-
[show abstract]
[hide abstract]
ABSTRACT: Objectives. To investigate the frequency of anti-infliximab antibodies in patients with RA and the associations with adverse drug reactions and treatment failure.Methods. Based on the DANBIO registry, patients with RA who initiated treatment with infliximab at Hvidovre Hospital between 2000 and 2008 and had available serum samples were identified. The patients were followed for 52 weeks. Anti-infliximab antibodies were determined prior to infusion at baseline and during follow-up (weeks 2, 6, 14 and 52 or at withdrawal) using the IMPACT indirect assay (Roche Diagnostics) and merged with clinical data prospectively registered in the DANBIO registry.Results. A total of 218 patients with RA were included (80% females, median age 56 years, disease duration 10 years, 65% RF positive, median DAS28 = 5.0). During the 52-week follow-up, 28 patients (13%) withdrew due to adverse events and 50 (23%) due to treatment failure. Antibodies were detected in 118 patients (54%) during follow-up. Patients with detectable anti-infliximab antibodies after 6 weeks had an increased risk of adverse drug reactions [hazard ratio (HR) = 5.06, 95% CI 2.36, 10.84; P < 0.0001] compared with patients without anti-infliximab antibodies. Similar results were observed in patients with anti-infliximab antibodies after 14 weeks (HR = 3.30, 95% CI 1.56, 6.99; P = 0.0009). Patients with detectable anti-infliximab antibodies during the 52-week follow-up were less likely to achieve sustained minimal disease activity and remission.Conclusion. Early anti-infliximab antibody formation increased the risk of adverse drug reactions, including infusion reactions. Anti-infliximab antibody formation during the 52-week follow-up decreased the likelihood of minimal disease activity and remission in patients with RA treated in routine care.
Rheumatology (Oxford, England) 03/2013; · 4.24 Impact Factor
-
Naja Dam Mygind,
Kasper Iversen,
Lars Køber,
Jens P Goetze,
Henrik Nielsen,
Soren Boesgaard,
Morten Bay, Julia S Johansen,
Olav Wendelboe Nielsen,
Vibeke Kirk,
Jens Kastrup
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: YKL-40 is an inflammatory biomarker associated with disease activity and mortality in patients with diseases characterized by inflammation and tissue remodelling. The aim of this study was to describe the prognostic value of YKL-40 in an unselected patient population. DESIGN: In consecutive patients admitted to hospital during a 1-year period, blood was collected and information regarding final diagnosis and mortality was collected. Median follow-up time was 11.5 years. SETTING: District hospital, Copenhagen, Denmark. PATIENTS: A total of 1407 patients >40 years of age were admitted acutely. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Median YKL-40 was increased in patients (157 μg/L, range 13-7704 μg/L) compared to healthy controls (40 μg/L, range 29-58 μg/L; P<0.001). Patients with YKL-40 in the highest quartile had a hazard ratio (HR) of 7.1 [95% confidence interval (CI) 4.2-12.0] for all-cause mortality in the first year, and 3.4 (95% CI 2.8-4.2) in the total study period, compared to those in the lowest quartile (HR=1). The HR for death for all patients with YKL-40 above the normal age-corrected 95th percentile was 2.1 (95% CI 1.6-2.7) after 1 year and 1.5 (95% CI 1.3-1.7) during the total study period, compared to patients with YKL-40 below the age-corrected 95-percentile. The results of multivariable analysis showed that YKL-40 was an independent biomarker of mortality; this was most significant in the first year. YKL-40 was a marker of prognosis in all disease categories. The HR for death was increased in patients with YKL-40 above the normal age-corrected 95-percentile in healthy subjects independent of type of disease (all P<0.001). CONCLUSION: The level of YKL-40 at admission is a strong predictor of overall mortality, independent of diagnosis, and could be useful as a biomarker in the acute evaluation of all patients. © 2012 The Association for the Publication of the Journal of Internal Medicine.
