Two novel genetic variants in the mineralocorticoid receptor gene associated with spontaneous preterm birth.

Inge Christiaens,Craig E Pennell,Q Wei Ang,Scott M Williams,Xin Fang,David M Olson,Lindsay N Gordon

doi:10.1186/s12881-015-0205-y

Abstract

BackgroundPreterm birth is the leading cause of mortality and morbidity in newborn infants. Its etiology is multifactorial with genes and environmental factors, including chronic maternal stress, contributing to its risk. Our objective was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in the stress response are associated with spontaneous preterm birth using a candidate gene approach.MethodsA total of 210 cases (singleton spontaneous preterm birth at <37 weeks) and 412 controls (singleton term birth at 38–42 weeks without a history of preterm birth) were studied. High quality maternal DNA was available from saliva samples of 190 cases and 369 controls and compared. Sociodemographic and medical data were collected. Sixteen SNPs, either tag SNPs located in key genes involved in the stress response identified in the Preterm Birth Genome Project database or SNPs found to be associated with adverse mental health outcomes in the published literature, were selected for genotyping and sequencing. SNPs were genotyped using Taqman® SNP genotyping assays. Univariate and multivariate logistic regression were performed.ResultsMultivariate analysis showed that two SNPs located in the mineralocorticoid receptor gene were significantly associated with spontaneous preterm birth: rs17484063 (OR 0.50, p = 0.038) and rs2883929 (OR 0.49, p = 0.017), regardless of maternal age, smoking, alcohol use, educational status, and history of spontaneous miscarriage.ConclusionThis report demonstrates an association between mineralocorticoid receptor gene polymorphisms, rs17484063 and rs2883929, and preterm birth, supporting a role for genetics in the association between chronic maternal stress and preterm birth. Potentially, this information may be used to predicting the risk of having a preterm delivery.

Highlights

Preterm birth is the leading cause of mortality and morbidity in newborn infants
The relationship between Single nucleotide polymorphism (SNP) and preterm birth has been extensively studied over the past decade; a synopsis of all genetic association studies that are published in the field of preterm birth can be found in the online PTBGene database [http://ric.einstein.yu.edu/ ptbgene/index.html] [12] which is associated with the Preterm Birth International Consortium’s (PREBIC) Preterm Birth Genome Project (PGP) [http://www.prebic.org/ projects-and-documents.html]
This study explores the relationship between spontaneous preterm birth and SNPs in genes regulating stress responses or mood

Summary

Introduction

Preterm birth is the leading cause of mortality and morbidity in newborn infants. Its etiology is multifactorial with genes and environmental factors, including chronic maternal stress, contributing to its risk. More than 1600 SNPs in 80 candidate genes in putative preterm birth pathways have been analyzed in both maternal and fetal DNA samples; of all these SNPs, only three variants were found to be significantly associated with preterm birth in meta-analyses, namely rs1042713 in the adrenergic beta-2 receptor gene (ADRB2), rs1799963 (coagulation factor II precursor; F2), and rs2430561 (interferon gamma; IFNG) This is unfortunate as the candidate SNP approach provides a reasonable method to associate genetic variations with preterm birth risk and to elucidate potential causal mechanisms, especially when combined with precise phenotyping and a suitable strategy for selection of both candidate SNPs and subjects. Maternal stress is associated with common mental health conditions including major depressive disorders and anxiety disorders [15] - conditions with heritability estimates of 40 to 50 percent [16]

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