Ykl-40

Serum glycoprotein (YKL-40) and high sensitivity C-reactive protein in type 2 diabetic patients in relation to cardiovascular El-Attar HA*, El Deeb MM**, El-Ghlied LA*** *professor,**lecturer , Chemical Pathology complications Department

***lecturer, Internal Medicine Department Medical Research Institute University of Alexandria YKL-40 YKL-40 YKL-40 is a human glycoprotein identified in 1989. The abbreviation YKL-40 is based on the one letter code for the first three Nterminal amino acids, tyrosine (Y), lysine

(K) and leucine (L) and the apparent molecular weight of YKL-40. The protein has several names:

YKL-40 Human cartilage glycoprotein-39(HC gp39) Breast regressing protein 39 (brp-39) 38-KDa heparin-binding glycoprotein (Gp38k) Chitinase-3-like-1 protein(CHI3L1) Chondrex 40 KDa mammary gland protein(MGP-40) Chitin

Chitin is a polymer of N-acetylglucosamine which has no mammalian counterpart. Following the cellulose in wood and paper, chitin is the second most abundant polysaccharide in nature. Chitinases, are key degrading enzymes that have been studied most intensely in lower life forms. The YKL-40 belongs to the family 18 of glycosyl hydrolases comprising chitinases

from various species, but YKL-40 is without any enzymatic properties. The glycoprotein YKL-40 contains a single polypeptide chain of 383 amino acids and has a calculated molecular mass of 40,476 Da and an isoelectric point of about 7.6. The YKL-40 gene is assigned to chromosome 1q31-q32 and consists of 10 exons and spans about 8 kilobases of

genomic DNA. The crystallographic three-dimensional structure of human YKL-40 Secretion of YKL-40 In vivo YKL-40 is secreted from cells with high level of metabolic activity and/or proliferation such as: macrophages neutrophils

synovial cells vascular smooth muscle and endothelial cells arthritic chondrocytes malignant cells from many different solid carcinomas. YKL-40 receptors The identity of cellular receptors mediating the biological effects of YKL-40 are currently not known.

Physiological role of YKL-40 YKL-40 plays active roles in human antiparasite, anti-infective defense and repair responses. 1- YKL-40 contributes to tissue remodeling and extracellular matrix degradation. Physiological role of YKL-40 2-YKL-40 mRNA and protein expression are found in tissues from all germ layers and are present during the early development

of the human musculoskeletal system where they seem associated with cell proliferation, differentiation and tissue morphogenesis Physiological role of YKL-40 3-In normal bone marrow the

myelometamyelocyte express YKL-40 protein, and it is stored in the specific granules of neutrophil granulocytes and released from fully activated cells. Physiological role of YKL-40 4-YKL-40 stimulates the proliferation of human connective tissue cells (fibroblasts, chondrocytes, synovial cells) in a dosedependent manner. 5-It regulates apoptosis, and contributes to fibrosis and wound healing.

YKL-40 in pathological conditions 1-Role of YKL-40 in inflammation The YKL-40 induces the maturation of monocytes to macrophages, and is secreted by macrophages during late stages of differentiation and by activated macrophages. YKL-40 in pathological conditions The glycoprotein YKL-40 is overexpressed

in many inflammatory conditions including: Meningitis Rheumatoid arthritis Osteoarthritis Inflammatory bowl disease Giant cell arthritis sarcoidosis YKL-40 in pathological conditions 2- Role of YKL-40 in malignancy The YKL-40 may play a role in cancer cell

proliferation, differentiation, survival, invasiveness, metastasis, angiogenesis and the inflammation and remodeling of the extracellular matrix surrounding the tumor. YKL-40 in pathological conditions Serum YKL-40 has been shown to be a helpful diagnostic and prognostic indicator in various

types of cancers, which include: Colorectal Breast

Lung Head and neck Prostate Ovarian cancer Malignant melanoma Involvement of YKL-40 in pathways pertaining to cell proliferation and survival Role of YKL-40 in oncogenic programming process

the heparin-binding protein YKL-40 was found to induce the co-activation of membrane receptor Syndecan1 (S1) with integrin v3 through binding to heparan sulfate (HS) and then trigger intracellular signaling cascades that involve focal adhesion kinase (FAK) and mitogen activated protein (MAP) Kinase. YKL-40 exerts antiapoptosis and function in angiogenesis through the activation of 2

major signaling pathways associated with mitogenesis and cell survival: Mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI-3K) mediated pathways. Diabetes Mellitus Diabetes mellitus is a group of chronic

metabolic conditions, all of which are characterized by elevated blood glucose levels resulting from the bodys inability to produce insulin or resistance to insulin action, or both. It is the most common non-communicable disease worldwide and the fourth to fifth leading cause of death in developed countries.

