suPAR in the General Population
The following factors are associated with an elevated suPAR level:
- Daily smoking1–5
- Previous AMI3
- Low HDL cholesterol/high LDL cholesterol1–3
- Unhealthy diet3,10
- Physical inactivity3
Moreover, elevated suPAR levels are associated with the future incidence of:
- Cardiovascular diseases1,2,8
- Type 2 diabetes1
- Renal failure7
Finally, a change towards a healthier lifestyle is associated with a decrease in suPAR levels – and the resultant suPAR is predictive of outcome (mortality). Hence, suPAR is not a death sentence – it is an early warning signal8.
In the general population, the suPAR level is higher in females than in males; the suPAR levels in young healthy males and females are about 2.5 ng/mL and 3.0 ng/mL, respectively. The suPAR level increases slightly with age but, above all, it is affected by lifestyle and risk factors. Among lifestyle factors smoking is definitely the most important ‒ daily smoking is associated with an increase in suPAR of 1-1.5 ng/mL compared to non-smokers1–5,7,8.
Moreover, an unhealthy diet3,9 and, to a lesser extent, physical inactivity may also increase the suPAR level3. However, the impact on suPAR is significantly smaller compared to the impact of smoking (about 0.2 ng/mL for an unhealthy diet). The association between alcohol consumption and suPAR is not clear2,3,5, but alcoholic liver disease causes very high suPAR levels9.
Cardiovascular risk factors affect the suPAR level, as there is a slightly positive association with LDL-cholesterol and a clearly negative association with HDL-cholesterol1–3. Previous AMI causes an increase in suPAR level of about 0.4 ng/mL3,7. Two studies have demonstrated an association between elevated blood pressure and suPAR1,2, but in a third study this could not be confirmed3. A BMI of 20-35 kg/m2 has no notable effect on the suPAR level, but in severe obesity (BMI > 40) the suPAR level is about 0.5 ng/mL higher than in normal weight individuals3.
“Patients with high suPAR should be very aggressively managed with risk factor control and lifestyle changes.”
Asst. Prof. Salim S. Hayek,
M.D., University of Michigan, USA
suPAR News Vol. 3, June 2020
suPAR and future development of diseases
In the general population an elevated suPAR level is associated with future development of cancer, cardiovascular diseases, and type 2 diabetes and is a predictor of premature mortality and renal failure (Figure 1)1,2,5,7.
Excitingly, data from the Danish Inter99 cohort8 show that the mortality risk is associated with the suPAR level itself, and not with the underlying risk factors which cause increased suPAR levels. For example, the mortality risk in non-smokers with a high suPAR level is increased compared to smokers with a low suPAR level. Thus, learning about the individual’s risk factors may indicate the reason for an elevated suPAR level, but it still seems that the individual´s risk is primarily correlated with the suPAR level8.
Figure 1. The left graph displays cancer incidence during a 12.6-year follow-up of 2,602 individuals in the Danish MONICA cohort. The suPAR level is below 3.4 ng/mL in the 1st quartile and above 4.9 ng/mL in the 4th quartile. The right graph displays mortality in the 1,310 males in the same study. The suPAR level is below 3.1 ng/mL in the 1st quartile and above 4.7 ng/mL in the 4th quartile. Figure modified from Eugen-Olsen et al., JIM 2010.
The overall impact of lifestyle and risk factors on suPAR
Please note that although the single factors mentioned above, in general, have very little impact on suPAR, the overall impact of a number of risk factors may be considerable. Adjusted analyses show that a 30-year-old non-smoking, and physically active male of normal weight on a healthy diet has a suPAR level of about 2.5 ng/mL, whereas a 30-year-old obese, heavily smoking and inactive male, on an unhealthy diet has a suPAR level of about 5.4 ng/mL3. This exceeds the difference between the 1st and 4th suPAR quartile in Figure 1 and therefore indicates a considerable risk difference.
A healthier lifestyle change generally reduces suPAR levels and, in turn, lowers the risk of mortality.
2. Borné, Y., Persson, M., Melander, O., Smith, J. G. & Engström, G. Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. Eur. J. Heart Fail. 16, 377–383 (2014).
3. Haupt, T. H. et al. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population. Biomark. Insights 9, 91–100 (2014).
4. Persson, M., Engström, G., Björkbacka, H. & Hedblad, B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmö Diet and Cancer Study. Atherosclerosis 220, 502–505 (2012).
5. Langkilde, A. et al. Increased plasma soluble uPAR level is a risk marker of respiratory cancer in initially cancer-free individuals. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 20, 609–618 (2011).
6. Persson, M., Engström, G., Björkbacka, H. & Hedblad, B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmö Diet and Cancer Study. Atherosclerosis 220, 502–505 (2012).
7. Hayek, S. S. et al. Soluble Urokinase Receptor and Chronic Kidney Disease. N. Engl. J. Med. 373, 1916–1925 (2015).
8 Haupt TH et al. Healthy lifestyles reduce suPAR and mortality in a Danish general population study. Immun Ageing. 22;16:1 (2019).
9. Zimmermann, H. W., Koch, A., Seidler, S., Trautwein, C. & Tacke, F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis. Liver Int. Off. J. Int. Assoc. Study Liver 32, 500–509 (2012).
10. Törnkvist PBS et al. Soluble urokinase plasminogen activator receptor is linearly associated with dietary quality and predicts mortality. Br J Nutr. 2019;121(6):699-708.