Epidemiology

Yang Xuan -  M.Sc. Epidemiology and Biostatistics
Division of Clinical Epidemiology and Ageing Research
German Cancer Research Center

Im Neuenheimer Feld 581
D-69120 Heidelberg

Phone: +49 (0)6221 42 1359
y.xuan(at)dkfz-heidelberg.de

2nd Affiliation: Network Aging Research (NAR), Fellow: Ben Schöttker, PhD

Evaluation of oxidative stress biomarkers as risk factors for myocardial infarction, stroke and type 2 diabetes mellitus in the general older population and as risk factors for diabetes complications

Summary of PhD thesis

The overall aim of this dissertation was to evaluate the associations of urinary and serum oxidative stress biomarkers with incident myocardial infarction, stroke and type 2 diabetes mellitus (T2DM) in the general population and with diabetes complications in T2DM patients using data from several large European cohort studies.

Serum derivatives of reactive oxygen metabolites (d-ROMs) and total thiol levels (TTL) are established biomarkers for reactive oxygen species burden and redox control status, respectively. I applied a matched case-control design and analyzed 476 myocardial infarction cases and 454 stroke cases as well as five controls per case individually matched by study center, age and sex from the populations-based ESTHER cohort (from Germany) and the HAPIEE cohorts (from Poland, Lithuania and Czech Republic). Findings from the pooled analysis indicate that both d-ROMs levels and TTL levels are associated with myocardial infarction and stroke incidence (TTL levels only with fatal myocardial infarction).

In addition, I assessed the association of d-ROMs and TTL levels with incident major cardiovascular events and all-cause mortality in 2,125 type 2 diabetes mellitus patients from two German cohort studies. Both oxidative stress biomarkers and the d-ROMs-to-TTL ratio were statistically significantly associated with all-cause mortality in the individual cohorts and in meta-analyses of both cohorts. In addition, the d-ROMs-to-TTL ratio was significantly associated with incident major cardiovascular events.

The 8-isoprostane and oxidized guanine/guanosine concentrations are reliable urinary biomarkers of oxidative stress. I assessed the association of oxidized guanine/guanosine (OxGua) and 8-isoprostane levels with incident myocardial infarction, incident stroke and cardiovascular mortality in 8,354 older adults from the ESTHER cohort. Both biomarkers were significantly associated with cardiovascular mortality. In addition, OxGua levels were significantly associated with total stroke incidence and 8-isoprostane levels with fatal stroke. Both urinary oxidative stress markers were not statistically associated with myocardial infarction incidence in the total population but in obese individuals. Generally, associations were stronger for fatal outcomes and in older and obese individuals. Moreover, adding 8-isoprostane and OxGua levels to the Systematic Coronary Risk Evaluation (SCORE) cardiovascular risk prediction score improved its abilities for 10-year cardiovascular mortality prediction.

Furthermore, the association of OxGua and 8-isoprostane levels with incident type 2 diabetes mellitus was evaluated using data from ESTHER cohort with 1,328 recorded incident type 2 diabetes mellitus cases over 14 years of follow-up. Weak but statistically significant associations of both biomarkers with type 2 diabetes mellitus incidence were observed in the total sample but stratified analyses showed that comparably stronger associations of both biomarkers with type 2 diabetes mellitus incidence were detected in the oldest age group of the cohort (65-75 years). This suggests that this association may become clinical apparent at older ages only, possibly due to reduced cellular repair capacity in aged cells.

The analyses conducted for the dissertation have several limitations. Because of the observational nature of the cohort studies used, residual confounding cannot be totally excluded. In addition, I would like to state that my results can only be generalized to Caucasian populations aged 50 years and older. However, with the strengths of the large sample size, the long follow-up interval, the large number of assessed potential confounders, and the validation of findings in external cohorts, results can be considered to be very robust.

Overall, the results suggest an important contribution of an imbalanced redox system to the etiology of cardiovascular events and T2DM in the general population and to mortality in T2DM patients. In clinical practice, the reliable and affordable lab measurements of the used oxidative stress biomarkers concentrations in easy to obtain urine/serum samples could be used to improve disease risk assessment in future in order to better identify subclinical signs at the earliest possible time and to find a target group for more intensive lifestyle interventions and/or pharmacological interventions.

Publications

• Schöttker B, Xuan Y, Gào X, Anusruti A, Brenner H. Oxidatively damaged DNA/RNA and 8-isoprostane levels are associated with the development of type 2 diabetes mellitus at older age: Results from a large cohort study. Diabetes Care. 2020;43(1):130-136.
• Xuan Y, Gao X, Anusruti A, Holleczek B, Jansen EHJM, Muhlack DC, Brenner H, Schöttker B. Association of serum markers of oxidative stress with incident major cardiovascular events, cancer incidence and all-cause mortality in type 2 diabetes patients: Pooled results from two cohort studies. Diabetes Care 2019;42(8):1436-1445.
• Xuan Y, Bobak M, Anusruti A, Jansen EHJM, Pająk A, Tamosiunas A, Saum KU, Holleczek B, Gao X, Brenner H, Schöttker B. Association of serum markers of oxidative stress with myocardial infarction and stroke: Pooled results from four large European cohort studies. Eur J Epidemiol 2019;34(5):471-481.
• Xuan Y, Gào X, Holleczek B, Brenner H, Schöttker B. Prediction of myocardial infarction, stroke and cardiovascular mortality with urinary biomarkers of oxidative stress: Results from a large cohort study. Int J Cardiol 2018;273:223-229.

Vita