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[交流] 荷兰莱顿大学医学院-CSC 生物信息 - 肥胖流行病分析博士招生

Causes and consequences of oxidative stress in the general population

Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
Contact details: Diana van Heemst PhD (d.van_heemst@lumc.nl), Raymond Noordam PhD (r.noordam@lumc.nl)

Vitamin E is an antioxidant of which its metabolites can be measured as (stable) markers of oxidative stress; high levels are indicative of a high load of oxidative stress in the body [1,2]. Oxidative stress has been generally considered an important factor in disease, including diabetes [1,2]. However, there is currently a lack of data available on stable markers of oxidative stress in large population-based cohort studies to investigate the causes and consequences of oxidative stress in more detail.
The Netherlands Epidemiology of Obesity (NEO) Study is a population-based cohort study with 6,671, predominantly overweighed, individuals included [3]. Within this cohort, Vitamin E metabolites (notably α-tocopheronolactone-glucuronide and α-tocopheronolactone-sulfate) are measured in 24-hour urine. The NEO study has in-depth information available on several phenotypes, including blood measurements (fasting and postprandial), metabolomics, diseases and medication use as well as information available on genetics and lifestyle.

The main aim of the present PhD project is to study the causes and consequences of oxidative stress in the general population.

Main project aims and context:
- Investigate the role of lifestyle factors on oxidative stress. The NEO study population has detailed data available on lifestyle factors, including smoking, alcohol intake, habitual food intake, physical activity and sleep. In this project, we will use state-of-the-art epidemiological/statistical methods to investigate the effect of these lifestyle factors on the level of oxidative stress independent of confounding factors.

- Adiposity in relation to oxidative stress. In the NEO study, we have extensive measurements available on different specific adiposity measures, which includes standard measures as body mass index and waist circumference, but also adiposity measured with magnetic resonance imaging (notably subcutaneous adiposity tissue and visceral adipose tissue) as well as mass spectrometry (hepatic triglyceride content). For this aim, we will determine how, and to what extent, the measures of adiposity available in the NEO cohort are associated with the level of oxidative stress.

- The role of oxidative stress in the development of cardiometabolic diseases. The NEO study has information available on both prevalent and incident diseases (diseases that developed after baseline measurement during follow-up). In this study, we will investigate whether oxidative stress is associated with prevalent as well as incident cardiometabolic diseases. In addition, we will investigate for this project aim to what extend oxidative stress mediates the association between the measures of adiposity in the NEO study and cardiometabolic diseases.

- Identification of genes involved in oxidative stress and causal inference in cardiometabolic disease. De NEO study has extensive genotyped and imputed data available to perform genome-wide association studies. For this aim, we will conduct a genome-wide association study to identify genes that are associate with an increased level of oxidative stress. Subsequently, these genetic variants will be used in Mendelian Randomization analyses to demonstrate whether oxidative stress is causally associated with the development of cardiometabolic diseases (e.g., type 2 diabetes mellitus, coronary artery disease, etc).

References
1. Sharma G, Muller D, O'Riordan S, Bryan S, Hindmarsh P, et al. (2010) A novel method for the direct measurement of urinary conjugated metabolites of alpha-tocopherol and its use in diabetes. Mol Nutr Food Res 54: 599-600.
2. Sharma G, Muller DP, O'Riordan SM, Bryan S, Dattani MT, et al. (2013) Urinary conjugated alpha-tocopheronolactone--a biomarker of oxidative stress in children with type 1 diabetes. Free Radic Biol Med 55: 54-62.
3. de Mutsert R, den Heijer M, Rabelink TJ, Smit JW, Romijn JA, et al. (2013) The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur J Epidemiol 28: 513-523.

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