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

C.J Petry,K Mooslehner,P Prentice,M.G Hayes,M Nodzenski,D.M Scholtens,I.A Hughes,C.L Acerini,K.K Ong,W.L Lowe,D.B Dunger

doi:10.1016/j.diabet.2017.03.002

C.J Petry, K Mooslehner + Show 9 more

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https://doi.org/10.1016/j.diabet.2017.03.002

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Journal: Diabetes & Metabolism	Publication Date: Apr 6, 2017
Citations: 20	License type: cc-by

Affiliation: University of Cambridge

Abstract

AimWe 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. MethodsIn 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). ResultsFour 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). ConclusionThis 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.

Highlights

Familial studies suggest that the risk for a pregnant woman developing gestational diabetes (GDM) might be partially genetically mediated
In this study we developed a composite fetal imprinted gene allele score that was strongly associated with late pregnancy maternal glucose concentrations and GDM in the two independent Cambridge cohorts
Significance of the association was not reached in Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants with European ancestry, the association was unidirectional with the associations in the Cambridge cohorts and genome wide significance was reached by meta-analysis

Summary

Introduction

Familial studies suggest that the risk for a pregnant woman developing gestational diabetes (GDM) might be partially genetically mediated. One genome-wide association study (GWAS) focussing on GDM has been published to date [3], with another one focussing on its endophenotype, maternal glucose concentrations in pregnancy [4]. Following the suggestion that the fetal genome may influence maternal pregnancy metabolism [10], we hypothesised that imprinted fetal growth genes might alter maternal glucose concentrations and GDM risk [11]. These genes are related to parent of origin effects reflecting the separate reproductive needs of each parent [12]. Paternally-expressed imprinted genes tend to enhance fetal growth, whereas maternally-expressed genes tend to reduce it, probably through changes in fetal demand and supply [13]

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