Observational and two-sample Mendelian randomization support a bidirectional relation between red blood cell traits and diastolic blood pressure

Introduction: Previous studies have found associations of red blood cell traits (hemoglobin and red blood cell count, RBC) with blood pressure; whether these associations are causal is unknown. We aimed to evaluate causal effects of the two traits on systolic (SBP) and diastolic blood pressure (DBP) by employing complementary observational and Mendelian randomization (MR) analyses.
Methods: Observational cross-sectional analyses were conducted by using multivariable logistic (for hypertension) and robust linear regression (for SBP and DBP) in the population-based Lifelines Cohort Study (n=167,729). Additionally, we performed bidirectional two sample MR analyses to explore the causal effect of the two exposure traits on SBP and DBP and vice versa, using genetic instrumental variables related to hemoglobin and RBC identified in UK Biobank (n=350,475) and International Consortium of Blood Pressure studies for SBP and DBP (n= 757,601). Effect estimates were transformed to represent standard deviations higher outcome per one-standard deviation higher exposure.
Results: In cross-sectional analyses we observed positive associations with blood pressure for both hemoglobin (OR=1.18, 95% CI: 1.16 to 1.20 for hypertension; B=0.11, 95% CI: 0.11 to 0.12 for SBP; B=0.11, 95% CI: 0.10 to 0.11 for DBP) and RBC (OR=1.14, 95% CI: 1.12 to 1.16 for hypertension; B=0.11, 95% CI: 0.10 to 0.12 for SBP; B=0.08, 95% CI: 0.08 to 0.09 for DBP). MR analyses suggested that higher hemoglobin and RBC cause higher DBP (inverse variance weighted [IVW] B=0.11, 95% CI: 0.07 to 0.16 for hemoglobin; B=0.07, 95% CI: 0.04 to 0.10 for RBC). Reverse MR analyses suggested causal effects of DBP on both hemoglobin (B=0.06, 95% CI: 0.03 to 0.09) and RBC (B=0.08, 95% CI: 0.04 to 0.11). No effects on SBP were found. 
Conclusion: Our results suggest bidirectional causal relationships of hemoglobin and RBC with DBP, but not with SBP.