Ober Carole, Tan Zheng, Sun Ying, Possick Jennifer D, Pan Lin, Nicolae Raluca, Radford Sadie, Parry Rodney R, Heinzmann Andrea, Deichmann Klaus A, Lester Lucille A, Gern James E, Lemanske Robert F, Nicolae Dan L, Elias Jack A, Chupp Geoffrey L
University of Chicago, Chicago, IL 60637, USA.
N Engl J Med. 2008 Apr 17;358(16):1682-91. doi: 10.1056/NEJMoa0708801. Epub 2008 Apr 9.
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.
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.
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)).
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.
几丁质酶样蛋白YKL - 40参与炎症和组织重塑过程。我们最近发现，哮喘患者血清YKL - 40水平升高，且与疾病严重程度、上皮下基底膜增厚及肺功能相关。我们推测，影响YKL - 40水平的单核苷酸多态性（SNP）也会影响哮喘状态和肺功能。
我们在欧洲裔创始人群体哈特派中开展了一项关于血清YKL - 40水平的全基因组关联研究，然后检测一个潜在的SNP与哮喘及肺功能之间的关联。在一个哮喘高危出生队列中对一个相关变异进行基因分型，该队列从出生到5岁期间测量YKL - 40水平，并在两个欧洲裔哮喘病例患者及对照的非相关人群中进行检测。
编码YKL - 40的几丁质酶3样1基因（CHI3L1）中的一个启动子SNP（-131C→G）与哈特派人群中血清YKL - 40水平升高（P = 1.1×10⁻¹³）、哮喘（P = 0.047）、支气管高反应性（P = 0.002）及肺功能指标（P = 0.046至0.002）相关。同一个SNP可用于预测两个病例对照人群中哮喘的存在（合并P = 1.2×10⁻⁵）以及出生队列中从出生（脐血样本）到5岁期间的血清YKL - 40水平（P = 8.9×10⁻³至2.5×10⁻⁴）。
CHI3L1是哮喘、支气管高反应性及肺功能降低的易感基因，循环YKL - 40水平升高是哮喘及肺功能下降的生物标志物。