Journal of Internal Medicine 11/2012; · 5.48 Impact Factor
-
Marina Harutyunyan,
Jens P Gøtze,
Per Winkel, Julia S Johansen,
Jørgen Fischer Hansen,
Gorm Boje Jensen,
Jørgen Hilden,
Erik Kjøller,
Hans J Kolmos,
Christian Gluud,
Jens Kastrup
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: We investigated whether the inflammatory biomarker YKL-40 could improve the long-term prediction of death made by common risk factors plus high-sensitivity C-reactive protein (hs-CRP) and N-terminal-pro-B natriuretic peptide (NT-proBNP) in patients with stable coronary artery disease (CAD). BACKGROUND: Non-hospitalized CAD patients are usually followed in general practice. There is a need for identify biomarkers which could help to foresee the prognoses of these patients. Elevated serum YKL-40 is a short-term predictor for myocardial infarction, cardiovascular mortality and all-cause mortality in patients with stable CAD. METHODS: Serum YKL-40, hs-CRP, and NT-proBNP were measured in 4265 (97.6%) of the 4372 patients with stable CAD included in the CLARICOR trial, and death was registered in a 6-years follow-up period. RESULTS: The median serum YKL-40 was 110μg/L [IQR=93], hs-CRP 2.8mg/L [IQR=4.74], and NT-proBNP 203ng/L [IQR=407]. During 6 years follow-up period 923 (21.1%) patients died. After adjustment for type of intervention, risk factors (age, sex, hypertension, diabetes, smoking status, and previous myocardial infarction) and medical treatment (diuretics, digoxin, and statin) serum YKL-40 (transformed as ln(max(82, YKL-40/μg/L)) was significantly associated with all-cause mortality [hazard ratio (HR)=1.55, 95% CI=1.39-1.73, p<0.001]. After additional adjustment for ln(hs-CRP) and ln(NT-proBNP) this was still true [HR=1.38, 95% CI=1.21-1.53, p<0.001]. CONCLUSIONS: Serum YKL-40 is a predictor of long-term mortality in patients with stable CAD independent of common risk factors and ln(hs-CRP) and ln(NT-proBNP). Serum YKL-40 can be used for prognostication in these patients.
Immunobiology 11/2012; · 3.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced). Several of these microRNAs have not before been related to diagnosis of pancreatic cancer (eg, miR-492, miR-614, miR-622). MiR-614, miR-492, miR-622, miR-135b* and miR-196 were most differently expressed. MicroRNA profiles of pancreatic and ampullary adenocarcinomas were correlated (0.990). MicroRNA expression profiles for pancreatic cancer described in the literature were consistent with our findings, and the microRNA profile for pancreatic adenocarcinoma (miR-196b-miR-217) was validated. We identified a more significant expression profile, the difference between miR-411 and miR-198 (P=2.06 × 10(-54)) and a diagnostic LASSO classifier using 19 microRNAs (sensitivity 98.5%; positive predictive value 97.8%; accuracy 97.0%). We also identified microRNA profiles to subclassify ampullary adenocarcinomas into pancreatobiliary or intestinal type. In conclusion, we found that combinations of two microRNAs could roughly separate neoplastic from non-neoplastic samples. A diagnostic 19 microRNA classifier was constructed which without micro-dissection could discriminate pancreatic and ampullary adenocarcinomas from chronic pancreatitis and normal pancreas with high sensitivity and accuracy. Ongoing prospective studies will evaluate if these microRNA profiles are useful on fine-needle biopsies for early diagnosis of pancreatic cancer.Modern Pathology advance online publication, 10 August 2012; doi:10.1038/modpathol.2012.122.
Modern Pathology 08/2012; · 4.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to identify a panel of microRNAs (miRNAs) that can predict overall survival (OS) in non micro-dissected cancer tissues from patients operated for pancreatic cancer (PC).
MiRNAs were purified from formalin-fixed paraffin embedded (FFPE) cancer tissue from 225 patients operated for PC. Only a few of those patients received adjuvant chemotherapy. Expressions of miRNAs were determined with the TaqMan MicroRNA Array v2.0. Two statistical methods, univariate selection and the Lasso (Least Absolute Shrinkage and Selection Operator) method, were applied in conjunction with the Cox proportional hazard model to relate miRNAs to OS.
