Selasa, 22 April 2008

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=1.1x10–13), 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=1.2x10–5) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9x10–3 to 2.5x10–4). 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. Carole Ober, Ph.D., Zheng Tan, Ph.D., Ying Sun, M.S., Jennifer D. Possick, M.D., Lin Pan, M.S., Raluca Nicolae, D.D.S., Sadie Radford, Rodney R. Parry, M.D., Andrea Heinzmann, M.D., Klaus A. Deichmann, M.D., Lucille A. Lester, M.D., James E. Gern, M.D., Robert F. Lemanske, Jr., M.D., Dan L. Nicolae, Ph.D., Jack A. Elias, M.D., and Geoffrey L. Chupp, M.D.

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