Genetics of glucose homeostasis in pregnancy and postpartum

Aims/hypothesis: Pregnancy is accompanied by maternal metabolic adaptations to ensure fetal growth and development, including insulin resistance, which occurs primarily during the second and third trimesters of pregnancy, and a decrease in fasting blood sugar levels over the course of pregnancy. Glucose-related traits are regulated by genetic and environmental factors and modulated by physiological variations throughout the life course. We addressed the hypothesis that there are both overlaps and differences between genetic variants associated with glycaemia-related traits during and outside of pregnancy.

Methods: Genome-wide SNP data were used to identify genetic variations associated with glycaemia-related traits measured during an OGTT performed at ~28 weeks' gestation in 8067 participants in the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Associations outside of pregnancy were determined in 3977 individuals who also participated in the HAPO Follow-Up Study at 11-14 years postpartum. A Bayesian classification algorithm was used to determine whether SNPs associated with fasting and 2 h glucose and fasting C-peptide during pregnancy had a pregnancy-predominant effect vs a similar effect during pregnancy and postpartum.

Results: SNPs in six loci (GCKR, G6PC2, GCK, PPP1R3B, PCSK1 and MTNR1B) were significantly associated with fasting glucose during pregnancy, while SNPs in CDKAL1 and MTNR1B were associated with 1 h glucose and SNPs in MTNR1B and HKDC1 were associated with 2 h glucose. Variants in CDKAL1 and MTNR1B were associated with insulin secretion during pregnancy. Variants in multiple loci were associated with fasting C-peptide during pregnancy, including GCKR, IQSEC1, PPP1R3B, IGF1 and BACE2. GCKR and BACE2 were associated with 1 h C-peptide and GCKR, IQSEC1 and BACE2 with insulin sensitivity during pregnancy. The associations of MTNR1B with 2 h glucose, BACE2 with fasting and 1 h C-peptide and insulin sensitivity, and IQSEC1 with fasting C-peptide and insulin sensitivity that we identified during pregnancy have not been previously reported in non-pregnancy cohorts. The Bayesian classification algorithm demonstrated that the magnitude of effect of the lead SNP was greater during pregnancy compared with 11-14 years postpartum in PCSK1 and PPP1R3B with fasting glucose, in three loci, including MTNR1B, with 2 h glucose, and in six loci, including IGF1, with fasting C-peptide.

Conclusions/interpretation: Our findings support the hypothesis that there are both overlaps and differences between the genetic architecture of glycaemia-related traits during and outside of pregnancy. Genetic variants at several loci, including PCSK1, PPP1R3B, MTNR1B and IGF1, appear to influence glycaemic regulation in a unique fashion during pregnancy. Future studies in larger cohorts will be needed to replicate the present findings, fully characterise the genetics of maternal glycaemia during pregnancy and determine similarities to and differences from the non-gravid state.