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Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) promoter, the gene encoding YKL-40, are associated with circulating YKL-40 levels and asthma prevalence. However, the effects of gene polymorphisms on asthma severity and airway expression of YKL-40 have not been examined.We sought to determine the effect of genetic variation in CHI3L1 on asthma severity and YKL-40 expression in subjects from the Yale Center for Asthma and Airways Disease and the Severe Asthma Research Program.SNPs spanning the CHI3L1 gene were genotyped in 259 Yale Center for Asthma and Airways Disease and 919 Severe Asthma Research Program subjects. Association and haplotype analyses were conducted to identify effects on airflow obstruction, YKL-40 levels, and asthma severity.Fifteen SNPs in CHI3L1 were associated with FEV1, serum YKL-40 levels, or both. rs12141494 (intron 6) was the only SNP in subjects of European ancestry in both cohorts that was associated with serum YKL-40 levels and postbronchodilator FEV1. Conditional analysis demonstrated that the effect on lung function was independent of the promoter SNP rs4950928, and haplotype analysis demonstrated that G alleles at rs12141494 and rs4950928 are associated with lower YKL-40 expression and higher FEV1 percent predicted values. In asthmatic subjects the risk allele A at rs12141494 was associated with severe asthma and higher YKL-40 expression in the airway (P ? .05).In contrast to the promoter SNP rs4950928, the intronic SNP rs12141494 in CHI3L1 is associated with asthma severity, lung function, and YKL-40 expression in the blood and airway. These data suggest that SNP rs12141494 modulates YKL-40 expression in the airway and contributes to airway remodeling and asthma severity.

SUBMITTER: Gomez JL

PROVIDER: S-EPMC4494869 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40.

Gomez Jose L JL Crisafi Gina M GM Holm Carole T CT Meyers Deborah A DA Hawkins Gregory A GA Bleecker Eugene R ER Jarjour Nizar N Cohn Lauren L Chupp Geoffrey L GL

The Journal of allergy and clinical immunology 20150113 1

<h4>Background</h4>Single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) promoter, the gene encoding YKL-40, are associated with circulating YKL-40 levels and asthma prevalence. However, the effects of gene polymorphisms on asthma severity and airway expression of YKL-40 have not been examined.<h4>Objective</h4>We sought to determine the effect of genetic variation in CHI3L1 on asthma severity and YKL-40 expression in subjects from the Yale Center for Asthma and Airways Disea ...[more]

PMID: 25592985

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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:YKL-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.In 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.Among 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.

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Dataset Information

Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40.

Publications

Genetic variation in chitinase 3-like 1 (CHI3L1) contributes to asthma severity and airway expression of YKL-40.

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