Free protein S level as a risk factor for coronary heart disease and stroke in a prospective cohort study of healthy United Kingdom men.

Plasma protein S (PS) levels are reportedly low in patients with venous thrombosis but high in coronary heart disease (CHD) patients. The authors examined the association between free PS concentration and CHD or stroke risk and assessed risk in combination with C-reactive protein (CRP) levels. Free PS concentration was determined in 6 annual visits among 3,052 middle-aged (49-64 years) United Kingdom men from the Second Northwick Park Heart Study, with 297 CHD events from 1989 to 2005. The highest (vs. first) quintile was associated with a significantly increased CHD risk after adjustment for all other risk factors and correction for regression dilution bias (hazard ratio = 1.85, 95% confidence interval: 1.08, 3.16; P = 0.024). Models that included all well-known risk factors plus PS quintiles improved prediction of CHD (net reclassification improvement (NRI) = 7.0% (P = 0.007), category-less NRI (>0) = 22.1% (P < 0.001)), and the likelihood ratio statistic increased significantly (P = 0.018). The increase in CHD risk was particularly strong when subjects also had high CRP levels. There was no association between free PS level and stroke risk. This study confirms the independent association of elevated free PS levels with future risk of CHD, although elevated PS levels added only modestly to prediction metrics. The novel finding of increased CHD risk, particularly when CRP and PS levels are high, requires further study.