{"doi":"10.12997/jla.2020.9.1.172","title":"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 (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations. Methods: Heritability and genome-wide association studies of plasma C24:0 and C22:0 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 C22:0 and C24:0 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 C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2. 83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 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 C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.","journal":"Journal of Lipid and Atherosclerosis","year":2020,"id":64355,"datarank":0.5333022092234121,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.0,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":340222,"name":"Ruibo Zhang","orcid":"0009-0003-6286-5798","position":1,"is_corresponding":false},{"id":275021,"name":"Qiong Yang","orcid":"0000-0002-3658-1375","position":2,"is_corresponding":false},{"id":340223,"name":"Meredith S. Duncan","orcid":"0000-0001-6922-8503","position":3,"is_corresponding":false},{"id":337722,"name":"Vanessa Xanthakis","orcid":"0000-0002-7352-621X","position":4,"is_corresponding":false},{"id":308930,"name":"Xuntian Jiang","orcid":"0000-0001-9048-7294","position":5,"is_corresponding":false},{"id":24661,"name":"Ramachandran S. Vasan","orcid":"0000-0001-7357-5970","position":6,"is_corresponding":false},{"id":340224,"name":"Jean E. Schaffer","orcid":"0000-0002-4954-6659","position":7,"is_corresponding":false},{"id":340225,"name":"Linda R. Peterson","orcid":"0000-0001-8766-4552","position":8,"is_corresponding":false},{"id":340221,"name":"Sharon Cresci","orcid":"0000-0002-5417-1054","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:12:32.635050Z","pmid":"32489964","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}