Lipidomics Profiling and Risk for Cardiovascular Disease: A Longitudinal Study in American Indians

Background: Dyslipidemia is an established risk factor for CVD. Standard lipid panel lacks description of the full spectrum of blood lipids. A longitudinal profiling of blood lipidome in relation to the risk of CVD is lacking in any racial/ethnic groups. Objective: Identify novel lipid species associated with risk of CVD in American Indians, independent of traditional risk factors (TRFs). Method: Using untargeted LC-MS, we repeatedly measured 1,542 lipid species in 3,916 fasting plasma samples from 1,958 participants who attended two exams (~5.5 years apart) and were followed up to 18 years in the Strong Heart Study. Elastic net was used to select baseline lipids and change in lipids (baseline to 5-year follow-up) associated with 18-year risk of CVD. Multivariate and network analyses were conducted to identify discriminatory lipidomic signatures and differential lipid networks associated with risk of CVD. Results: Of 1,911 participants free of CVD at both baseline (2001-2003) and 5-year follow-up (2006-2009), 222 developed CVD after 18 years of follow-up. High-resolution LC-MS detected 1,542 lipid species (518 known). After adjusting for TRFs (age, sex, center, smoking, BMI, hypertension, diabetes, LDL-c, and albuminuria), elevated baseline levels of 21 known lipids, including cholesterol esters, sphingolipids, glycerophospholipids, and fatty acids, were significantly associated with increased (HR: 1.08 to 1.26) or decreased (HR: 0.81 to 0.91) risk of CVD. Longitudinal change in 13 lipids, including cholesterol esters, sphingolipids, glycerophospholipids, and fatty acids, were either positively (HR: 1.03 to 1.28) or inversely (HR: 0.75 to 0.92) associated with risk of CVD at 18-year follow-up. A lipid score comprising 10 baseline lipids significantly improved risk prediction beyond TRFs (ROC increases from 0.823 to 0.837, P = 0.009). Multivariate and network analyses identified distinct lipidomic signatures and lipid networks associated with risk of CVD. Conclusion: Novel molecular lipids significantly predict risk of CVD beyond TRFs in American Indians. Our findings provide novel lipid molecules for risk stratification and shed light on the mechanism linking lipid dysregulation to CVD in American Indians.