Ykl40
Introduction
YKL-40, also known as Chitinase-3-like protein 1 (CHI3L1), is a chitinase-like protein that lacks enzymatic chitinase activity but is known to bind chitin. [1] It is encoded by the CHI3L1 gene. [1] This protein has been implicated in various biological processes, particularly inflammation and tissue remodeling. [1] Research indicates that serum YKL-40 levels can serve as a biomarker for certain inflammatory conditions, notably asthma. [1]
Background
Circulating YKL-40 levels have been found to be elevated in patients with asthma and correlate with asthma severity, thickness of the subepithelial basement membrane, and pulmonary function. [1] Genetic studies have shown that variation in CHI3L1, particularly single-nucleotide polymorphisms (SNPs) in its promoter region, can influence serum YKL-40 levels, gene expression, and transcript levels. [1] The heritability of YKL-40 levels is substantial, with broad heritability estimated at 1.0±0.16, suggesting that genetic differences largely account for variations in serum YKL-40 levels among individuals. [1]
Biological Basis
YKL-40 is a protein produced by the CHI3L1 gene. Although it is classified as a chitinase-like protein, it does not possess chitinase enzyme activity. [1] Instead, its role appears to involve binding to chitin and participating in processes related to inflammation and tissue remodeling. [1] A specific promoter SNP, rs4950928 (-131C→G), located in the core promoter of CHI3L1, has been identified as a significant determinant of YKL-40 levels. [1] The minor G allele of rs4950928 disrupts the binding site for MYC and MAX transcription factors, leading to reduced CHI3L1 transcription, lower messenger RNA levels, and consequently, reduced circulating YKL-40 protein. [1] This genetic effect on YKL-40 levels is observable from birth. [1] Other SNPs, such as rs4950929, rs946263, and rs2153101, are in strong linkage disequilibrium with rs4950928 and are similarly associated with serum YKL-40 levels. [1]
Clinical Relevance
Elevated serum YKL-40 levels are considered a biomarker for asthma, correlating with its severity and impact on lung function. [1] The rs4950928 SNP in CHI3L1 is significantly associated with serum YKL-40 levels, asthma risk, bronchial hyperresponsiveness, and impaired pulmonary function measures, including forced expiratory volume in 1 second (FEV1) and the FEV1:forced vital capacity (FVC) ratio. [1] Individuals carrying the minor G allele of rs4950928 tend to have lower YKL-40 levels and are found to be protected against asthma and the decline in lung function, independently of allergic pathways. [1] This SNP can be used to predict the presence of asthma in certain populations. [1]
Social Importance
The study of YKL-40 and its genetic determinants, such as the CHI3L1 gene, contributes to a deeper understanding of the genetic architecture of complex diseases like asthma. [1] Identifying loci that influence YKL-40 levels can lead to the discovery of additional genes that significantly impact asthma risk and lung function. [1] For instance, the rs4950928 SNP accounts for a notable 9.4% of the variance in serum YKL-40 levels in some populations. [1] The potential for YKL-40 as a therapeutic target for inflammatory diseases like asthma is also recognized, as evidenced by patent activity related to chitinases and chitinase-like molecules. [1]
Study Design and Generalizability Constraints
Research into ykl40 is subject to limitations concerning study design and the generalizability of findings. Many studies often rely on cohorts characterized by specific demographic profiles, such as those predominantly composed of individuals of European descent, who are often middle-aged to elderly. [2] This demographic homogeneity, along with the use of founder populations like the Hutterites or the North Finland Birth Cohort, restricts the applicability of observed genetic associations to younger individuals or populations of different ancestries . [1], [2], [3], [4] Furthermore, DNA collection at later examination points in some cohorts may introduce a survival bias, potentially skewing results by excluding individuals who did not live long enough to participate in these later assessments. [2]
The moderate sample sizes in some investigations also present a significant constraint, leading to inadequate statistical power to reliably detect genetic effects of modest magnitude . [2], [5] This limitation increases the risk of false negative findings, where true associations are missed due to insufficient power. Additionally, the approach of pooling sexes for analyses, while mitigating the multiple testing problem, might obscure sex-specific genetic associations that could influence ykl40 levels or related phenotypes differently in males and females. [6]
Statistical Inference and Replication Challenges
The rigorous statistical demands of genome-wide association studies (GWAS) introduce several analytical challenges. The extensive number of tests performed in GWAS increases the likelihood of false positive associations, even when stringent significance thresholds are applied . [4], [5] While methods such as genomic control and principal component analysis are employed to minimize the impact of population stratification, residual substructure within seemingly homogenous groups can still lead to inflated Type I error rates . [7], [8] Moreover, the current generation of GWAS platforms often utilizes only a subset of all available single nucleotide polymorphisms (SNPs) from resources like HapMap, potentially missing causal variants or entire genes due to incomplete coverage of genetic variation . [5], [6]
A substantial hurdle for validating genetic findings is the often-observed lack of replication across independent cohorts. A significant proportion of reported associations may not replicate, which can be attributed to various factors including false positive findings in initial studies, inadequate statistical power in replication cohorts, or genuine differences in study populations that modify genotype-phenotype relationships . [2], [3], [4] The ultimate validation of identified genetic associations necessitates consistent replication in diverse cohorts, alongside functional studies to elucidate the biological mechanisms at play. [2]
Phenotypic Measurement and Unaccounted Variables
The precise definition and measurement of phenotypes related to ykl40 can also pose limitations. For instance, the diagnosis of complex conditions like asthma often relies on multiple criteria, which can introduce variability in phenotype ascertainment. [1] Furthermore, the use of proxy markers for certain physiological functions, such as cystatin C for kidney function or TSH for thyroid function, may not fully capture the underlying biological complexity or could reflect additional physiological processes beyond their primary intended measure. [4] The development of many existing equations for estimating physiological parameters in small, selected samples further complicates their application to large, population-based cohorts. [4]
Beyond genetic factors, environmental influences and gene-environment interactions are crucial, yet often unexamined, modulators of ykl40 levels and related traits. Genetic variants can exert context-specific effects, with their impact modulated by environmental factors such as diet or lifestyle. [5] The absence of comprehensive investigations into these interactions means that a substantial portion of phenotypic variation may remain unexplained. While studies may identify high heritability for traits like YKL-40 levels, indicating a strong genetic component, the specific genetic variants identified through GWAS may only account for a fraction of this observed heritability, leaving a 'missing heritability' gap that could be attributable to rare variants, structural variations, or complex non-additive genetic effects . [1], [9]
Variants
Genetic variations play a crucial role in modulating an individual's susceptibility to various conditions, particularly those involving inflammation and tissue remodeling, processes in which the YKL-40 protein is a key player. The CHI3L1 gene encodes the YKL-40 protein, a chitinase-like protein that, despite lacking enzymatic chitinase activity, binds to chitin and is deeply implicated in inflammatory responses and tissue remodeling. [1] Elevated serum levels of YKL-40 are observed in patients with asthma and correlate with disease severity, subepithelial basement membrane thickening, and compromised pulmonary function, making it a significant biomarker. [1] Specific single-nucleotide polymorphisms (SNPs) within the CHI3L1 gene, such as the intronic rs880633 variant located in exon 5, are associated with altered serum YKL-40 levels, asthma risk, bronchial hyperresponsiveness, and lung function impairments. [1] Another variant, rs35405821, also within CHI3L1, contributes to the intricate genetic landscape that influences YKL-40 production and the broader network of inflammatory pathways.
