pan
Lin
L
Nicolae
Raluca
R
Radford
Sadie
S
Parry
Rodney R
RR
Heinzmann
Andrea
A
Deichmann
Klaus A
KA
Lester
Lucille A
LA
Gern
James E
JE
Lemanske
Robert F
RF
Nicolae
Dan L
DL
Elias
Jack A
JA
Chupp
Geoffrey L
GL
D054392:Adipokines; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D000071451:Chitinase-3-Like Protein 1; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics*; D006801:Humans; D037102:Lectins; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012123:Pulmonary Ventilation / Q000235:genetics
D054392:Adipokines; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins