Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations

ABSTRACT

OBJECTIVE: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C240 and C220) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C220 and C240 concentrations.METHODS: Heritability and genome-wide association studies of plasma C240 and C220 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.RESULTS: The multivariable-adjusted heritability for C220 and C240 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C220 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C220 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C240 ceramide concentrations. All 9 were also significantly related to plasma C220 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C240 ceramide concentrations (p=9.94E-09).CONCLUSION: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C220 and C240 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C240 and C220 ceramide modulation.