High expression of miR-212 and miR-675 and low expression of miR-148a*, miR-187, and let-7g* predicted short OS independent of age, gender, calendar year of operation, KRAS mutation status, tumor stage, American Society of Anesthesiologists (ASA) score, localization (not miR-148a*), and differentiation of tumor. A prognostic index (PI) based on these five miRNAs was calculated for each patient. The median survival was 1.09 years (Confidence Interval [CI] 0.98-1.43) for PI > median PI compared to 2.23 years (CI 1.84-4.36) for PI < median. MiR-212, miR-675, miR-187, miR-205, miR-944, miR-431, miR-194*, miR-148a*, and miR-769-5p showed the strongest prediction ability by the Lasso method. Thus miR-212, miR-675, miR-187, and miR-148a* were predictors for OS in both statistical methods.
The combination of five miRNAs expression in non micro-dissected FFPE PC tissue can identify patients with short OS after radical surgery. The results are independent of chemotherapy treatment. Patients with a prognostic index > median had a very short median OS of only 1 year.
World Journal of Surgery 08/2012; 36(11):2699-707. · 2.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied.
KRAS and BRAF mutations were analyzed in formalin-fixed, paraffin-embedded tumor samples from primarily chemotherapy-naive patients operated on with radical intentions for PDAC (n = 170) and A-AC (n = 107).
Eighty percent of PDAC patients had KRAS mutations (codon 12 mutations: 74%) and 67% with A-AC (codon 12 mutations: 54%). BRAF mutations were less common, 16% in PDAC and 12% in A-AC, and no V600E mutations were found. Fourteen percent with PDAC and 7% with A-AC had mutations in both KRAS and BRAF. Multivariate analysis, including KRAS status, stage, and American Society of Anesthesiologists physical status classification system score, demonstrated that KRAS mutations in patients with A-AC were associated with short recurrence-free survival (RFS) (hazard ratio, 2.45; 95% confidence interval, 1.19-5.06; P = 0.015) and overall survival (OS) (1.93, 95% 1.12-3.31; P = 0.018). KRAS mutations in patients with PDAC were not associated with RFS and OS. BRAF mutations were not associated with RFS and OS.
KRAS mutations frequencies were high in PDAC and A-AC. KRAS mutations were associated with poor prognosis in patients with A-AC, but not in patients with PDAC.
Pancreas 07/2012; 41(5):759-66. · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Interleukin-6 (IL-6) is an immunomodulatory cytokine produced by both normal cells and tumor cells, including melanoma cells. The specific biological function of IL-6 in melanoma is unknown. The present study examined whether the serum concentration of IL-6 can predict prognosis in patients with metastatic melanoma. IL-6 was measured by ELISA in serum samples from 103 patients with metastatic melanoma obtained before IL-2-based immunotherapy. Patients with metastatic melanoma had higher serum IL-6 than healthy individuals (median 3.4 ng/l, range 0.3-93 ng/l vs. median 1.4 ng/l, range 0.25-22.5 ng/l, P<0.0001). Pretreatment serum IL-6 was elevated in 43% of the patients. Patients with elevated pretreatment serum IL-6 had shorter overall survival (OS) compared with patients with normal serum IL-6 (P<0.0002). The median OS was 10.8 months [95% confidence interval (CI): 8.86-13.46] in patients with normal serum IL-6 compared with 4.5 months (95% CI: 3.04-7.39) in patients with elevated serum IL-6. Multivariate Cox analysis showed that serum IL-6 [hazard ratio (HR)=1.82, 95% CI: 1.19-2.78, P=0.006] and serum lactate dehydrogenase (HR=2.02, 95% CI: 1.31-3.11, P=0.001) were independent prognostic biomarkers of OS. A combination variable of elevated serum IL-6 and elevated serum lactate dehydrogenase almost quadrupled the risk of early death (HR=3.67, 95% CI: 2.17-6.20, P<0.0001) compared with patients with normal serum levels of these two biomarkers. Elevated serum IL-6 is an independent prognostic biomarker of short OS in patients with metastatic melanoma. A larger retrospective study is ongoing to confirm the findings. To validate serum IL-6 further as a prognostic biomarker, a prospective study is required.
