Observational and genetic plasma <scp>YKL</scp>‐40 and cancer in 96,099 individuals from the general population

Kjærgaard, Alisa D; Nordestgaard, Børge G.; Johansen, Julia S.; Bojesen, Stig E.

doi:10.1002/ijc.29638

Cited by 19 publications

(31 citation statements)

References 48 publications

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“…Kucur et al [25] demonstrated elevated serum YKL- 40 levels in patients with primary PCa but not in benign prostatic hyperplasia. In contrast, Kjaergaard et al [26] found that YKL-40 levels measured in healthy individuals were not associated with later development of PCa. This suggests that YKL-40 levels might be used for the detection but not for the prediction of later occurrence of PCa.…”

Section: Discussionmentioning

confidence: 93%

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

et al. 2018

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Introduction: High baseline YKL-40 serum levels are associated with drug resistance in several solid tumours. However, their role in predicting docetaxel (DOC) resistance in prostate cancer (PCa) is unknown. Methods: Pre-treatment serum levels of YKL-40 and prostate-specific antigen (PSA) were analyzed in 109 castration-resistant prostate cancer patients who underwent DOC-therapy. Responsive patients were retreated by repeated series of DOC. Results were compared with the clinical parameters as well as overall (OS) and disease-specific survival (DSS). Results: YKL-40 but not PSA serum levels were significantly higher in patients with baseline resistance to DOC (p = 0.035). Higher YKL-40 and PSA levels were detected in patients with bone metastasis (p = 0.032; p = 0.010) and in those who were not pre-treated with radical prostatectomy (p = 0.011, p = 0.008). High YKL-40 levels were associated with shorter OS (p = 0.037) and DSS (p = 0.017) in patients who received DOC in the first-line setting. In multivariable analysis, ECOG performance status (p = 0.009), presence of any metastases (p = 0.016) and high PSA levels (p = 0.005) remained independent predictors for DSS. Conclusions: YKL-40 may help to identify patients with baseline resistance to DOC and therefore may help to optimize treatment decisions. In accordance, high pre-treatment YKL-40 serum levels were associated with shorter OS and DSS in patients who received DOC as first-line therapy.

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Section: Discussionmentioning

confidence: 93%

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

et al. 2018

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“…We have previously reported that a baseline increased plasma YKL-40 was associated with up to a 41-fold increased risk of alcoholic liver disease, and less than a 2fold increased risk of lung cancer, with no evidence to support causal relationships [17,19]. This suggests that plasma YKL-40 is a marker rather than a causal factor in the development of these diseases.…”

Section: Introductionmentioning

confidence: 94%

“…We used two independent cohorts of the Danish general population: the 1991-1994 examination of the Copenhagen City Heart Study (CCHS) [22] and the Copenhagen General Population Study (CGPS) [17][18][19] initiated in 2003 and with ongoing enrollment.…”

Section: Participantsmentioning

confidence: 99%

“…Plasma YKL-40 is such a biomarker. A promoter SNP rs4950928 in the gene for YKL-40 (CHI3L1) explains 14% of the variation, and genotype is associated with doubling and tripling in plasma YKL-40 concentrations compared with the reference genotype [17][18][19]. Furthermore, this SNP is likely functional since MYC/MAX transcriptional factors bind better to the major than the minor allele of rs4950928 [20].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, this SNP is likely functional since MYC/MAX transcriptional factors bind better to the major than the minor allele of rs4950928 [20]. The better binding to the major allele results in increased CHI3L1 transcription [21], and consequently higher plasma YKL-40 concentrations for each additional major allele [17][18][19]. Thus, this SNP only affects concentrations of plasma YKL-40, and not the protein function.…”

Section: Introductionmentioning

confidence: 99%

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Biomarker de-Mendelization: principles, potentials and limitations of a strategy to improve biomarker prediction by reducing the component of variance explained by genotype

