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ENQUIRE PROJECT DETAILS BY GENERAL PUBLIC |
| Project Details |
| Funding Scheme : | General Research Fund | ||||||||||||||||||||||||
| Project Number : | 780210 | ||||||||||||||||||||||||
| Project Title(English) : | Biomarkers of Obesity-related Cardiometaolic Risks in Chinese | ||||||||||||||||||||||||
| Project Title(Chinese) : | 華人肥胖相關心臟代謝風險的生化標記研究 | ||||||||||||||||||||||||
| Principal Investigator(English) : | Prof Cheung, Bernard Man Yung | ||||||||||||||||||||||||
| Principal Investigator(Chinese) : | 張文勇 | ||||||||||||||||||||||||
| Department : | Department of Medicine | ||||||||||||||||||||||||
| Institution : | The University of Hong Kong | ||||||||||||||||||||||||
| E-mail Address : | mycheung@hku.hk | ||||||||||||||||||||||||
| Tel : | 22554347 | ||||||||||||||||||||||||
| Co - Investigator(s) : |
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| Panel : | Biology & Medicine | ||||||||||||||||||||||||
| Subject Area : | Medicine, Dentistry & Health | ||||||||||||||||||||||||
| Exercise Year : | 2010 / 11 | ||||||||||||||||||||||||
| Fund Approved : | 609,445 | ||||||||||||||||||||||||
| Project Status : | Completed | ||||||||||||||||||||||||
| Completion Date : | 31-12-2012 | ||||||||||||||||||||||||
| Project Objectives : |
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| Abstract as per original application (English/Chinese): |
The modern world, characterized by food abundance and sedentary lifestyle, is witnessing a rapid rise in the prevalence of obesity. Obesity is a major risk factor for cardiovascular diseases, including coronary artery disease, peripheral vascular disease and stroke, which are leading causes of disability and death in Hong Kong. The metabolic syndrome describes the clustering of multiple cardiometabolic risk factors frequently found in obese individuals, including abdominal obesity, high glucose level, high blood pressure and abnormal lipid profile. Together, these contribute to the increased risk of cardiovascular diseases. There is a need to identify biomarkers, whether biochemical or genetic, that may allow early identification of individuals at-risk for the metabolic syndrome and eventual cardiovascular diseases, for targeting of preventive therapy. As obesity is a key component of the metabolic syndrome, serum protein markers or genetic variants that are associated with obesity are potential candidates as biomarkers for the metabolic syndrome and cardiovascular diseases.
Obesity is characterized by the accumulation of excess fat mass. Fat cells actively secrete many factors, known as adipokines, that have effects on metabolism and inflammation and may play a role linking obesity, the metabolic syndrome and cardiovascular disease. There is also genetic influence on the development of obesity and recent genome-wide association studies have identified several obesity-susceptibility genes. Our previous work suggest that some of these genes are also associated with obesity in our population.
In this study, we will explore the role of circulating levels of three adipokines (resistin, lipocalin-2 and zinc-alpha-2-glycoprotein), variants of their genes and three obesity-susceptibility genes identified from genome-wide association studies (glucosamine-6-phosphate deaminase-2 gene, fat mass and obesity-related gene and melanocortin-4 receptor gene) in the prediction of the metabolic syndrome in Chinese. We shall be utilizing the available database and samples collected from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS), the longest prospective population-based study with comprehensive cardiovascular risk factor assessment conducted amongst Southern Chinese. We shall also conduct the long-term 15-year follow-up of these subjects for assessment of the development of cardiovascular diseases and examine the role of the above adipokines and genetic variants as biomarkers of cardiovascular disease in our population. |
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| Realisation of objectives: | Altogether, 1618 subjects have returned for follow-up. There were 748 men (age, mean±SD, 59.1±11.1 yrs) and 870 women (age, 58.5±9.9 yrs). In the whole cohort (n=2895) that started in 1995, there had been 258 deaths; 278 subjects who refused to return; 85 subjects who changed their telephone numbers and 656 subjects who could not be contacted. We have analysed the clinical data, stored DNA and blood samples of these subjects. We have succeeded in attaining the four objectives: 1. We have investigated whether the circulating levels of various hormones such as lipocalin-2 predict MetS over 6 years in Chinese (CRISPS-2 to CRISPS-3). Lipocalin-2 plasma concentrations have been measured in 1925 subjects. We found that plasma lipocalin-2 concentration is related to blood pressure. We also investigated two other circulating factors, adiponectin and tumor necrosis factor-alpha receptor 2, and found that they could predict the development of diabetes. For ZAG (zinc-alpha-2-glycoprotein), we found that neither its serum protein level at CRISP2 nor its SNPs were predictive of MetS. 2. We have investigated the association of obesity-related genes, including GNPDA2, FTO and MC4R, with cardiometabolic risk factors and MetS in cross-sectional analyses (CRISPS-3) and prospectively over 12 years (CRISPS-1 to CRISPS-3). We studied single nucleotide polymorphisms (SNPs) in the three obesity-susceptibility genes, rs10938397 (GNPDA2), rs8050136 (FTO) and rs17782313 (MC4R), in i) 354 subjects with and 994 subjects without central obesity at both baseline and a 12-year follow-up, ii) 2214 subjects (816 cases and 1398 controls) in an MetS cross-sectional case–control study and iii) 225 subjects with and 1221 subjects without MetS at both baseline and the 12-year follow-up. We demonstrated that FTO and GNPDA2 variants predicted persistent central obesity, and contributed to the risk of persistent MetS, in the Chinese population, further supporting their importance as obesity-susceptible genes. 3. Using Death Registry and Hong Kong Hospital Authority computerized records, we have been able to estimate the prevalence and cumulative incidence of CVD, including coronary artery disease, heart failure, stroke, peripheral vascular disease and cardiovascular mortality in the CRISPS cohort. We found that elevated circulating adipocyte-fatty acid binding protein levels predicted incident cardiovascular events at the 12-year follow-up. 4. We found that the combined use of serum interleukin-6 and C-reactive protein was better than either alone in predicting cardiovascular events in our cohort. Neither lipocalin 2 nor ZAG was an independent predictor of cardiovascular events, as protein or genetic biomarker. | ||||||||||||||||||||||||