Melanoma research 05/2012; 22(4):287-93. · 2.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors.
TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response.
After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response.
In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.
Pharmacogenetics and Genomics 05/2012; 22(8):577-89. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: TNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA).
In the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n = 160), adalimumab (n = 56) or etanercept (n = 21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher's exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR = 4.43, 95% CI: 1.99-10.09, p = 7.211×10(-5)) and with EULAR good response vs. moderate/no response (OR = 4.54, 95% CI: 2.29-8.99, p = 3.336×10(-6)). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR = 4.01, 95% CI: 1.92-8.49, p = 5.067×10(-5)).
Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.
PLoS ONE 01/2012; 7(6):e38539. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The secreted glycoprotein YKL-40 participates in cell differentiation, inflammation, and cancer progression. High YKL-40 expression is reported during early human development, but its functions are unknown. Six human embryonic stem cell (hESC) lines were cultured in an atmosphere of low or high oxygen tension, in culture medium with or without basic fibroblast growth factor, and on feeder layers comprising mouse embryonic fibroblasts or human foreskin fibroblasts to evaluate whether hESCs and their progeny produced YKL-40 and to characterize YKL-40 expression during differentiation. Secreted YKL-40 protein and YKL-40 mRNA expression were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative RT-PCR. Serial-sectioned colonies were stained for YKL-40 protein and for pluripotent hESC (OCT4, NANOG) and germ layer (HNF-3β, PDX1, CD34, p63, nestin, PAX6) markers. Double-labeling showed YKL-40 expression in OCT4-positive hESCs, PAX6-positive neuroectodermal cells, and HNF-3β-positive endodermal cells. The differentiating progeny showed strong YKL-40 expression. Abrupt transition between YKL-40 and OCT4-positive hESCs and YKL-40-positive ecto- and neuroectodermal lineages was observed within the same epithelial-like layer. YKL-40-positive cells within deeper layers lacked contact with OCT4-positive cells. YKL-40 may be important in initial cell differentiation from hESCs toward ectoderm and neuroectoderm, with retained epithelial morphology, whereas later differentiation into endoderm and mesoderm involves a transition into the deeper layers of the colony.
Journal of Histochemistry and Cytochemistry 12/2011; 60(3):188-204. · 2.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Despite progress in management of patients with heart failure (HF) these patients still have a poor prognosis. We tested the hypothesis whether the inflammatory biomarker YKL-40 alone or in combination with high-sensitivity C-reactive protein (hs-CRP) and/or N-terminal-pro-B natriuretic peptide (NT-proBNP) could be a new prognostic biomarker for all-cause mortality in patients with HF.
A total of 717 of the 1000 patients with severe left ventricular systolic dysfunction included in the EchoCardiography and Heart Outcome Study were included in Denmark and had blood sample available for serum YKL-40 determination. Mean age of patients was 70 years, and 73% were male. During the 7 years follow-up period 458 patients died. Patients were categorised according to serum YKL-40 at entry into four quartiles: quartile I with median serum YKL-40=60 μg/L (5-95% Confidence interval (CI): 30-82), quartile II: YKL-40=107 μg/L (CI: 86-132), quartile III: YKL-40=169 μg/L (CI: 142-221), and quartile IV: YKL-40=286 μg/L (CI: 230-770). Hazard ratios for all-cause mortality were with quartile I as reference 1.33 (CI: 0.99-1.80), 1.35 (CI: 0.99-1.82), and 1.54 (CI: 1.14-2.08) for serum YKL-40 II to IV quartiles, respectively following multivariable adjustment for cardiovascular risk factors (age, left ventricular ejection fraction, gender, history of heart failure, ischemic heart disease, chronic pulmonary disease, diabetes mellitus, stroke, hypertension, NT-proBNP, hs-CRP, and renal function).
