BACKGROUND - Circulating biomarkers have been previously associated with atherosclerosis related risk factors, but the nature of these associations is incompletely understood.

METHODS - We performed multivariable-adjusted regressions and two-sample Mendelian randomization (MR) analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451,933 participants of the UK Biobank.

RESULTS - After multiple-testing correction (alpha=1.3*10^-4), we found a total of 15, 9, 21, 22, 26, 24 and 26 biomarkers strongly associated with coronary artery disease (CAD), ischemic stroke, atrial fibrillation, type 2 diabetes (T2D), systolic blood pressure (SBP), body mass index (BMI) and waist-to-hip ratio (WHR); respectively. The MR analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with T2D and CAD. Particularly interesting findings included a protective role of insulin-like growth factor 1 in SBP, and the strong causal association of lipoprotein(a) in CAD development (β, -0.13; per SD change in exposure and outcome and OR, 1.28; P=2.6*10^-4 and P=7.4*10^-35, respectively). In addition, our results indicated a causal role of increased alanine aminotransferase in the development of T2D and hypertension (OR, 1.59 and β,0.06, per SD change in exposure and outcome; P=4.8*10^-11 and P=6.0*10^-5). Our results suggest that it is unlikely that C-reactive protein and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease.

CONCLUSIONS - We confirmed and extended known associations, and reported several novel causal associations providing important insights regarding the etiology of these diseases, which can help accelerate new prevention strategies.