Dataset Information

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.

SUBMITTER: Ober C

PROVIDER: S-EPMC2629486 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Ober Carole C 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

The New England journal of medicine 20080409 16

<h4>Background</h4>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.<h4>Methods</h4>We carried out a genomewide association study of serum ...[more]

PMID: 18403759

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Project description:Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/A?42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (A?42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center. We tested correlations between YKL-40 and CSF Tau/A?42 ratio, A?42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/A?42 ratio, A?42, tau, and ptau181.We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau181 (r?=?0.521) and the strength of the correlation significantly increased with the addition of genetic information (r?=?0.573, p?=?0.006).CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.

Project description:BackgroundYKL-40, encoded by the chitinase 3-like 1 (CHI3L1) gene, is a chitinase-like protein involved in innate immune function hypothesized to play a role in the progression of atherosclerosis that may have differential roles in myocardial infarction (MI), as compared to stroke.Methods and resultsIn a nested case-control study conducted within a prospective cohort of 23 294 initially healthy women of European ancestry, we (1) measured plasma concentration of YKL-40 among 359 participants who subsequently developed cardiovascular events and among 359 age-, smoking-, and hormone replacement therapy-matched participants who remained free of disease during 17 years of follow-up, (2) compared effects of YKL-40 on vascular risk to that associated with 3 alternative inflammatory biomarkers (high-sensitivity C-reactive protein) ([hsCRP], soluble intracellular adhesion molecule 1, and fibrinogen), and (3) evaluated the role of 41 single-nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 gene (CHI3L1) as determinants of YKL-40 levels and incident vascular events. YKL-40 levels were higher in women with hypertension, diabetes, and obesity and correlated modestly with high-density lipoprotein cholesterol, triglycerides, and hsCRP, but not with low-density lipoprotein cholesterol. Baseline YKL-40 level was significantly associated with incident thromboembolic stroke with a magnitude of effect (a 40% per quartile increase in odds ratio [OR], P=0.019) comparable to that of hsCRP (a 52% per quartile increase in OR, P=0.006). By contrast, no significant association was observed between YKL-40 and incident MI. Genetic variation in CHI3L1 was strongly associated with YKL-40 levels; however, in this sample set, we did not observe a statistically significant association between genotype and future vascular events.ConclusionsAmong initially healthy U.S. women, plasma levels of the proinflammatory chitenase-like protein, YKL-40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke, but not MI, a differential effect consistent with limited previous data.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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