Serum YKL-40 is significantly associated with all-cause mortality in patients with HF and could potentially be a new prognostic biomarker in these patients.
Immunobiology 11/2011; 217(6):652-6. · 3.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Earlier detection of patients with metastatic colorectal cancer (mCRC) might improve their treatment and survival outcomes. In this study, we used proton nuclear magnetic resonance ((1)H-NMR) to profile the serum metabolome in patients with mCRC and determine whether a disease signature may exist that is strong enough to predict overall survival (OS). In 153 patients with mCRC and 139 healthy subjects from three Danish hospitals, we profiled two independent sets of serum samples in a prospective phase II study. In the training set, (1)H-NMR metabolomic profiling could discriminate patients with mCRC from healthy subjects with a cross-validated accuracy of 100%. In the validation set, 96.7% of subjects were correctly classified. Patients from the training set with maximally divergent OS were chosen to construct an OS predictor. After validation, patients predicted to have short OS had significantly reduced survival (HR, 3.4; 95% confidence interval, 2.06-5.50; P = 1.33 × 10(-6)). A number of metabolites concurred with the (1)H-NMR fingerprint of mCRC, offering insights into mCRC metabolic pathways. Our findings establish that (1)H-NMR profiling of patient serum can provide a strong metabolomic signature of mCRC and that analysis of this signature may offer an independent tool to predict OS.
Cancer Research 11/2011; 72(1):356-64. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: YKL-40 is a glycoprotein secreted by macrophages and neutrophils in tissues with inflammation. Plasma YKL-40 is increased in patients with coronary artery disease (CAD) and associated with cardiovascular and all-cause mortality. Furthermore, plasma YKL-40 seems related to the number of diseased main vessels in patients with stable CAD. The aim was to further study the relation between YKL-40 and stenosis degree, stenosis type and actual ischemia in stable CAD patients.
Plasma YKL-40 and hsCRP levels were determined from 206 consecutive patients with stable angina pectoris admitted for coronary angiography. Plasma YKL-40 in 245 healthy subjects was used for comparison. In addition to one to three vessel stenosis scores, two new scores for evaluating coronary angiographies were established for discriminating between focal and diffuse CAD and the extent of myocardial ischemia.
YKL-40 levels in CAD patients (median: 52 μg/L and quartiles: 37-85 μg/L) were significantly increased (p < 0.001) compared to the healthy controls. In univariate analyses plasma YKL-40 was significantly associated with ischemic myocardium score, age, hypertension, peripheral vascular disease and serum creatinine levels. In multivariate analyses YKL-40 was related to hsCRP, peripheral artery disease, hypertension, and statin treatment.
Plasma YKL-40 was increased in patients with CAD compared to controls. YKL-40 was related to the ischemic myocardium, but not to degree of CAD using different scoring systems. Therefore, YKL-40 is not related to the extent of CAD, but to some other pathophysiological mechanisms of importance for the prognosis.
Scandinavian journal of clinical and laboratory investigation 09/2011; 71(5):439-47. · 1.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Plasma levels of YKL-40 are elevated in patients with systemic infection, inflammatory disorders and cancer. Both monocytes/macrophages, neutrophils, and cancer cells have the capacity to produce YKL-40, but the regulation during the inflammatory response is unknown. To study the possible role of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α in the regulation of YKL-40 plasma levels, we included healthy men, who received either recombinant human (rh)IL-6 (n=6), rhTNF-α (n=8) or vehicle (n=7) for 3h. The plasma levels of IL-6 and TNF-α reached ∼ 150 and ∼ 18 pg/ml, respectively, during the infusions. Following the IL-6 infusion, the plasma level of YKL-40 increased from ∼ 30 to ∼ 57 ng/ml (p<0.05) at 24h, and returned to normal values after 48 h. The plasma level of YKL-40 did not change during TNF-α infusion or infusion of vehicle. These data demonstrate that IL-6, but not TNF-α, has a key-role in the regulation of plasma YKL-40 levels during inflammation.
