{"doi":"10.1210/clinem/dgab155","title":"Characterizing a Common CERS2 Polymorphism in a Mouse Model of Metabolic Disease and in Subjects from the Utah CAD Study","abstract":"CONTEXT: Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP; rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. OBJECTIVE: The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. DESIGN: We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles. RESULTS: In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count. CONCLUSIONS: The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2021,"id":179269,"datarank":0.6976844965588987,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.2560186496839326,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.2560186496839326,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":16,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.13876148.v1"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":355669,"name":"Annelise M. Poss","orcid":"0000-0002-4008-9711","position":1,"is_corresponding":false},{"id":251369,"name":"J. Alan Maschek","orcid":"0000-0003-3217-2299","position":2,"is_corresponding":false},{"id":232411,"name":"James E. Cox","orcid":"0000-0002-5977-2350","position":3,"is_corresponding":false},{"id":479066,"name":"Paul N. Hopkins","orcid":"0000-0002-9118-0427","position":4,"is_corresponding":false},{"id":402603,"name":"Steven C. Hunt","orcid":"0000-0001-8235-2170","position":5,"is_corresponding":false},{"id":271648,"name":"Mary C. Playdon","orcid":"0000-0001-6082-0447","position":6,"is_corresponding":false},{"id":232413,"name":"William L. Holland","orcid":"0000-0001-9950-1435","position":7,"is_corresponding":false},{"id":232983,"name":"Scott A. Summers","orcid":"0000-0002-4919-0592","position":8,"is_corresponding":false},{"id":666235,"name":"Rebekah J. Nicholson","orcid":"0000-0001-8929-3580","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:47:44.875897Z","pmid":"33705551","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":[]}