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High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies

journal contribution
posted on 12.11.2020, 00:58 by Habtamu B Beyene, Gavriel Olshansky, Adam Alexander T Smith, Corey Giles, Kevin Huynh, Michelle Cinel, Natalie A Mellett, Gemma Cadby, Joseph Hung, Jennie Hui, John Beilby, Gerald F Watts, Jonathan Shaw, Eric K Moses, Dianna J Magliano, Peter J Meikle
Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.

Funding

This research was supported by the National Health and Medical Research Council of Australia (Project grant APP1101320). This work was also supported in part by the Victorian Government's Operational Infrastructure Support Program. JSS and DJM are supported by Senior Research Fellowships from the National Health and Medical Research Council of Australia. HBB was supported by the Baker institute and Monash University Scholarships. The 1994/95 Busselton health survey was supported by a grant from the Health Promotion Foundation of Western Australia, and the authors acknowledge the generous support for the 1994/1995 Busselton Health Study follow-up from Western Australia and the Great Wine Estates of the Margaret River region of Western Australia. Support from the Royal Perth Hospital Medical Research Foundation is also gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

National Health and Medical Research Council of Australia | APP1101320

Victorian Government's Operational Infrastructure Support Program

Baker institute Scholarship

Monash University Scholarship

Health Promotion Foundation of Western Australia

Western Australia

Great Wine Estates of the Margaret River region of Western Australia

Royal Perth Hospital Medical Research Foundation

History

Publication Date

28/09/2020

Journal

PLoS Biology

Volume

18

Issue

9

Article Number

e3000870

Pagination

37p.

Publisher

Public Library of Science

ISSN

1544-9173

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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