The CHIT1 gene encodes a genuine chitinase enzyme, which, unlike the chitinase-like YKL-40, actively degrades chitin and is involved in mediating airway inflammation. [1] Variants like rs80241012, rs946849, and rs17474061 in CHIT1 can influence the enzyme's activity or expression, thereby impacting the body's inflammatory and tissue remodeling responses, which are intertwined with YKL-40 biology. Furthermore, variants such as rs2153101, rs871799, and rs140716503, located in the CHI3L1 - CHIT1 intergenic region, highlight the complex genetic interplay between these two functionally related genes. These genetic differences can lead to altered immune responses that may contribute to conditions like asthma, where YKL-40 is a key biomarker, and are often explored in genome-wide association studies of pulmonary function. [10]
Genetic variants in genes like TRIB1AL and ADORA1 also represent important modulators of physiological processes that can indirectly affect systemic inflammation and YKL-40-related pathways. The rs28601761 variant, associated with TRIB1AL (likely referring to TRIB1), is primarily linked to lipid metabolism, a critical biological process known to influence inflammatory responses and cardiovascular health. [11] Dysregulation of lipid profiles can intensify inflammatory conditions, potentially impacting YKL-40 expression and activity. Similarly, ADORA1 encodes the Adenosine A1 Receptor, a G-protein coupled receptor that regulates diverse cellular functions, including neuronal activity, cardiac rhythm, and inflammatory signaling. Variants such as rs12125460, rs3753474, and rs10800901 in ADORA1 could modify receptor sensitivity or expression, thereby influencing immune cell function and the overall inflammatory environment, which in turn might affect YKL-40 levels or its pathological contributions. [12]
Beyond direct inflammatory and metabolic regulators, variations in other genes involved in fundamental cellular processes can also contribute to diseases where YKL-40 plays a role. For instance, FANCI is a crucial component of the DNA repair pathway, and variants like rs188263039, rs117809422, and rs188631178 could compromise genomic stability, leading to cellular stress that indirectly affects inflammatory responses. The rs17602253 variant, located in the SLC39A12 - CACNB2 locus, impacts a zinc transporter and a calcium channel subunit, respectively; both zinc homeostasis and calcium signaling are vital for immune cell function and maintaining cellular integrity, which are factors often investigated in studies of kidney function and endocrine traits. [4] Additionally, USP3 and its antisense RNA USP3-AS1, with variant rs62012778, are involved in deubiquitination, a process essential for protein stability and immune signaling pathways. The long non-coding RNA BCL10-AS1 (rs116057745) and PPFIA4 (rs1890414, rs189886398), which is instrumental in cell adhesion and signaling, represent further genetic factors whose variations could influence cellular communication, tissue integrity, and the inflammatory cascades that interact with YKL-40 activity. [13]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs880633 rs35405821 |
CHI3L1 | protein measurement ykl40 measurement |
| rs2153101 rs871799 rs140716503 |
CHI3L1 - CHIT1 | ykl40 measurement |
| rs28601761 | TRIB1AL | mean corpuscular hemoglobin concentration glomerular filtration rate coronary artery disease alkaline phosphatase measurement ykl40 measurement |
| rs12125460 rs3753474 rs10800901 |
ADORA1 | ykl40 measurement |
| rs188263039 rs117809422 rs188631178 |
FANCI | ykl40 measurement |
| rs17602253 | SLC39A12 - CACNB2 | ykl40 measurement |
| rs80241012 rs946849 rs17474061 |
CHIT1 | ykl40 measurement protein measurement |
| rs62012778 | USP3, USP3-AS1 | ykl40 measurement |
| rs116057745 | BCL10-AS1 | ykl40 measurement |
| rs1890414 rs189886398 |
PPFIA4 | ykl40 measurement |
Defining YKL-40: A Chitinase-like Protein and Inflammatory Biomarker
YKL-40, also known as Chitinase-3-like protein 1 (CHI3L1), is a chitinase-like protein that plays a significant role in inflammation and tissue remodeling processes in the human body. Although it belongs to the chitinase family, YKL-40 itself lacks direct chitinase enzymatic activity; instead, it is characterized by its ability to bind ubiquitously expressed chitin. [1] This protein is encoded by the CHI3L1 gene, and variations within this gene, particularly in its promoter region, have been linked to altered serum YKL-40 levels and differential gene expression. [1] Functionally, YKL-40 serves as an important biomarker, with elevated circulating levels frequently observed in patients with inflammatory conditions such as asthma. [1]
The conceptual framework surrounding YKL-40 positions it as a key mediator in inflammatory responses and tissue repair mechanisms. Its involvement in these biological pathways suggests its utility beyond a simple inflammatory marker, indicating a potential role in the pathogenesis and progression of various diseases characterized by chronic inflammation and structural changes. The precise definition of YKL-40 as a chitinase-like protein underscores its structural similarity to active chitinases while highlighting its distinct functional characteristic of lacking enzymatic activity, emphasizing its role in binding and signaling rather than catalytic breakdown. [1] This distinction is crucial for understanding its mechanisms of action in physiological and pathological states.
