title: Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1.
abstract: Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby HKDC1 gene. We further find that experimentally reducing or increasing HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational glucose regulation in which the effects of genetic variants in multiple regulatory elements alter glucose homeostasis by coordinately reducing expression of the novel hexokinase HKDC1.
authors: 1] Duke University Program in Genetics &Genomics, Durham, North Carolina 27708, USA [2] Center for Genomic &Computational Biology, Duke University School of Medicine, Durham, North Carolina 27708, USA.
authors: Cong
authors: C
authors: Guo
authors: Division of Endocrinology, Metabolism &Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Anton E
authors: AE
authors: Ludvik
authors: Sarah W. Stedman Nutrition &Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors: Michelle E
authors: ME
authors: Arlotto
authors: Division of Endocrinology, Metabolism &Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: M Geoffrey
authors: MG
authors: Hayes
authors: Division of Endocrinology, Metabolism &Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Loren L
authors: LL
authors: Armstrong
authors: Department of Preventive Medicine, Division of Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Denise M
authors: DM
authors: Scholtens
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Christopher D
authors: CD
authors: Brown
authors: 1] Sarah W. Stedman Nutrition &Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA [2] Department of Pharmacology &Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA [3] Division of Endocrinology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors: Christopher B
authors: CB
authors: Newgard
authors: 1] Sarah W. Stedman Nutrition &Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA [2] Division of Endocrinology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors: Thomas C
authors: TC
authors: Becker
authors: 1] Division of Endocrinology, Metabolism &Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612, USA.
authors: Brian T
authors: BT
authors: Layden
authors: Division of Endocrinology, Metabolism &Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: William L
authors: WL
authors: Lowe
authors: 1] Center for Genomic &Computational Biology, Duke University School of Medicine, Durham, North Carolina 27708, USA [2] Department of Biostatistics &Bioinformatics, Duke University Medical School, Durham, North Carolina 27710, USA.
authors: Timothy E
authors: TE
authors: Reddy
mesh_terms: D015153:Blotting, Western; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D056945:Hep G2 Cells; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology*; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006593:Hexokinase
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