A Sex-Specific Comparative Analysis of Oxidative Stress Biomarkers Predicting the Risk of Cardiovascular Events and All-Cause Mortality in the General Population: A Prospective Cohort Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Data Collection
2.3. Measurements of Oxidative Stress Biomarkers: Free Thiols, Homocysteine, Bilirubin, Gamma-Glutamyl Transferase, and HDL Cholesterol
2.4. Study Outcomes and Definitions
2.5. Statistical Analysis
2.6. Selection of Potentially Confounding Factors: The Directed Acyclic Graph (DAG)
3. Results
3.1. Baseline Cohort Characteristics
3.2. Cross-Sectional Associations between Biomarkers and Baseline Characteristics
3.3. Sex-Specific Prospective Associations between Oxidative Stress Biomarkers and CV Events and All-Cause Mortality
3.4. Incremental Value of Oxidative Stress Biomarkers over Clinical Risk Factors
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable | Total | Men | Women | p-Value |
---|---|---|---|---|
n = 5955 | n = 2917 | n = 3038 | ||
Age (years) | 51.6 [43.3;61.7] | 52.4 [43.8;63.9] | 50.9 [43.0;59.7] | <0.001 |
Ethnicity Caucasian, n (%) Asian, n (%) African, n (%) Other, n (%) | 5676 (95.3) 120 (2.0) 56 (0.9) 63 (1.1) | 2779 (95.3) 61 (2.1) 25 (0.9) 34 (1.2) | 2897 (95.4) 59 (1.9) 31 (1.0) 29 (1.0) | 0.750 |
BMI (kg/m2) | 26.0 [23.6;28.9] | 26.4 [24.2;28.8] | 25.6 [23.1;28.9] | <0.001 |
Waist circumference (cm) | 91 [82;100] | 96 [89;103] | 85 [78;94] | <0.001 |
Smoking Never, n (%) Former, n (%) Current, n (%) | 1757 (29.5) 2472 (41.5) 1655 (27.8) | 756 (25.9) 1322 (45.3) 802 (27.5) | 1001 (32.9) 1150 (37.9) 853 (28.1) | 0.640 |
Alcohol use No, n (%) Yes, n (%) | 1454 (24.4) 4450 (74.7) | 502 (17.2) 2386 (81.8) | 952 (31.3) 2064 (67.9) | <0.001 |
Blood pressure SBP (mmHg) DBP (mmHg) | 123 [112;136] 73 [67;79] | 127 [117;139] 76 [70;82] | 117 [108;131] 69 [64;76] | <0.001 <0.001 |
Comorbidity | ||||
CVD history, n (%) Hypertension, n (%) Non-insulin-treated type 2 diabetes, n (%) | 217 (3.6) 1717 (28.8) 144 (2.4) | 155 (5.3) 932 (32.0) 74 (2.5) | 62 (2.0) 785 (25.8) 70 (2.3) | <0.001 <0.001 0.560 |
Study biomarkers | ||||
Serum free thiols (μmol/g) | 5.05 ± 1.02 | 5.12 ± 1.03 | 4.98 ± 1.01 | <0.001 |
Bilirubin (umol/L) | 7.0 [5.0;9.0] | 8.0 [6.0;10.0] | 6.0 [5.0;8.0] | <0.001 |
Homocysteine (umol/L) | 12.0 [10.0;14.0] | 13.0 [11.0;15.0] | 11.0 [9.0;13.0] | <0.001 |
HDL cholesterol (mg/dL) | 47.4 [40.2;56.0] | 42.5 [36.9;49.3] | 52.5 [45.3;60.6] | <0.001 |
Gamma-GT (U/L) | 23.0 [16.0;37.0] | 30.0 [21.0;47.0] | 18.0 [13.0;27.0] | <0.001 |
Laboratory parameters | ||||
Hemoglobin (mmol/L) | 8.5 ± 0.8 | 9.0 ± 0.6 | 8.1 ± 0.6 | <0.001 |
hs-CRP (mg/L) | 1.3 [0.6;2.9] | 1.2 [0.6;2.7] | 1.4 [0.6;3.2] | 0.002 |
Albumin (g/L) | 44.0 [42.0;45.0] | 44.0 [43.0;46.0] | 43.0 [42.0;45.0] | <0.001 |
Creatinine (μmol/L) | 82.1 [73.9;92.4] | 90.4 [83.2;98.9] | 74.9 [68.8;82.1] | <0.001 |
eGFR (mL/min/1.73 m2) | 94.5 [82.2;104.7] | 94.6 [82.6;105.4] | 94.5 [82.0;104.1] | 0.176 |
Total cholesterol (mmol/L) | 5.4 [4.7;6.1] | 5.4 [4.8;6.1] | 5.4 [4.7;6.1] | 0.904 |