Measurement and Genetic Determinants of YKL-40 Levels
The measurement of YKL-40 levels typically involves analyzing frozen serum specimens, and for genetic studies, these levels are often natural-log transformed to meet the distributional requirements of statistical methods. [1] Key covariates such as age and sex are routinely included in analyses to adjust for their potential influence on YKL-40 concentrations. [1] Research has demonstrated that serum YKL-40 levels are a highly heritable trait, with broad heritability estimated at 1.0±0.16 and narrow heritability at 0.51±0.10 in certain populations, indicating that individual differences are largely attributable to genetic factors. [1] This high heritability suggests the presence of autosomal loci with significant nonadditive genetic effects contributing to YKL-40 levels. [1]
Specific genetic variants, such as single-nucleotide polymorphisms (SNPs) within the CHI3L1 gene, have been strongly associated with variations in serum YKL-40 concentrations. For instance, the rs4950928 genotype has shown a significant association with mean natural-log–transformed serum YKL-40 levels, demonstrating a clear genetic influence on this biomarker. [1] These genetic determinants not only explain a substantial portion of the variability in YKL-40 levels among individuals but also provide insights into the molecular pathways regulating its expression and secretion, offering potential targets for therapeutic intervention or risk stratification.
Clinical Significance and Disease Associations
YKL-40 levels hold considerable clinical significance, particularly in respiratory diseases, where they have been established as a biomarker for asthma. [1] Elevated circulating YKL-40 levels are correlated with asthma severity, increased thickness of the subepithelial basement membrane in the airways, and impaired pulmonary function. [1] In specific populations, serum YKL-40 levels have been found to be inversely correlated with forced expiratory volume in 1 second (FEV1), a critical measure of lung function, further underscoring its relevance in assessing respiratory health. [1]
Beyond its role as a biomarker, variations in YKL-40 levels, often influenced by genetic polymorphisms in CHI3L1, are associated with the risk of developing asthma and bronchial hyperresponsiveness. [1] These associations extend to other lung function parameters, with significant differences observed in the ratio of FEV1 to forced vital capacity (FVC) across different genotypes influencing YKL-40 levels. [1] The multifaceted involvement of YKL-40 in inflammation, tissue remodeling, and its strong correlation with clinical outcomes in respiratory diseases highlight its potential as a diagnostic, prognostic, and severity marker, contributing to a more comprehensive understanding and management of these conditions.
Biomarker Assessment and Clinical Correlation
Diagnosis related to YKL-40 primarily involves the assessment of serum YKL-40 levels, which serve as a circulating biomarker for certain inflammatory conditions, particularly asthma. Elevated serum YKL-40 levels are observed in patients with asthma and correlate with disease severity, subepithelial basement membrane thickening, and compromised pulmonary function. [1] These levels are measured from frozen serum specimens and are considered a biomarker for asthma and the decline in lung function. [1] However, YKL-40 is implicated in general inflammation and tissue remodeling, suggesting its elevation may indicate a broader inflammatory state rather than being solely specific to asthma. [1]
Clinical evaluation for conditions associated with elevated YKL-40, such as asthma, involves a comprehensive assessment of symptoms like cough, wheeze, and shortness of breath. Pulmonary function tests are crucial, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the FEV1:FVC ratio. While serum YKL-40 levels show a significant inverse correlation with FEV1, they do not correlate with FVC, FEV1:FVC ratio, or forced expiratory flow between 25% and 75% of FVC (FEF25–75). [1] Bronchial hyperresponsiveness, assessed through methacholine inhalation or airway reversibility, is another key diagnostic criterion for asthma. [1]
Genetic Predisposition and Molecular Markers
Genetic testing plays a significant role in understanding the predisposition to elevated YKL-40 levels and related conditions. Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) upstream of the CHI3L1 gene, which encodes YKL-40, as having the most significant associations with serum YKL-40 levels. [1] Notably, a specific promoter SNP, −131C→G (rs4950928), in CHI3L1 is strongly associated with elevated serum YKL-40 levels (P = 1.1×10−13). [1] This SNP has also been linked to an increased risk of asthma, bronchial hyperresponsiveness, and reduced pulmonary function measures. [1] The heritability of YKL-40 levels is substantial, with a broad heritability estimate of 1.0±0.16, indicating that genetic differences largely account for variations in serum YKL-40 levels among individuals. [1]
