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

Abstract

Background Numerous studies, including our own, have demonstrated that maternal stress - chronic or prenatal - can increase the risk of preterm birth. Genetic predisposition plays a major role in the etiology of both preterm birth and common mental disorders such as major depressive disorder. Objective 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. Methods Maternal DNA from saliva of 190 cases (singleton spontaneous preterm birth at <37 weeks) and 369 controls (singleton term birth at 38-42 weeks without a history of preterm birth) were 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(registered trademark) SNP genotyping assays. Univariate and multivariate logistic regression was performed. Results Four tag SNPs, all located in the mineralocorticoid receptor (MR) gene were associated with spontaneous preterm birth: rs17484063, rs2883929, rs4835136, and rs7680420 (p<0.05) Univariate analysis showed that maternal age, smoking, alcohol use, educational status, and a history of spontaneous miscarriage were associated with preterm birth (p<0.05) and were included as covariates in the multivariate model. After adjustment, two SNPs remained significantly associated with spontaneous preterm birth: rs17484063 (OR 0.50, p=0.038) and rs2883929 (OR 0.49, p=0.017). For each additional minor allele, the risk of preterm birth was halved. Conclusions Using a candidate gene approach, we discovered two novel polymorphisms, rs17484063 and rs2883929, both located in the MR gene that associate with spontaneous preterm birth. This is the first report to our knowledge demonstrating an association between these polymorphisms and preterm birth supporting a potential role for genetics in the association between chronic maternal stress and preterm birth.