Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans

Background Large‐artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large‐artery stiffness in humans remains incompletely understood. Methods and Results We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants. Analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Interaction analyses assessed the effect modification by sex on these relationships. We evaluated causal associations between plasma protein levels and PP, using inverse variance–weighted Mendelian randomization as the main analysis and Bayesian colocalization as a sensitivity analysis. A 5% false discovery rate threshold was used to account for multiple comparisons. Measured levels of 871 proteins were significantly associated with PP when adjusting for age, sex, mean arterial pressure, and body mass index, and 61 remained significantly associated after further adjusting for stroke volume. Top associations included NPPB (natriuretic peptide B), thrombospondin‐2, paraoxonase‐2, and sclerostin. Genetic analyses indicated that genetically predicted levels for 16 proteins were significantly associated with PP after false discovery rate correction, including fibroblast growth factor 5 (β IVW per SD change in protein levels=0.47 [95% CI, 0.34–0.61]), NPPB (β IVW =−1.40 [95% CI, −1.85 to −0.95]), insulin‐like growth factor binding 3 (β IVW =−1.143 [95% CI, −1.57 to −0.71]), and furin (β IVW , 1.31 [95% CI, 0.88–1.73]). Conclusions Using complementary epidemiological approaches to triangulate findings, our study identifies novel proteins with a putative causal effect on PP. Notably, our findings identify NPPB with high statistical confidence. This may have potentially impactful implications given the current availability of Food and Drug Administration–approved medications to boost NPPB effects.