Cytokine 07/2011; 55(1):152-5. · 3.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study investigates the association between single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene and serum concentrations of YKL-40 in Danish patients with rheumatoid arthritis (RA) and healthy controls as well as the association with RA in the Danish population. The CHI3L1 gene is located on chromosome 1q32.1 and encodes the YKL-40 glycoprotein. YKL-40 concentrations are elevated in the serum of patients with RA compared to healthy subjects, and YKL-40 has been suggested to be an auto-antigen and may play a role in development of RA and in inflammation.
Eight SNPs in the CHI3L1 gene and promotor were genotyped in 308 patients with RA and 605 controls (healthy blood donors) using TaqMan allele discrimination assays. Serum concentrations of YKL-40 were determined by an enzyme-linked immunosorbent assay (ELISA).
We found significant association between the serum concentrations of YKL-40 and polymorphism in the CHI3L1 gene among both patients with RA and controls. The g.-131(C > G) polymorphism (rs4950928) was most strongly associated with age adjusted serum concentrations of YKL-40 in patients with RA (P < 2.4e-8) and controls (P < 2.2e-16). No significant allelic- or genotypic association with RA was found in this Danish cohort.
We suggest that the g.-131(C > G) promoter polymorphism has a substantial impact on serum concentrations of YKL-40 in patients with RA and healthy subjects. However, the polymorphism does not seem to confer risk to RA itself. The effect of CHI3L1 polymorphism on clinical outcome or the response to treatment in patients with RA remains to be investigated.
Arthritis research & therapy 06/2011; 13(3):R109. · 4.27 Impact Factor
-
Oncology 06/2011; 80(1-2):138-9. · 2.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Plasma YKL-40 is a new biomarker in patients with cancer and inflammatory diseases. High plasma YKL-40 is associated with poor prognosis. Our aim was to determine reference levels in healthy subjects.
Plasma YKL-40 was determined in 3130 participants aged 20-80 years from the Danish general population, the Copenhagen City Heart Study. They had no known disease at time of blood sampling in 1991-1994 and remained healthy and alive during a 16-year follow-up period. In 644 participants, YKL-40 was measured again in samples taken 10 years after the first.
The median plasma YKL-40 was 40 μg/L (2.5-97.5% reference levels: 14-155) with no difference between sexes. YKL-40 increased exponentially with age. For age-adjusted reference levels, the YKL-40 percentile as a function of age in years and plasma YKL-40 in μg/L was derived: percentile=100/(1+(YKL-40^-3)*(1.062^age)*5000). In subjects with two YKL-40 measurements 10 years apart, the mean increase in YKL-40 was 1.5 μg/L/year (SE: 0.2), while the mean change in the calculated age percentile was minimal (-0.3; SE: 0.1).
Plasma YKL-40 increases with age within and across healthy individuals from the general population. Age-stratified or age-adjusted reference levels are important when YKL-40 test results are evaluated.
Clinica chimica acta; international journal of clinical chemistry 04/2011; 412(9-10):709-12. · 2.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased plasma concentrations of YKL-40, also called chitinase-3-like-1 protein (CHI3L1), have been correlated with disease severity in a variety of malignant and inflammatory diseases. The objective of the current study was to assess pretransplant recipient and donor CHI3L1 polymorphisms and plasma YKL-40 concentrations as prognostic biomarkers in a cohort of 149 patients treated with hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies. Recipients with pretransplant YKL-40 concentrations above the age-adjusted 95th percentile (high) had higher relapse-related mortality (33% versus 18%, P = .04; hazard ratio (HR) = 4.41, P = .01), lower progression-free survival (38% versus 64%, P < .01; HR = 2.84, P = .01), and overall survival (42% versus 69%, P = .01; HR = 3.09, P = .01). Recipients transplanted with donors with high YKL-40 concentrations had an increased probability and risk of grade 2-4 acute graft-versus-host disease (aGVHD) (93% versus 62%, P < .01; HR = 2.25, P = .02). CHI3L1 polymorphisms were associated with plasma YKL-40 concentrations, but not with clinical outcomes. In conclusion, our study suggests that plasma YKL-40 could function as a biomarker for relapse risk and treatment-related toxicity, and possibly as a tool complementing clinical risk scores such as the HCT comorbidity index.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(9):1299-307. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We hypothesized that elevated plasma YKL-40 levels are associated with increased risk of ischemic cardiovascular disease in the general population. In contrast to C-reactive protein (CRP) produced in the liver in response to inflammation, YKL-40 is produced by lipid-laden macrophages inside the vessel wall.
