Effect of Relative Protein Intake on Hypertension and Mediating Role of Physical Fitness and Circulating Fatty Acids: A Mendelian Randomization Study.

OBJECTIVE:To investigate the causal effect of protein intake on hypertension and the related mediating pathways. PATIENTS AND METHODS:Using genome-wide association study summary statistics of European ancestry, we applied univariable and multivariable Mendelian randomization to estimate the bidirectional associations of relative protein intake and related metabolomic signatures with hypertension (FinnGen: Ncase=42,857/Ncontrol=162,837; UK Biobank: Ncase=77,723/Ncontrol=330,366) and blood pressure (International Consortium of Blood Pressure: N=757,601) and two-step Mendelian randomization to assess the mediating roles of 40 cardiometabolic factors therein. Mendelian randomization estimates of hypertension from FinnGen and UK Biobank were meta-analyzed without heterogeneity. We performed the study from May 15, 2023, to September 15, 2023. RESULTS:Each 1-SD higher relative protein intake was causally associated with 69% (odds ratio, 0.31; 95% CI, 0.11 to 0.89) lower hypertension risk independent of the effects of other macronutrients, and was the only macronutrient associated with 2.21 (95% CI, 0.52 to 3.91) mm Hg lower pulse pressure, in a unidirectional manner. Higher plant protein-related metabolomic signature (glycine) was associated with lower hypertension risk and pulse pressure, whereas higher animal protein-related metabolomic signatures (leucine, isoleucine, valine, and isovalerylcarnitine [only systolic blood pressure]) were associated with higher hypertension risk, pulse pressure, and systolic blood pressure. The effect of relative protein intake on hypertension was causally mediated by frailty index (mediation proportion, 40.28%), monounsaturated fatty acids (13.81%), saturated fatty acids (11.39%), grip strength (5.34%), standing height (3.99%), and sitting height (3.61%). CONCLUSION:Higher relative protein intake causally reduces the risk of hypertension, partly mediated by physical fitness and circulating fatty acids.