Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups.
OBJECTIVE
Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy.


METHODS
We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics.


RESULTS
The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCF7L2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08).


CONCLUSIONS
Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants.
Freathy
Rachel M
RM
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Hayes
M Geoffrey
MG
Urbanek
Margrit
M
Lowe
Lynn P
LP
Lee
Hoon
H
Ackerman
Christine
C
Frayling
Timothy M
TM
Cox
Nancy J
NJ
Dunger
David B
DB
Dyer
Alan R
AR
Hattersley
Andrew T
AT
Metzger
Boyd E
BE
Lowe
William L
WL
D001724:Birth Weight / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D000081410:Germinal Center Kinases; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000235:genetics*; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D011256:Pregnancy Outcome; D011254:Pregnancy in Diabetics / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D044465:White People / Q000235:genetics
D000081410:Germinal Center Kinases; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D017346:Protein Serine-Threonine Kinases