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Through transcriptomic analysis, we examined samples from two randomized controlled trials: PREDIMED and PREDIMED\u2010Plus, with 151 and 89 elderly adults, respectively. Blood cells were isolated at baseline and after a 12\u2010month intervention. In the PREDIMED trial, participants followed different Mediterranean diets: one supplemented with extra\u2010virgin olive oil (traditional Mediterranean diet enriched with extra\u2010virgin olive oil [MedDiet\u2010EVOO]), another with nuts (MedDiet enriched with nuts MedDiet\u2010Nuts [MedDiet\u2010Nuts]), and a low\u2010fat control diet. The PREDIMED\u2010Plus trial compared an energy\u2010reduced Mediterranean diet (Er\u2010MedDiet) with physical activity to an ad libitum Mediterranean diet. Over time, mild but significant upregulation of genes like ATP binding cassette subfamily A member 1 (<jats:italic>ABCA1<\/jats:italic>), retinoid X receptor alpha (<jats:italic>RXRA<\/jats:italic>), retinoid X receptor beta (<jats:italic>RXRB<\/jats:italic>), and <jats:italic>Nuclear Receptor Subfamily 1 Group H Member 3 (NR1H3)<\/jats:italic> was observed in response to MedDiet\u2010EVOO, MedDiet\u2010Nuts, and Er\u2010MedDiet. Notably, <jats:italic>RXRA<\/jats:italic> expression was higher in both MedDiet\u2010EVOO and MedDiet\u2010Nuts compared to the control diet. Differences in gene expression, particularly <jats:italic>RXRA<\/jats:italic>, ATP binding cassette subfamily G member 1 (<jats:italic>ABCG1<\/jats:italic>), <jats:italic>NR1H3<\/jats:italic>, and <jats:italic>Peroxisome Proliferator Activated Receptor Delta (PPARD)<\/jats:italic>, were evident between MedDiet\u2010Nuts and the control diet. In the PREDIMED\u2010Plus trial, no significant differences in gene expression were found between dietary groups. Principal component analysis (PCA) and linear discriminant analysis (LDA) showed overlapping gene expression profiles across different Mediterranean diet interventions. In conclusion, our study highlights the cardiovascular health benefits of long\u2010term adherence to a Mediterranean diet, both normocaloric and hypocaloric, primarily reflected by mild upregulation of cholesterol efflux\u2010related genes\u2014specifically involving <jats:italic>RXRA<\/jats:italic>, <jats:italic>RXRB<\/jats:italic>, <jats:italic>ABCA1<\/jats:italic>, <jats:italic>ABCG1<\/jats:italic>, <jats:italic>Nuclear Receptor Subfamily 1 Group H Member 2(NR1H2)<\/jats:italic>, and <jats:italic>PPARD<\/jats:italic>\u2014among elderly adults at high cardiovascular risk. This suggests a potential mechanism by which these diets may exert cardiovascular protective effects.<\/jats:p>","DOI":"10.1002\/mnfr.70050","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T07:33:24Z","timestamp":1747812804000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mediterranean Diet Modulates Gene Expression of Cholesterol Efflux Receptors in High\u2010Risk Cardiovascular Patients"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6777-1649","authenticated-orcid":false,"given":"Javier","family":"Hernando\u2010Redondo","sequence":"first","affiliation":[{"name":"Consorcio CIBER, Pathophysiology of Obesity and Nutrition (CIBERobn) Instituto de Salud Carlos III  Madrid Spain"},{"name":"Unit of Cardiovascular Risk and Nutrition Hospital del Mar Medical Research Institute  Barcelona Spain"},{"name":"Ph.D. Program in Food Science and 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