Serum Alkaline Phosphatase and Risk of Incident Cardiovascular Disease: Interrelationship with High Sensitivity C-Reactive Protein

BACKGROUND Alkaline phosphatase (ALP) has been suggested to be associated with cardiovascular disease (CVD) risk, however, important aspects of the association, such as shape and independence from established risk factors, have yet to be characterized in detail. We assessed the association of ALP with CVD risk and determined its utility for CVD risk prediction. METHODS Alkaline phosphatase activity was measured at baseline in the PREVEND prospective cohort involving 6,974 participants aged 28-75 years without pre-existing CVD. Hazard ratios (95% confidence intervals [CI]) and measures of risk discrimination and reclassification were assessed. RESULTS During a median follow-up of 10.5 years, 737 participants developed CVD. Serum ALP was correlated with several risk markers for CVD, with strongest correlations for age (r = 0.30; P < 0.001), gamma-glutamyltransferase (r = 0.26; P < 0.001), and C-reactive protein (CRP) (r = 0.25; P < 0.001). There was a non-linear "J-shaped" relationship between ALP and CVD risk. In analyses adjusted for conventional risk factors, the hazard ratio (95% CI) for CVD in a comparison of the top quintile versus bottom quintiles 1-4 of ALP values was 1.34 (1.14 to 1.56; P<0.001), which persisted after additional adjustment for potential confounders 1.33 (1.13 to 1.55; P<0.001). However, the association was somewhat attenuated after adjustment for CRP 1.24 (1.05 to 1.45; P=0.009). Addition of information on ALP to a CVD risk prediction model containing established risk factors did not improve the C-index or net reclassification. CONCLUSIONS Available evidence suggests a non-linear association between ALP activity and CVD risk, which is partly dependent on CRP. Taking account of conventional risk factors, additional information on ALP does not improve CVD risk assessment.