| Summary of objectives addressed: |
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| Research Outcome | |||||||||||||||||||||||||
| Major findings and research outcome: | 1. Obesity-related hormones predict the development of cardiometabolic disease In our cohort of nearly 2000 subjects, we found that plasma level of lipocalin-2 was related to hypertension and its development, while plasma levels of adiponectin and tumour necrosis factor-alpha receptor 2 were related to diabetes and its development. Cheung et al. Plasma Lipocalin-2 Concentration is Related to Blood Pressure and is Increased in Hypertension. Presented at the 6th European Congress of Pharmacology. https://bps.conference-services.net/resources/344/3046/pdf/EPHAR2012_0348.pdf Woo et al. Combined use of serum adiponectin and tumor necrosis factor-alpha receptor 2 levels was comparable to 2-hour post-load glucose in diabetes prediction. PLoS One. 2012;7(5):e36868. 2. Genetic polymorphisms predict central obesity We demonstrated that single base pair variants in the FTO and GNPDA2 genes predicted central obesity in the Chinese population. Moreover, we found evidence that obesity-related hormones regulate each other at the genetic level. For instance, the interleulin-6 gene and the adiponectin gene control plasma adrenomedullin level, which is a known marker of cardiovascular risk. Cheung et al. Genetic variants associated with persistent central obesity and the metabolic syndrome in a 12-year longitudinal study. Eur J Endocrinol. 2011 Mar;164(3):381-8. Wong et al. A single nucleotide polymorphism of interleukin-6 gene is related to plasma adrenomedullin levels. Clin Endocrinol (Oxf). 2013 Oct;79(4):504-9. Wong et al. Plasma Level of Adrenomedullin Is Influenced by a Single Nucleotide Polymorphism in the Adiponectin Gene. PLoS One. 2013 Aug 1;8(8):e70335. 3. Predictors of cardiovascular disease We confirmed that C-reactive protein and interleukin-6 were significant predictors of cardiovascular disease in the Chinese population, and also discovered that adipocyte-fatty acid binding protein was also an important predictor of cardiovascular disease Lam et al. The combined use of serum interleukin-6 and C-reactive protein is better than either alone in predicting cardiovascular events in a Chinese population. Endocrine Abstracts 2012; 29 P298. Chow et al. Elevated circulating adipocyte-fatty acid binding protein levels predict incident cardiovascular events in a community-based cohort: a 12-year prospective study. J Am Heart Assoc 2013; 2 (1), pp. e004176. 4. Predictors of cancer development In addition to the original objectives of the proposal, we discovered that the plasma levels of interleukin-6 and soluble tumour necrosis factor receptor 2 (a surrogate marker of tumour necrosis factor-alpha) predicted the development of cancers. Our finding supports the hypothesis that chronic low grade inflammation caused by obesity could increase the risk of malignancy. Yeung et al. The adipokines TNF-α and IL6 predicted incident cancer development in a Chinese community-based cohort. Endocrine Abstracts 2012; 29 P1210. | ||||||||||||||||||||||||
| Potential for further development of the research and the proposed course of action: |
We found that genetic SNPs often influence the plasma level of a hormone. This is useful for performing Mendelian randomization experiments, and the knowledge of the genotype helps in the interpretation of the plasma level of the hormone in individuals. We have confirmed the usefulness of C-reactive protein and interleukin-6 in predicting the development of cardiovascular disease, but importantly, we have identified lipocalin-2 and adipocyte-fatty acid binding protein as important players as well as novel markers in the development of cardiovascular disease. | ||||||||||||||||||||||||
| Layman's Summary of Completion Report: | Obesity is associated with hypertension, diabetes and abnormal lipid levels, which are components of the metabolic syndrome and risk factors for cardiovascular diseases including coronary artery disease and stroke. There is a need to identify biomarkers, whether biochemical or genetic, that may allow early identification of individuals at risk. In our long term follow up study of people in the general population in Hong Kong, we have found that certain hormones that can be measured in the blood (including adiponectin and adipocyte-fatty acid binding protein), and certain genetic markers (single nucleotide polymorphisms in the FTO and GNPDA2 genes) that can be detected in the DNA, allow the prediction of aspects of the metabolic syndrome and the occurrence of cardiovascular disease. In particular, we found that plasma level of lipocalin-2 was related to hypertension and its development, while plasma levels of adiponectin and tumour necrosis factor-alpha receptor 2 were related to diabetes and its development. We found that circulating adipocyte-fatty acid binding protein levels in the blood predicted cardiovascular disease at the 12-year follow-up. Our work further confirms the importance of obesity as a precursor to the long term development of the metabolic syndrome and cardiovascular disease. | ||||||||||||||||||||||||
| Research Output | |||||||||||||||||||||||||
| Peer-reviewed journal publication(s) arising directly from this research project : (* denotes the corresponding author) |
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| Recognized international conference(s) in which paper(s) related to this research project was/were delivered : |
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| Other impact (e.g. award of patents or prizes, collaboration with other research institutions, technology transfer, etc.): |
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| SCREEN ID: SCRRM00542 |