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

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.