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Longitudinal lipidomic signatures of all-cause and CVD mortality in American Indians: findings from the Strong Heart Study

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Abstract

Dyslipidemia is an independent and modifiable risk factor for aging and age-related disorders. Routine lipid panel cannot capture all individual lipid species in blood (i.e., blood lipidome). To date, a comprehensive assessment of the blood lipidome associated with mortality is lacking in large-scale community-dwelling individuals, especially in a longitudinal setting. Using liquid chromatograph-mass spectrometry, we repeatedly measured individual lipid species in 3,821 plasma samples collected at two visits (~ 5.5 years apart) from 1,930 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with risks for all-cause mortality and CVD mortality (mean follow-up period: 17.8 years) in American Indians, followed by replication of top hits in European Caucasians in the Malmö Diet and Cancer-Cardiovascular Cohort (n = 3,943, mean follow-up period: 23.7 years). The model adjusted age, sex, BMI, smoking, hypertension, diabetes, and LDL-c at baseline. We then examined the associations between changes in lipid species and risk of mortality. Multiple testing was controlled by false discovery rate (FDR). We found that baseline levels and longitudinal changes of multiple lipid species, e.g., cholesterol esters, glycerophospholipids, sphingomyelins, and triacylglycerols, were significantly associated with risks of all-cause or CVD mortality. Many lipids identified in American Indians could be replicated in European Caucasians. Network analysis identified differential lipid networks associated with risk of mortality. Our findings provide novel insight into the role of dyslipidemia in disease mortality and offer potential biomarkers for early prediction and risk reduction in American Indians and other ethnic groups.

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Data availability

The phenotype data used in the Strong Heart Family Study can be requested through the Strong Heart Study (https://strongheartstudy.org/). The lipidomic data in the SHS can be obtained from the corresponding author upon a reasonable request. Clinical and lipidomic data used in the Malmö Diet and Cancer-Cardiovascular Cohort can be requested through the MDC Steering Committee (https://www.malmo-kohorter.lu.se/malmo-cohorts).

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Acknowledgements

We thank the Strong Heart Study (SHS) participants, the Indian Health Service facilities, and the participating tribal communities for their extraordinary cooperation and involvement, which has contributed to the success of the SHS. The content expressed in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Indian Health Service (IHS).

Funding

This study was supported by the National Institute of Health (NIH) grant R01DK107532-01A1 (JZ). The Strong Heart Study (SHS) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030. The study was previously supported by research grants: R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and by cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, 2004 Mowry Rd, Gainesville, FL, 32610, USA

    Guanhong Miao & Jinying Zhao

  2. Center for Genetic Epidemiology and Bioinformatics, University of Florida, Gainesville, FL, USA

    Guanhong Miao & Jinying Zhao

  3. West Coast Metabolomics Center, University of California-Davis, Davis, CA, USA

    Oliver Fiehn

  4. Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Kimberly M. Malloy, Ying Zhang & Elisa T. Lee

  5. MedStar Health Research Institute, Hyattsville, MD, USA

    Barbara V. Howard

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  1. Guanhong Miao
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  2. Oliver Fiehn
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  3. Kimberly M. Malloy
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  4. Ying Zhang
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  5. Elisa T. Lee
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  6. Barbara V. Howard
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  7. Jinying Zhao
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Contributions

JZ and OF conceptualized and designed the study, obtained the funding and generated the data. GM conducted the statistical analyses. JZ and GM drafted the manuscript. All coauthors provided critical review of the manuscript and contributed to data interpretation.

Corresponding author

Correspondence to Jinying Zhao.

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The Strong Heart Family Study (SHFS) protocols were approved by the Institutional Review Boards of participating institutions and the American Indian tribes. The Malmö Diet and Cancer-Cardiovascular Cohort (MDC-CC) was approved by the Ethics Committee at Lund University.

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The authors declare no conflicts of interest.

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Miao, G., Fiehn, O., Malloy, K.M. et al. Longitudinal lipidomic signatures of all-cause and CVD mortality in American Indians: findings from the Strong Heart Study. GeroScience 45, 2669–2687 (2023). https://doi.org/10.1007/s11357-023-00793-7

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