Kjærgaard

Bojesen

Nordestgaard

et al. 2018

Preprint

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In observational studies, the Mendelian randomization approach can be used to circumvent confounding, bias and reverse causation, and to assess a potential causal association between a biomarker and risk of disease. If, on the other hand, a substantial component of variance of a non-causal biomarker is explained by genotype, then genotype could potentially attenuate the observational association and the strength of the prediction.In order to reduce the component of variance explained by genotype, an approach that can be seen as the inverse of Mendelian randomization -biomarker de-Mendelizationappears plausible.Plasma YKL-40 is a good candidate for demonstrating principles of biomarker de-Mendelization because it is a non-causal biomarker with a substantial component of variance explained by genotype. This approach is an attempt to improve the observational association and the strength of a predictive biomarker; it is explicitly not aimed at detection of causal effects.We studied 21 161 individuals form the Danish general population with measurements of YKL-40 concentration and rs4950928 genotype. Four different methods for biomarker de-Mendelization are explored for alcoholic liver cirrhosis and lung cancer.De-Mendelization methods only improved predictive ability slighly. We observed an interaction between genotype and markers of developing disease with respect to YKL-40 concentration.Even when genotype explains 14% of the variance in a non-causal biomarker, we found no useful empirical improvement in risk prediction by biomarker de-Mendelization. This could reflect the predictive interaction between genotype and disease development being removed which counterbalanced any beneficial properties of the method in this situation. The CGPS is a prospective cohort study initiated in 2003 with ongoing enrollment and emphasis on participants aged 20-100. Measurements of both plasma YKL-40 concentrations and CHI3L1 rs4950928 genotype were available in 13 180 individuals, examined 2003 through 2011. Ethics The studies were conducted according to the Declaration of Helsinki and approved by Herlev Hospital and a Danish scientific ethical committee (No. 100.2039/91 and 01-144/01). All participants gave written informed consent. Endpoints Diagnoses of alcoholic liver cirrhosis and lung cancer were defined according to the World Health Organization International Classification of Diseases; the 8th and 10th edition for alcoholic liver cirrhosis (ICD8: 571.09; ICD10: K70.3) and the 7th and 10th edition for lung cancer (ICD7: 162-164; 462; 562; 962-964. ICD10: C33-34; C37-38). Diagnoses were obtained from the national Danish Patient Registry, the national Danish Causes of Death Registry, and the national Danish Cancer Registry, with a very high degree of completeness [19]. Date of death was obtained from the national Danish Civil RegistrationSystem. We did not lose track of any participant. YKL-40 analysisPlasma concentrations of YKL-40 were determined in duplicates in samples frozen for 12-15 years at -80°C in the CCHS (N=7981) ...

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Combined plasma C‐reactive protein, interleukin 6 and YKL‐40 for detection of cancer and prognosis in patients with serious nonspecific symptoms and signs of cancer

et al. 2022

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Background and methods Inflammation is a hallmark of cancer and its progression. Plasma levels of C‐reactive protein (CRP), interleukin‐6 (IL‐6) and YKL‐40 reflect inflammation, and are elevated in patients with cancer. This study investigated whether plasma CRP, IL‐6 and YKL‐40 had diagnostic value in 753 patients referred with nonspecific signs and symptoms of cancer to a diagnostic outpatient clinic. Results In total, 111 patients were diagnosed with cancer within 3 months and 30 after 3 months. CRP, IL‐6 and YKL‐40 were elevated in 44%, 60% and 45% of the cancer patients, and in 15%, 33% and 25% of the patients without cancer. Elevated levels of all three markers were associated with risk of cancer within 3 months: CRP (odds ratio (OR) 4.41, 95% confidence interval (CI) 2.86–6.81), IL‐6 (OR = 2.89, 1.91–4.37) and YKL‐40 (OR = 2.42, 1.59–3.66). Multivariate explorative analyses showed that increasing values were associated with the risk of getting a cancer diagnosis (continuous scale: CRP (OR = 1.28, 1.12–1.47), carcinoembryonic antigen (CEA) (OR = 1.61, 1.41–1.98), CA19‐9 (OR = 1.15, 1.03–1.29), age (OR = 1.29, 1.02–1.63); dichotomized values: CRP (OR = 2.54, 1.39–4.66), CEA (OR = 4.22, 2.13–8.34), age (OR = 1.42, 1.13–1.80)). CRP had the highest diagnostic value (area under the curve = 0.69). Combined high CRP, IL‐6 and YKL‐40 was associated with short overall survival (HR = 3.8, 95% CI 2.5–5.9, p < 0.001). Conclusion In conclusion, plasma CRP, IL‐6 and YKL‐40 alone or combined cannot be used to identify patients with cancer, but high levels were associated with poor prognosis. CRP may be useful to indicate whether further diagnostic evaluation is needed when patients present with nonspecific signs and symptoms of cancer.

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Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

Cited by 19 publications

References 48 publications

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

Biomarker de-Mendelization: principles, potentials and limitations of a strategy to improve biomarker prediction by reducing the component of variance explained by genotype

Combined plasma C‐reactive protein, interleukin 6 and YKL‐40 for detection of cancer and prognosis in patients with serious nonspecific symptoms and signs of cancer

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