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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Guo C,Ludvik AE,Arlotto ME,Hayes MG,Armstrong LL,Scholtens DM,Brown CD,Newgard CB,Becker TC,Layden BT,Lowe WL,Reddy TE

doi

10.1038/ncomms7069

subject

Has Abstract

pub_date

2015-02-04 00:00:00

pages

6069

issn

2041-1723

pii

ncomms7069

journal_volume

6

pub_type

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