The −131C→G SNP can predict the presence of asthma in case-control populations and serum YKL-40 levels from birth through five years of age in birth cohorts. [1] Prior research has also linked SNPs in the CHI3L1 promoter to elevated serum YKL-40 levels, differential gene expression, and a higher risk of schizophrenia, as well as to sarcoidosis. [14] This highlights the utility of genetic markers in identifying individuals at risk for conditions associated with altered YKL-40 expression, even though the direct causal pathway between CHI3L1 variation, YKL-40 levels, and all associated phenotypes is still under investigation. [1]
Differential Diagnosis and Diagnostic Challenges
When considering YKL-40 in a diagnostic context, it is crucial to perform a differential diagnosis due to its involvement in various inflammatory and tissue remodeling processes. While elevated YKL-40 is a biomarker for asthma, it is also associated with a range of other inflammatory conditions and sarcoidosis, necessitating a broader clinical perspective. [1] Distinguishing asthma from other respiratory conditions or inflammatory diseases requires integrating clinical history, physical examination, and specific diagnostic tests like spirometry and bronchial provocation tests. [1] Atopy, identified by a positive skin-prick test for common allergens, can also provide context in allergic asthma cases. [1]
Diagnostic challenges arise because the relationship between CHI3L1 genetic variations, YKL-40 levels, and clinical phenotypes can be complex. For instance, while the −131C→G SNP is a significant predictor of lung function measures like FEV1:FVC and FEF25–75, serum YKL-40 levels themselves may not show the same association with these specific parameters. [1] Furthermore, genetic variations in CHI3L1 might influence asthma risk and lung function independently of circulating YKL-40 levels, suggesting that YKL-40 acts as an intermediate phenotype rather than a sole, direct mediator of all disease aspects. [1] Therefore, a comprehensive diagnostic approach considering both genetic factors and direct YKL-40 measurement alongside clinical and functional assessments is essential to avoid misdiagnosis and effectively manage conditions where YKL-40 plays a role.
The Chitinase-like Protein YKL-40: Structure and Function
YKL-40 is a specific protein encoded by the CHI3L1 gene, also known as chitinase 3-like 1. Although it is classified as a chitinase-like protein, it notably lacks enzymatic chitinase activity. [1] Instead of catalytic breakdown, YKL-40 functions by binding to chitin, a polysaccharide ubiquitously found in various biological contexts. [1] This binding capability suggests its involvement in processes that do not require enzymatic action but rather structural interaction or signaling within cellular functions.
The presence and activity of YKL-40 have been strongly implicated in inflammation and the complex processes of tissue remodeling. [1] Its role in these fundamental biological mechanisms positions it as a significant biomolecule in the body's response to injury and disease. Understanding its molecular interactions, particularly its chitin-binding property, is crucial for deciphering its broader physiological impact and its contribution to regulatory networks.
Genetic Regulation of YKL-40 Levels
The regulation of YKL-40 levels is largely governed by genetic mechanisms, with the CHI3L1 gene being central to its expression. Single-nucleotide polymorphisms (SNPs) located within the promoter region of the CHI3L1 gene have been identified as key determinants of serum YKL-40 concentrations. [1] These genetic variations are associated not only with elevated circulating YKL-40 levels but also with differential gene expression and transcript levels of CHI3L1. [1] This highlights how specific regulatory elements can influence the transcriptional machinery, thereby modulating the production of the YKL-40 protein.
A specific promoter SNP, rs4950928 (-131C→G), has been significantly associated with elevated serum YKL-40 levels. [1] The high broad heritability of serum YKL-40 levels, estimated at 1.0±0.16, further underscores that individual differences in this protein's concentration are almost entirely attributable to genetic differences, including those with significant nonadditive effects. [1] This robust genetic control suggests that CHI3L1 variants play a crucial role in establishing an individual's baseline YKL-40 levels, which can then influence various physiological and pathophysiological processes.
YKL-40 in Inflammation and Tissue Remodeling
YKL-40, despite lacking enzymatic activity, plays a significant role in fundamental pathophysiological processes, particularly inflammation and tissue remodeling. [1] Its involvement aligns with the broader understanding of chitinases, which are evolutionarily conserved proteins known to mediate airway inflammation, as observed in mouse models of asthma. [1] This positions YKL-40 as a key biomolecule in the intricate regulatory networks governing the body's inflammatory responses and cellular functions.