Prevalence of DM Worldwide, it is estimated that 366 million people have diabetes and half of them are not aware that they have the disease. If the current trend is maintained the number of people living with diabetes is expected to reach 522 million by 2030. Complications of diabetes mellitus

Acute complications 1-Hypoglycemia secondary to treatment overdose. 2-Ketoacidosis. 3-Nonketotic hyperosmolar coma. Chronic complications Microvascular Macrovascular

1-Diabetic retinopathy 1- Coronary artery disease 2- Diabetic nephropathy 2-Peripheral arterial disease 3- Diabetic neuropathy

3-Thromboembolic stroke Diabetes mellitus (DM) is a powerful and independent risk factor for cardiovascular disease which remains to be the major cause of death in type 2 diabetic patients. The central pathological mechanism in cardiovascular disease is the process of atherosclerosis

Chronic perturbation of the vasculature, which occurs in diabetes, leads to increased incidence, size, and complexity of atherosclerotic plaques with increased incidence of cardiovascular complications. The inflammatory marker YKL-40 and

cardiovascular complications of diabetes Subclinical inflammation induces endothelial dysfunction which appears to be the earliest event in atherogenesis, and plays a pivotal role in all phases of atherosclerosis from the initiation of the fatty streak to plaque rupture with culmination in acute coronary syndrome.

YKL-40 is a marker of inflammation and endothelial dysfunction. It is closely related to both the early and late phases in the development of atherosclerosis. Stages of development of atherosclerosis YKL-40 in the early stage of atherosclerosis

YKL-40 is produced and secreted by monocytes during differentiation to macrophages and is also secreted by activated macrophages. YKL-40 in the late stage of atherosclerosis YKL-40 promotes migration of vascular

endothelial cells, suggesting that YKL-40 promotes the process of atherosclerotic plaque formation, in which vascular smooth muscle cells (VSMCs) are induced to migrate through the intima in response to exogenous signals. Thus YKL-40 may be of pathogenic importance in the low-grade inflammation that precedes the development of cardiovascular disease in Type 2 DM.

AIM OF THE WORK The aim of the present work was to study serum YKL-40 in Type 2 diabetic patients in relation to cardiovascular complications. SUBJECTS AND METHODS

80 subjects were divided into 3 groups GROUP 1 GROUP 2 GROUP 3 16 apparently healthy

volunteers 16 patients suffering from Type 2 DM without clinically evident cardiovascular complications

48 patients suffering from Type 2 DM with cardiovascular complications Subjects with acute or chronic inflammation, autoimmune disease or malignancy were excluded.

To all subjects the following was done: I-Full clinical examination Full history taking Complete physical examination II-Investigations

ECG CIMT Fundus examination Lab investigations To all studied subjects, the following

laboratory investigations were done: Complete urine analysis Urinary albumin, creatinine and calculation of urinary albumin to creatinine ratio Fasting and postprandial glucose Glycated hemoglobin Creatinine and uric acid ALT Total cholesterol, HDL-C, TG and calculation of LDL-C

eGFR hsCRP. YKL-40 RESULTS Distribution of Coronary artery disease (CAD), stroke, peripheral arterial disease (PAD),

nephropathy, neuropathy and retinopathy in the group of diabetic patients with cardiovascular complications Item percent IHD 100%

Stroke PAD Nephropathy 8.3% 4.16%

66.67% Neuropathy Retinopathy 81.25% 68.75% M ean ofY K L-40(n g/m L ) 300

* 250 200 * 150 100

50 0 Controls Without cardiovascular complications With cardiovascular complications

