title: Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis.
abstract: Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs. Mouse studies have revealed that ACSL1 channels acyl-CoAs to β-oxidation, thereby reducing glucose utilization, and is required for diabetes-accelerated atherosclerosis. The role of ACSL1 in humans is unknown. We therefore examined common variants in the human ACSL1 locus by genetic association studies for fasting glucose, diabetes status, and preclinical atherosclerosis by using the MAGIC and DIAGRAM consortia; followed by analyses in participants from the Multi-Ethnic Study of Atherosclerosis, the Penn-T2D consortium, and a meta-analysis of subclinical atherosclerosis in African Americans; and finally, expression quantitative trait locus analysis and identification of DNase I hypersensitive sites (DHS). The results show that three SNPs in ACSL1 (rs7681334, rs735949, and rs4862423) are associated with fasting glucose or diabetes status in these large (>200,000 subjects) data sets. Furthermore, rs4862423 is associated with subclinical atherosclerosis and coincides with a DHS highly accessible in human heart. SNP rs735949 is in strong linkage disequilibrium with rs745805, significantly associated with ACSL1 levels in skin, suggesting tissue-specific regulatory mechanisms. This study provides evidence in humans of ACSL1 SNPs associated with fasting glucose, diabetes, and subclinical atherosclerosis and suggests links among these traits and acyl-CoA synthesis.
authors.affiliation: Center for Public Health Genomics University of Virginia, Charlottesville, VA Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.affiliation: Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Xin-Qun
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wojczynski
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Siebenthall
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.affiliation: Department of Medicine UW Diabetes Institute, University of Washington, Seattle, WA Center for Non-Communicable Diseases, Karachi, Pakistan.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Center for Public Health Genomics University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Medicine UW Diabetes Institute, University of Washington, Seattle, WA Center for Non-Communicable Diseases, Karachi, Pakistan bornf@u.washington.edu.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
mesh_terms: D001741:Black or African American / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D002114:Calcinosis / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D003066:Coenzyme A Ligases / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting / Q000097:blood*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics
chemical_list: D001786:Blood Glucose; D002843:Chromatin; D003066:Coenzyme A Ligases; C583414:ACSL1 protein, human
keywords: endocrine disorders; fatty acid; fatty acid/metabolism; genetics; genomics