(OR06-03-26) Plasma Proteins Shed Light on Causal Mechanisms by Which the Dietary Approaches to Stop Hypertension (DASH) Diet Reduces Blood Pressure

Objectives: The Dietary Approaches to Stop Hypertension (DASH) diet reduced systolic blood pressure (SBP) in two randomized, controlled, feeding studies. However, causal mechanisms by which the DASH diet reduces SBP are unclear, and challenges remain in determining whether short-term dietary interventions prevent long-term cardiovascular outcomes, such as coronary artery disease (CAD) or type 2 diabetes (T2D). We leverage plasma proteomics and human genetic analyses to identify potential causal protein biomarkers and estimate their effects on SBP and incident CAD and T2D.

Methods: We previously identified 71 circulating proteins, assessed with aptamers (SomaScan) that altered after 8-week feeding of the DASH diet in the DASH (n=215) and 4-week feeding of the DASH diet in the DASH-Sodium (n=396) trials, after correcting for multiple comparisons (false discovery rate < 0.05). We evaluated 71 significant proteins in a series of two-sample bidirectional Mendelian randomization (MR) analyses. Potential instrumental variables were independent cis-pQTLs (± 1MB transcription start site) with p < 5.0 x 10^-8, and LD-clumped at r² < 0.001 to obtain independent variants. The summary data for SBP, CAD, and T2D were obtained from large European ancestry meta-analyses GWAS.

Results: Of the 71 proteins perturbed by the DASH diet, 42 could be instrumented with cis-pQTLs, and MR analyses found that 3 had causal effects on SBP. Genetically-determined lower levels of INHBC and higher levels of PLXNB2 were causally associated with reductions in SBP, directionally concordant with the protein perturbations and main effects of the DASH diet. These directionally specific effects of INHBC, and PLXNB2 were also causally associated with lower risk of incident CAD, and T2D, respectively. Genetically-determined higher levels of one protein (MET), higher in those who consumed the DASH vs. control diets, was associated with elevations in SBP.

Conclusions: From dozens of diet-responsive proteins, we identified two that had beneficial effects on SBP. This allowed us to triangulate potential long-term effects of these causal protein biomarkers on T2D and CAD, leveraging the powerful randomized design of the DASH trials and human genetics. These proteins represent mediators through which the DASH diet reduces SBP.

Funding Sources: NIH