Development and validation of a plasmalogen score as an independent modifiable marker of metabolic health: population based observational studies and a placebo-controlled cross-over studyResearch in context
Habtamu B. Beyene,
Kevin Huynh,
Tingting Wang,
Sudip Paul,
Michelle Cinel,
Natalie A. Mellett,
Gavriel Olshansky,
Thomas G. Meikle,
Gerald F. Watts,
Joseph Hung,
Jennie Hui,
John Beilby,
John Blangero,
Eric K. Moses,
Jonathan E. Shaw,
Dianna J. Magliano,
Corey Giles,
Peter J. Meikle
Affiliations
Habtamu B. Beyene
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia
Kevin Huynh
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia; Baker Department of Cardiometabolic Health, Melbourne University, Melbourne, VIC, Australia
Tingting Wang
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia; Baker Department of Cardiometabolic Health, Melbourne University, Melbourne, VIC, Australia
Sudip Paul
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
Michelle Cinel
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Natalie A. Mellett
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Gavriel Olshansky
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Thomas G. Meikle
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia
Gerald F. Watts
Medical School, University of Western Australia, Perth, WA, Australia; Cardiometabolic Service, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA, Australia
Joseph Hung
Medical School, University of Western Australia, Perth, WA, Australia
Jennie Hui
PathWest Laboratory Medicine of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia; School of Population and Global Health, University of Western Australia, Crawley, WA, Australia
John Beilby
School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
John Blangero
South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley, Brownsville, TX, USA
Eric K. Moses
School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
Jonathan E. Shaw
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
Dianna J. Magliano
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
Corey Giles
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia; Baker Department of Cardiometabolic Health, Melbourne University, Melbourne, VIC, Australia; Corresponding author. Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia.
Peter J. Meikle
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC, Australia; Baker Department of Cardiometabolic Health, Melbourne University, Melbourne, VIC, Australia; Corresponding authors. Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia.
Summary: Background: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle. Methods: We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men). We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years). Findings: In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21–0.43), 0.39 (95% CI 0.25–0.61) and 0.42 (95% CI 0.30–0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively, and a 34% lower mortality risk (HR = 0.66; 95% CI 0.56–0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score. Interpretation: The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimise the practical implementation of the Pls Score in clinical and population settings. Funding: National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).
