UK Biobank plasma proteomic data identify predictors of arterial stiffness and high blood pressure

Abstract Background Large artery stiffness is a hallmark of vascular ageing in hypertension. The pathophysiological mechanisms shared between these two conditions are not fully understood. Purpose Our study aimed to prioritize biomarkers potentially involved in high blood pressure and arterial stiffness pathogenesis using UK Biobank plasma proteomic data. Methods We used the machine-learning XGBoost algorithm to identify top predictors of arterial stiffness index (ASI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) among 2,923 plasma proteins in 9,532 UK Biobank Caucasian subjects. Secondly, these biomarkers were leveraged using Mendelian Randomization (MR) analyses from several genome-wide association studies (UK Biobank, Fenland, eQTLGen and GTEx) to select predictors potentially causally related to BP and ASI. Kaplan-Meier curves and Cox regressions were used to prioritize the proteins associated with both incident hypertension and cardiovascular death. Finally, we compared the aortic expression of the analytes between Angiotensin II-infused and control mice using RNA-Seq data. Results We identified 25, 15 and 55 proteins as top predictors of ASI, SBP and DBP, respectively. Among these proteins, MR showed a potential causal relationship of GDF15 and ANGPT2 with ASI and a potential causal relationship of TNFRSF13C, NCAN, NADK, ANGPT2, MXRA8, ICAM4, VWC2, CXCL16 with SBP or DBP. Only 3 of these proteins were associated with both incident hypertension [GDF15 (HR=1.27, p<0.001), ANGPT2 (HR=1.09, p=0.009), VWC2 (HR=1.08, p=0.021)] and cardiovascular death [GDF15 (HR=1.62, p<0.001), ANGPT2 (HR=1.32, p<0.001), VWC2 (HR=1.26, p<0.001)]. Only GDF15 (p=0.011) and ANGPT2 (p<0.001) aortic expression in the media and adventitia, respectively, were increased in Ang II-infused mice. Conclusions Among 2,923 UK Biobank proteins, we identified 2 predictors of ASI or BP which are also potentially causally related with these indices. These proteins’ expression is increased in the aorta of hypertensive mice. Moreover, these analytes are also associated with an increased risk of developing hypertension and dying due to cardiovascular causes. Mechanistic studies are needed to elucidate the role of these proteins in arterial stiffness and hypertension.