Guo-Chong Chen1, Jin Choul Chai1, Bing Yu2, Gregory A Michelotti3, Megan L Grove2, Amanda M Fretts4, Martha L Daviglus5, Olga L Garcia-Bedoya5,6, Bharat Thyagarajan7, Neil Schneiderman8, Jianwen Cai9, Robert C Kaplan1,10, Eric Boerwinkle2,11, Qibin Qi1,12. 1. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA. 2. Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. 3. Metabolon, Inc., Durham, NC, USA. 4. Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington School of Public Health, Seattle, WA, USA. 5. Institute for Minority Health Research, University of Illinois at Chicago, IL, USA. 6. Department of Medicine, University of Illinois at Chicago, IL, USA. 7. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 8. Health Division, Department of Psychology, University of Miami, Coral Gables, FL, USA. 9. Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 10. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 11. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. 12. Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.
Abstract
BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies. OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort. METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores. RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031). CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.
BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies. OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort. METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores. RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031). CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.
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