Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

Background and Purpose-Systolic blood pressure (SBP) during exercise has been found to predict a future diagnosis of hypertension, coronary heart disease, and cardiovascular disease death. No studies have been conducted to show a relationship between SBP during exercise test and stroke. The aim of the present study was to study the associations between SBP rise, percent maximum SBP at 2 minutes after exercise, and the risk of stroke in a population-based sample of men with no prior coronary heart disease. Methods-SBP was measured every 2 minutes during and after the exercise test. The subjects were a population-based sample of 1026 men without clinical coronary heart disease, antihypertensive medication, or prior stroke at baseline. During an average follow-up of 10.4 years, there were 46 cases of stroke (38 ischemic strokes). Results-Men with SBP rise Ͼ19.7 mm Hg per minute of exercise duration had a 2.3-fold increased risk of any stroke and a 2.3-fold increased risk of ischemic stroke compared with men whose SBP rise was Ͻ16.1 mm Hg/min. Similarly, percent maximum SBP at 2 minutes after exercise (SBP at 2 minutes' recovery divided by maximum SBP) was associated (highest tertile) with a 4.6-fold increased risk of any stroke and a 5.2-fold increased risk of ischemic stroke. Conclusions-SBP rise during exercise and percent maximum SBP at 2 minutes after exercise were directly and independently associated with the risk of all stroke and ischemic stroke. Exercise SBP testing may be recommended as an additional tool in the prediction of future stroke.

VO2peak can be used as a very powerful predictor of future fatal cardiac events beyond that predicted by many conventional risk factors. On the prognostic consideration, unfit men with unfavourable risk profiles or underlying chronic disease are the risk groups that will benefit most from preventive measures.

Cardiorespiratory fitness is a predictor of SCD in addition to that predicted by conventional risk factors. There was a slight improvement in the level of discrimination, although the net reclassification index did not change while using cardiorespiratory fitness with conventional risk factors.