UMMS Affiliation

Department of Ophthalmology and Visual Sciences

Publication Date


Document Type



Cardiology | Cardiovascular Diseases | Dietetics and Clinical Nutrition



Biological mechanisms underlying the association of a healthy diet with chronic diseases remain unclear. Targeted proteomics may facilitate the understanding of mechanisms linking diet to chronic diseases.

Methods and Results

We examined 6360 participants (mean age 50 years; 54% women) in the Framingham Heart Study. The associations between diet and 71 cardiovascular disease (CVD)-related proteins were examined using 3 diet quality scores: the Alternate Healthy Eating Index, the modified Mediterranean-style Diet Score, and the modified Dietary Approaches to Stop Hypertension diet score. A mediation analysis was conducted to examine which proteins mediated the associations of diet with incident CVD and all-cause mortality. Thirty of the 71 proteins were associated with at least 1 diet quality score (P < 0.0007) after adjustment for multiple covariates in all study participants and confirmed by an internal validation analysis. Gene ontology analysis identified inflammation-related pathways such as regulation of cell killing and neuroinflammatory response (Bonferroni corrected P < 0.05). During a median follow-up of 13 years, we documented 512 deaths and 488 incident CVD events. Higher diet quality scores were associated with lower risk of CVD (P < /=0.03) and mortality (P < /=0.004). After adjusting for multiple potential confounders, 4 proteins (B2M [beta-2-microglobulin], GDF15 [growth differentiation factor 15], sICAM1 [soluble intercellular adhesion molecule 1], and UCMGP [uncarboxylated matrix Gla-protein]) mediated the association between at least 1 diet quality score and all-cause mortality (median proportion of mediation ranged from 8.6% to 25.9%). We also observed that GDF15 mediated the association of the Alternate Healthy Eating Index with CVD (median proportion of mediation: 8.6%).


Diet quality is associated with new-onset CVD and mortality and with circulating CVD-related proteins. Several proteins appear to mediate the association of diet with these outcomes.


cardiovascular disease, diet quality, mediator, mortality, proteomics

Rights and Permissions

Copyright © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

DOI of Published Version



Kim Y, Lu S, Ho JE, Hwang SJ, Yao C, Huan T, Levy D, Ma J. Proteins as Mediators of the Association Between Diet Quality and Incident Cardiovascular Disease and All-Cause Mortality: The Framingham Heart Study. J Am Heart Assoc. 2021 Sep 21;10(18):e021245. doi: 10.1161/JAHA.121.021245. Epub 2021 Sep 6. PMID: 34482708; PMCID: PMC8649513. Link to article on publisher's site

Journal/Book/Conference Title

Journal of the American Heart Association

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Link to Article in PubMed

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.