LDL cholesterol (mmol/L) | 3.4 [2.7;4.2] | 3.5 [2.7;4.2] | 3.3 [2.7;4.1] | 0.407 |
Triglycerides (mg/dL) | 97.2 [70.5;140.8] | 109.4 [77.1;157.9] | 89.4 [65.7;123.1] | <0.001 |
Glucose (mmol/L) | 4.7 [4.4;5.2] | 4.8 [4.5;5.3] | 4.7 [4.3;5.1] | <0.001 |
Follow-up (10 years) | ||||
CV events, n (%) | 402 (6.8) | 289 (9.9) | 113 (3.7) | <0.001 |
Mortality, n (%) | 316 (5.3) | 220 (7.5) | 96 (3.2) | <0.001 |
FT | Bilirubin | HDL | γ-GT | HCys | ||
---|---|---|---|---|---|---|
Cardiovascular Events (CV) | ||||||
Model 1 * | M | 0.33 [0.24–0.47], p < 0.001 | 0.97 [0.81–1.16], p = 0.758 | 0.95 [0.89–1.00], p = 0.084 | 1.25 [1.11–1.40], p < 0.001 | 2.04 [1.70–2.44], p < 0.001 |
F | 0.36 [0.22–0.60], p < 0.001 | 0.94 [0.71–1.24], p = 0.657 | 0.91 [0.85–0.98], p = 0.014 | 1.44 [1.20–1.73], p < 0.001 | 2.31 [1.61–3.32], p < 0.001 | |
Model 2 | M | 0.68 [0.47–0.98], p = 0.039 | 0.86 [0.71–1.03], p = 0.104 | 0.93 [0.88–0.99], p = 0.026 | 1.08 [1.06–1.09], p < 0.001 | 1.65 [1.32–2.06], p < 0.001 |
F | 0.80 [0.43–1.46], p = 0.458 | 0.81 [0.60–1.10], p = 0.182 | 0.95 [0.88–1.02], p = 0.142 | 1.22 [1.00–1.50], p = 0.056 | 1.50 [0.99–2.27], p = 0.053 | |
Model 3 | M | 0.76 [0.52–1.11], p = 0.152 | 0.957 [0.78–1.17], p = 0.665 | 0.96 [0.90–1.02], p = 0.203 | 1.11 [0.97–1.27], p = 0.142 | 1.62 [1.29–2.05], p < 0.001 |
F | 0.82 [0.45–1.49], p = 0.514 | 0.91 [0.67–1.24], p = 0.552 | 0.96 [0.89–1.04], p = 0.368 | 1.07 [0.86–1.34], p = 0.555 | 1.27 [0.83–1.94], p = 0.264 | |
Model 4 | M | 0.63 [0.40–0.99], p = 0.045 | 0.98 [0.79–1.23], p = 0.879 | 0.96 [0.90–1.03], p = 0.301 | 1.00 [0.85–1.18], p = 0.982 | 1.58 [1.20–2.08], p = 0.001 |
F | 0.82 [0.40–1.66], p = 0.574 | 0.99 [0.69–1.42], p = 0.940 | 0.96 [0.88–1.05], p = 0.386 | 1.05 [0.81–1.37], p = 0.699 | 1.29 [0.78–2.12], p = 0.320 | |
All-cause mortality | ||||||
Model 1 | M | 0.22 [0.15–0.32], p < 0.001 | 1.11 [0.90–1.36], p = 0.335 | 0.91 [0.86–0.96], p < 0.001 | 1.19 [1.04–1.37], p = 0.014 | 2.02 [1.64–2.49], p < 0.001 |
F | 0.41 [0.23–0.72], p = 0.002 | 0.82 [0.61–1.09], p = 0.173 | 0.92 [0.85–1.00], p = 0.050 | 1.34 [1.09–1.65], p = 0.006 | 3.21 [2.22–4.65], p < 0.001 | |
Model 2 | M | 0.60 [0.40–0.90], p = 0.015 | 0.86 [0.69–1.08], p = 0.864 | 0.89 [0.84–0.93], p < 0.001 | 1.32 [1.14–1.52], p < 0.001 | 1.361 [0.98–1.74], p = 0.065 |
F | 1.06 [0.54–2.08], p = 0.876 | 0.67 [0.49–0.93], p = 0.016 | 0.95 [0.88–1.04], p = 0.272 | 1.11 [0.88–1.40], p = 0.365 | 2.23 [1.46–3.39], p < 0.001 | |
Model 3 | M | 0.66 [0.43–1.01], p = 0.056 | 0.94 [0.74–1.19], p = 0.606 | 0.89 [0.85–0.94], p < 0.001 | 1.29 [1.10–1.50], p = 0.001 | 1.21 [0.89–1.63], p = 0.221 |
F | 0.97 [0.50–1.89], p = 0.926 | 0.73 [0.52–1.01], p = 0.059 | 0.96 [0.88–1.04], p = 0.329 | 1.03 [0.81–1.32], p = 0.793 | 1.95 [1.27–2.98], p = 0.002 | |
Model 4 | M | 0.52 [0.32–0.85], p = 0.009 | 0.98 [0.76–1.28], p = 0.903 | 0.90 [0.85–0.94], p < 0.001 | 1.17 [0.98–1.41], p = 0.089 | 1.24 [0.87–1.76], p = 0.241 |