Bar chart showing YKL-40 levels in both diabetic groups in relation to the control group. It was found that YKL-40 level was significantly higher in both the diabetic groups without and with cardiovascular complications when compared to the control group (p=0.017, 0.000)

respectively. Moreover YKL-40 levels were significantly elevated in the diabetic group with cardiovascular complications when compared to the diabetic group without cardiovascular complications (p=0.005) Box plot presentation showing median levels and

interquartile range of hsCRP in both diabetic groups in relation to the control group. As regard hsCRP its level was significantly higher in both the diabetic groups without and with cardiovascular complications when compared to the control group (p=0.000) for both. Also hsCRP levels were significantly elevated in the diabetic group with

cardiovascular complications when compared to the diabetic group without cardiovascular complications (p=0.024) Some significant correlations 160 140

120 100 80 60 40 r= 0.668 p= 0.005 20 0 0

50 100 150 200 250

300 350 400 YKL-40 (ng/ml) Significant positive correlation between YKL-40 (ng/ml) and systolic blood pressure (mmHg) and in the group of diabetic patients without cardiovascular complications.

450 350 r=0.603 p=0.013 300 T G (m g /d l)

250 200 150 100 50 0 0 50 100

150 200 250 300 350

400 450 YKL-40 (ng/ml) Significant positive correlation between YKL-40 (ng/ml) and TG (mg/dl) in the group of diabetic patients without cardiovascular complications. 300

r= -0.366 p= 0.011 eGFR 250 200 150

100 50 0 0 100 200

300 400 500 600 YKL-40 (ng/ml) Significant negative correlation between YKL-40 (ng/ml) and eGFR

(ml/min/1.73m2) in the group of diabetic patients with cardiovascular complications. 9000 r= 0.386 p= 0.007 A lb / c r r a tio (m g /g ) 8000 7000

6000 5000 4000 3000 2000 1000 0 0 100

200 300 400 500 YKL-40 (ng/ml) Significant positive correlation between YKL-40 (ng/ml) and

Alb/cr ratio (mg/g) in the group of diabetic patients with cardiovascular complications. 600 45 r= 0.371 p= 0.009 D u r a tio n o f D M (y e a r s)

40 35 30 25 20 15 10 5 0 0

100 200 300 400 500 YKL-40 (ng/ml)

Significant positive correlation between YKL-40 (ng/ml) and duration of DM (years) in the group of diabetic patients with cardiovascular complications. 600 3.93 10

11 Efficiency % NPV % PPV % Specificity % Sensitivity %

Diabetic with cardio vascular complications Diabetic without cardio vascular complications Clinical (sensitivity, specificity, positive predictive value, negative predictive value and efficiency) for hsCRP and YKL-40 in diabetic patients It can be noticed that YKL-40 had better specificity and positive predictive value than

hsCRP in discriminating between diabetic patients without and with cardiovascular complications In the present work, by drawing receiver operating characteristic (ROC) curve between diabetic patients without and with cardiovascular complications the AUC for hsCRP was 0.676, p=0.036 and for YKL-40 was 0.743, p=0.004.

AUC p hsCRP 0.676* 0.036 YKL-40

0.743* 0.004 ROC curve for hsCRP and YKL-40 between diabetic patients without and with cardiovascular complications. CONCLUSI ON

The inflammatory glycoprotein YKL-40 was significantly higher in patients with type 2 diabetes mellitus than controls and cardiovascular complications contributed to its greater elevation. YKL-40 was positively correlated with several cardiovascular risk factors such as triglycerides, systolic blood pressure and mean blood pressure in the group of diabetic patients without cardiovascular

complications. In the group of diabetic patients with cardiovascular complications YKL-40 showed positive correlation with duration of diabetes mellitus and urinary albumin to creatinine ratio denoting that longer duration of inflammation leads to increased YKL-40 levels with subsequent generalized vascular

damage reflected by albuminuria. There was no correlation between both inflammatory markers YKL-40 and hsCRP implying that they are produced and secreted independently of each other. YKL-40 had a better specificity and positive predictive value than hsCRP in discriminating between diabetic patients without cardiovascular complications from

those with cardiovascular complications. Recommendat ions 1. An extension of the work on a larger sample size of Egyptian patients with type 2 DM with and without cardiovascular complications in order to collect more data to find out whether YKL-40 can be considered as a marker of early

inflammation in relation to hsCRP. 2. Conducting a genetic study aiming at the discovery of possible polymorphisms in the YKL-40 gene among Egyptians that could influence its serum level and biological action.

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