Identification of protein biomarkers of the dietary approaches to stop hypertension diet in randomized feeding studies and validation in an observational study

Authors: KIM, HYUNJU - Johns Hopkins University; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GANZ, PETER - University Of California San Francisco (UCSF); DU, SHUTONG - Johns Hopkins University; TANG, OLIVE - Johns Hopkins University; YU, BING - University Of Texas Health Science Center; CHATTERJEE, NILANJAN - Johns Hopkins University; APPEL, LAWRENCE - Johns Hopkins University; CORESH, JOSEF - Johns Hopkins University; REBHOLZ, CASEY - Johns Hopkins University

Submitted to: Journal of the American Heart Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/20/2023
Publication Date: 4/1/2023
Citation: Kim, H., Lichtenstein, A.H., Ganz, P., Du, S., Tang, O., Yu, B., Chatterjee, N., Appel, L.J., Coresh, J., Rebholz, C.M. 2023. Identification of protein biomarkers of the dietary approaches to stop hypertension diet in randomized feeding studies and validation in an observational study. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.122.028821.
DOI: https://doi.org/10.1161/JAHA.122.028821

Interpretive Summary: The Dietary Approaches to Stop Hypertension (DASH) diet is recommended for heart disease risk reduction. Assessment of adherence to the DASH diet relies on self-reported data. Identification of objective biomarkers of the DASH diet would provide a more accurate diet assessment method, This in turn would facilitate a better understanding of dietary modifications, in this case the DASH diet, and heart disease risk reduction. To this end our aim was to identify blood protein biomarkers of the DASH dietary pattern. To accomplish this we used serum samples from two large feeding trials to measure protein metabolites (small molecules) and compare the findings during periods when they consumed the control and experimental diets. To validate the findings we then used plasma samples from a large observational study for which dietary data was collected. Seventy-one proteins were identified that were different between periods when participants consumed the control vs DASH or DASH-Na diets. Of those, 19 were also identified in the validation study. These findings indicate that blood protein metabolites may serve as objective biomarkers of dietary patterns, in this case the DASH diets.

Technical Abstract: Background: The Dietary Approaches to Stop Hypertension (DASH) diet is recommended for CVD prevention. Assessment of adherence to the DASH diet relies on self-reported data. Objective biomarkers of the DASH diet can improve existing diet assessment and improve our understanding of the mechanisms underlying diet and CVD risk. Objectives: We aimed to identify protein biomarkers of the DASH dietary pattern in using data from two randomized feeding studies and validate them in a large observational study, the Atherosclerosis Risk in Communities (ARIC) study. Methods: Large-scale proteomic profiling was conducted in serum specimens (SomaLogic) collected at the end of 8-week and 4-week DASH diet interventions in multi-center, randomized controlled feeding studies of the DASH trial (N=215) and the DASH-sodium trial (N=396), respectively. We used multivariable linear regression models were used to compare the relative abundance of 7,240 proteins between the DASH diet and between the control diet interventions. Estimates were meta-analyzed across the feeding studies. Then, in the ARIC study (N=10,490), we used multivariable linear regression models to investigate the associations between the DASH diet score and significant proteins. We calculated C-statistics to examine whether the validated proteins improved the prediction of the DASH vs. control diet interventions in the feeding studies, and those in the highest vs. lowest 3 quartiles of the DASH diet score in the ARIC study, beyond participant characteristics. Results: At a false discovery rate <0.05, 43 proteins were significantly different between the DASH diet and control diet in the DASH and the DASH-Sodium trials. Of the 43 proteins, 14 proteins were validated in the ARIC Study. Some of these 14 proteins were related to dietary intake (retinol-binding protein 4, folate receptor beta), inflammation (hepatocyte growth factor receptor, neutral ceramidase, and N-acetylmuramoyl-L-alanine amidase), and collagen deposition (collagen triple helix repeat-containing protein 1, lymphatic vessel endothelial hyaluronic acid receptor 1, and procollagen C-endopeptidase enhancer 1). Addition of the 14 proteins significantly improved the prediction of the DASH diet in the feeding studies (range of difference in C-statistics=0.242-0.248, P-values <0.001 for both tests) and the ARIC study (difference in C-statistics=0.014, P-value<0.001). Conclusions: We identified 14 proteins robustly associated with the DASH diet in 3 studies, which may serve as biomarkers of the DASH diet, and suggest the potential pathways that are associated with the DASH diet.