F | 1.03 [0.48–2.22], p = 0.940 | 0.68 [0.48–0.98], p = 0.040 | 1.05 [0.83–1.34], p = 0.684 | 1.10 [0.84–1.44], p = 0.475 | 2.30 [1.14–3.76], p < 0.001 |
Biomarker | Men | p-Value | Women | p-Value |
---|---|---|---|---|
Cardiovascular (CV) Events | ||||
Base model *, C-statistic | 0.772 | - | 0.806 | - |
−2LL | 3082.4 | - | 1215.3 | - |
Base model + FT, C-statistic | 0.774 | - | 0.805 | - |
ΔC-statistic | 0.002 | - | −0.001 | - |
−2LL | 3078.5 | - | 1214.9 | - |
LHR Chi-square | 3.90 | 0.048 | 0.31 | 0.577 |
Base model + bilirubin, C-statistic | 0.772 | 0.806 | ||
ΔC-statistic | <0.001 | <0.001 | ||
−2LL | 3082.4 | 1215.2 | ||
LHR Chi-square | 0.02 | 0.879 | 0.006 | 0.940 |
Base model + HDL, C-statistic | 0.772 | 0.807 | ||
ΔC-statistic | <0.001 | 0.001 | ||
−2LL | 3081.6 | 1214.7 | ||
LHR Chi-square | 0.84 | 0.358 | 0.60 | 0.439 |
Base model + γ-GT, C-statistic | 0.772 | 0.806 | ||
ΔC-statistic | <0.001 | <0.001 | ||
−2LL | 3082.4 | 1215.1 | ||
LHR Chi-square | 0.001 | 0.982 | 0.15 | 0.700 |
Base model + HCys, C-statistic | 0.777 | 0.804 | ||
ΔC-statistic | 0.005 | −0.002 | ||
−2LL | 3072.6 | 1214.3 | ||
LHR Chi-square | 9.79 | 0.002 | 0.97 | 0.325 |
Base model + HCys + FT, C-statistic | 0.779 | 0.803 | ||
ΔC-statistic | 0.002 | −0.003 | ||
−2LL | 3070.3 | 1214.1 | ||
LHR Chi-square | 12.1 | 0.002 | 1.16 | 0.560 |
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Bourgonje, M.F.; Abdulle, A.E.; Kieneker, L.M.; la Bastide-van Gemert, S.; Bakker, S.J.L.; Gansevoort, R.T.; Gordijn, S.J.; van Goor, H.; Bourgonje, A.R. A Sex-Specific Comparative Analysis of Oxidative Stress Biomarkers Predicting the Risk of Cardiovascular Events and All-Cause Mortality in the General Population: A Prospective Cohort Study. Antioxidants 2023, 12, 690. https://doi.org/10.3390/antiox12030690
Bourgonje MF, Abdulle AE, Kieneker LM, la Bastide-van Gemert S, Bakker SJL, Gansevoort RT, Gordijn SJ, van Goor H, Bourgonje AR. A Sex-Specific Comparative Analysis of Oxidative Stress Biomarkers Predicting the Risk of Cardiovascular Events and All-Cause Mortality in the General Population: A Prospective Cohort Study. Antioxidants. 2023; 12(3):690. https://doi.org/10.3390/antiox12030690
Chicago/Turabian StyleBourgonje, Martin F., Amaal E. Abdulle, Lyanne M. Kieneker, Sacha la Bastide-van Gemert, Stephan J. L. Bakker, Ron T. Gansevoort, Sanne J. Gordijn, Harry van Goor, and Arno R. Bourgonje. 2023. "A Sex-Specific Comparative Analysis of Oxidative Stress Biomarkers Predicting the Risk of Cardiovascular Events and All-Cause Mortality in the General Population: A Prospective Cohort Study" Antioxidants 12, no. 3: 690. https://doi.org/10.3390/antiox12030690
APA StyleBourgonje, M. F., Abdulle, A. E., Kieneker, L. M., la Bastide-van Gemert, S., Bakker, S. J. L., Gansevoort, R. T., Gordijn, S. J., van Goor, H., & Bourgonje, A. R. (2023). A Sex-Specific Comparative Analysis of Oxidative Stress Biomarkers Predicting the Risk of Cardiovascular Events and All-Cause Mortality in the General Population: A Prospective Cohort Study. Antioxidants, 12(3), 690. https://doi.org/10.3390/antiox12030690