Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1

Cong Guo, Anton E. Ludvik, Michelle E. Arlotto, M. Geoffrey Hayes, Loren L. Armstrong, Denise M. Scholtens, Christopher D. Brown, Christopher B. Newgard, Thomas C. Becker, Brian T. Layden, William L. Lowe and Timothy E. Reddy ()
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Cong Guo: Duke University Program in Genetics & Genomics
Anton E. Ludvik: Metabolism & Molecular Medicine, Northwestern University Feinberg School of Medicine
Michelle E. Arlotto: Sarah W. Stedman Nutrition & Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine
M. Geoffrey Hayes: Metabolism & Molecular Medicine, Northwestern University Feinberg School of Medicine
Loren L. Armstrong: Metabolism & Molecular Medicine, Northwestern University Feinberg School of Medicine
Denise M. Scholtens: Northwestern University Feinberg School of Medicine
Christopher D. Brown: Perelman School of Medicine, University of Pennsylvania
Christopher B. Newgard: Sarah W. Stedman Nutrition & Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine
Thomas C. Becker: Sarah W. Stedman Nutrition & Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine
Brian T. Layden: Metabolism & Molecular Medicine, Northwestern University Feinberg School of Medicine
William L. Lowe: Metabolism & Molecular Medicine, Northwestern University Feinberg School of Medicine
Timothy E. Reddy: Center for Genomic & Computational Biology, Duke University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7069

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