Dataset Information

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations.

ABSTRACT:

Aim

We hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy.

Methods

In the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios).

Results

Four fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value=2×10^-4) and INS rs2585 (P-value=7×10^-4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value=1×10^-3) and KCNQ1(OT1) rs7929804 (P-value=4×10^-3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value=4.3×10^-6, n=981, r²=2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value=1×10^-3, n=89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value=3.2×10^-8, rs2585, P-value=3.6×10^-5) and the composite fetal imprinted gene allele score association (P-value=1.3×10^-8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value=0.4; rs7929804, P-value=0.2).

Conclusion

This study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.

SUBMITTER: Petry CJ

PROVIDER: S-EPMC5507297 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. METHODS:Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n =?200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n =?567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. RESULTS:The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R =?0.14, p =?2.9?×?10-?3, n =?386) and maternally-transmitted fetal FAM99A rs7131362 (R =?0.18, p =?6.2?×?10-?3, n =?351; association with maternal-untransmitted allele R =?0.08, p =?0.07, n =?328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10-?3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). CONCLUSIONS:Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.

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