Circulating Sphingolipids and All‐Cause Mortality: The Strong Heart Family Study

Abstract

Background A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population. Methods and Results The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long‐chain (ie, 16:0) and very‐long‐chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001–2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4‐year follow‐up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44–1.96) for ceramide‐16 (Cer‐16), 0.82 (95% CI, 0.71–0.95) for Cer‐20, 0.60 (95% CI, 0.51–0.70) for Cer‐22, 0.67 (95% CI, 0.56–0.79) for Cer‐24, 1.80 (95% CI–1.57, 2.05) for sphingomyelin‐16 (SM‐16), 0.54 (95% CI, 0.47–0.62) for SM‐20, 0.50 (95% CI, 0.44–0.57) for SM‐22, and 0.59 (95% CI, 0.52–0.67) for SM‐24. Conclusions The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base. Registration URL: https://www.clinicatrials.gov ; Unique identifier: NCT00005134.