We measured plasma YKL-40 in 8,899 21- to 93-year-old participants of the Copenhagen City Heart Study 1991-1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart disease. Hazard ratios were calculated for plasma YKL-40 levels in 10-year age percentile categories of 34 to 66%, 67 to 90%, and 91 to 100% versus 0 to 33%.
Multifactorially and CRP-adjusted hazard ratios for ischemic stroke were 1.2 (95% confidence interval, 0.9-1.6) for 33 to 66%, 1.8 (1.3-2.4) for 67 to 90%, and 2.3 (1.5-3.3) for 91 to 100% versus the 0 to 33% percentile category (p-trend < 0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9-1.5), 1.6 (1.2-2.0), and 2.2 (1.6-3.2) (p-trend < 0.001). Hazard ratios for myocardial infarction were not significant, whereas corresponding hazard ratios for ischemic heart disease were 1.0 (0.8-1.2), 1.2 (1.0-1.5), and 1.3 (1.0-1.6) (p-trend = 0.01). Stratifying for CRP or other risk factors gave similar results. A doubling in plasma YKL-40 was associated with multifactorially and CRP-adjusted increased risk of 20% (95% confidence interval, 11%-30%) for ischemic stroke, 16% (8%-24%) for ischemic cerebrovascular disease, 3% (-5%-11%) for myocardial infarction, and 7% (1%-12%) for ischemic heart disease.
In the general population, elevated plasma YKL-40 levels are associated with increased risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels.
Annals of Neurology 11/2010; 68(5):672-80. · 11.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased plasma YKL-40 is associated with short-term survival in patients with cardiovascular disease and cancer. We tested the hypothesis that increased plasma YKL-40 is associated with total and disease-specific mortality in the general population.
We measured plasma YKL-40 in 8899 study participants, aged 20-95 years, in the Copenhagen City Heart Study from the Danish general population who were followed for 16 years: 3059 died, 2158 had ischemic cardiovascular disease, 2271 had cancer, and 2820 had other diseases associated with increased YKL-40. Hazard ratios for early death and absolute 10-year mortality rates were calculated according to plasma YKL-40 percentile groupings computed within sex and age decade: 0%-33%, 34%-66%, 67%-90%, 91%-95%, and 96%-100%.
Median survival age decreased from 83 years for participants with plasma YKL-40 in category 0%-33% to 69 years in category 96%-100% (trend, P < 0.0001). Risk of early death was increased (multifactorially adjusted hazard ratios) by 10% for YKL-40 category 34%-66%, by 30% for 67%-90%, by 70% for 91%-95%, and by 90% for 96%-100% vs YKL-40 category 0%-33% (trend, P < 0.0001). Corresponding increases in participants with ischemic cardiovascular disease were 10%, 20%, 80%, and 60% (P < 0.0001); in those with cancer were 10%, 20%, 50%, and 70% (P < 0.0001); and in those with other diseases were 10%, 20%, 40%, and 60% (P < 0.0001). Highest absolute 10-year mortality rates were 78% and 90% in women and men, respectively, who were >70 years old, smoked, and were in YKL-40 category 96%-100%.
Increased plasma YKL-40 is associated with risk of early death from cardiovascular disease, cancer, and other diseases in the general population.
Clinical Chemistry 10/2010; 56(10):1580-91. · 7.91 Impact Factor
