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A Linear and Non-Linear Mendelian Randomization Analysis of the Association Between Diastolic Blood Pressure and Cardiovascular Events: The J Curve Revisited.

Background: Recent clinical guidelines support intensive blood pressure (BP) treatment targets. However, observational data suggest that excessive diastolic BP (DBP) lowering might increase the risk of myocardial infarction (MI); reflecting a J- or U-shaped relationship. Methods: We analyzed 47,407 participants from 5 cohorts (median age 60 years). First, to corroborate prior observational analyses, we used traditional statistical methods to test the shape of association between DBP and CVD. Second, we created polygenic risk scores (PRS) of DBP and SBP and generated linear Mendelian randomization (MR) estimates for the effect of DBP on CVD. Third, using novel non-linear MR approaches, we evaluated for non-linearity in the genetic relationship between DBP and CVD. Comprehensive MR interrogation of DBP required us to also model SBP, given the two are strongly correlated. Results: Traditional observational analysis of our cohorts suggested a J-shaped association between DBP and MI. By contrast, linear MR analyses demonstrated an adverse effect of increasing DBP increments on CVD outcomes, including MI (MI Hazard ratio = 1.07 per unit mmHg increase in DBP, p<0.001). Furthermore, non-linear MR analyses found no evidence for a J-shaped relationship, instead confirming that MI risk decreases consistently per unit decrease in DBP, even among individuals with low values of baseline DBP. Conclusions: In this analysis of the genetic effect of DBP, we found no evidence for a non-linear J- or U-shaped relationship between DBP and adverse CVD outcomes; including MI.