Elevated serum YKL-40 levels serve as a biomarker for asthma and have been correlated with the severity of the condition. [1] Beyond its role in inflammation, YKL-40 is also implicated in structural changes within tissues, specifically showing a correlation with the thickening of the subepithelial basement membrane. [1] This dual involvement in inflammation and tissue remodeling underscores its broad impact on tissue integrity and disease progression. Furthermore, SNPs in the CHI3L1 promoter have been associated with a higher risk of schizophrenia, suggesting its influence extends beyond inflammatory conditions. [1]
YKL-40 and Lung Health: Implications in Asthma
The biological implications of YKL-40 are particularly pronounced in the context of lung health and respiratory diseases such as asthma. Elevated circulating YKL-40 levels are not only a biomarker but also correlate with asthma severity and impaired pulmonary function. [1] Specifically, serum YKL-40 levels have been found to be significantly inversely correlated with forced expiratory volume in 1 second (FEV1), a critical measure of lung function. [1] This suggests a direct link between the protein's abundance and the functional capacity of the lungs at the organ level.
Genetic variations within the CHI3L1 gene significantly influence lung-related phenotypes. The promoter SNP rs4950928 (-131C→G) is associated with an increased risk of asthma, bronchial hyperresponsiveness, and reduced measures of pulmonary function, including the FEV1:FVC ratio. [1] While YKL-40 is considered an intermediate phenotype for asthma susceptibility, studies suggest that CHI3L1 variation may exert effects on asthma risk and lung function that are independent of circulating YKL-40 levels. [1] This indicates a complex interplay where genetic factors might influence lung health through multiple pathways, some directly impacting tissue biology and others mediated by YKL-40, leading to systemic consequences.
Biomarker for Inflammatory and Respiratory Conditions
YKL-40 is a chitinase-like protein that plays a role in inflammation and tissue remodeling processes within the body. Elevated serum YKL-40 levels are a recognized biomarker for asthma, with studies consistently showing higher levels in affected individuals compared to healthy controls. [1] These circulating levels are not merely indicative of disease presence but also correlate with asthma severity, the thickening of the subepithelial basement membrane, and overall pulmonary function. [1] This correlation suggests its utility in monitoring disease activity and progression, potentially guiding therapeutic interventions. While primarily highlighted for asthma, YKL-40 has also been implicated in a broader range of inflammatory conditions, underscoring its general relevance in inflammatory pathogenesis. [1]
Genetic Predisposition and Risk Stratification
Genetic factors significantly influence YKL-40 levels, with the trait demonstrating high heritability, indicating that individual differences are largely attributable to genetic variations. [1] Specifically, single-nucleotide polymorphisms (SNPs) located upstream of the CHI3L1 gene, which encodes YKL-40, are strongly associated with serum YKL-40 concentrations. [1] A prominent promoter SNP, -131C→G (rs4950928), in CHI3L1 is not only linked to elevated YKL-40 levels but also acts as a susceptibility gene for asthma and reduced lung function. [1] This genetic variant holds promise for risk stratification, as it can predict the presence of asthma in various populations and circulating YKL-40 levels from birth through early childhood, thereby informing personalized prevention strategies for at-risk individuals. [1] Furthermore, variations in CHI3L1 have been associated with other conditions such as schizophrenia, suggesting broader implications for genetic risk assessment beyond respiratory diseases. [1]
Prognostic Indicator in Asthma and Lung Function
Circulating YKL-40 levels serve as a prognostic biomarker for asthma and the decline in lung function over time. Research has identified a significant inverse correlation between serum YKL-40 levels and forced expiratory volume in 1 second (FEV1), a critical measure of lung function, suggesting its potential in predicting disease progression and long-term outcomes. [1] Beyond direct protein levels, the -131C→G SNP in CHI3L1 can independently predict bronchial hyperresponsiveness and specific pulmonary function measures, including the FEV1:FVC ratio and forced expiratory flow between 25% and 75% of the FVC (FEF25–75). [1] This dual utility, encompassing both direct YKL-40 levels and their genetic determinants, highlights its value in assessing the long-term implications of asthma and guiding treatment selection by identifying individuals at higher risk for adverse respiratory outcomes. [1]
References
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