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

Christiaens I, Ang QW, Gordon LN, Fang X, Williams SM, Pennell CE, Olson DM - BMC Med. Genet. (2015)

Bottom Line: High quality maternal DNA was available from saliva samples of 190 cases and 369 controls and compared.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.Multivariate 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.

View Article: PubMed Central - PubMed

Affiliation: Obstetrics and Gynaecology, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. ingechristiaens@doctors.org.uk.

ABSTRACT

Background: 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. 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.

Methods: A 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.

Results: Multivariate 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.

Conclusion: This 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.

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Related in: MedlinePlus

Selection of SNPs. For details, see Methods
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Fig1: Selection of SNPs. For details, see Methods

Mentions: Single nucleotide polymorphisms in genes involved in the stress response or mental health were selected using two different strategies (Fig. 1). To address the first part of our aim, a PubMed literature search was conducted to find published reports regarding genetic variants in genes involved in the regulation of the HPA axis and the meso-corticolimbic system and their associations with adverse mental health outcomes, especially major depressive disorder. Candidate SNPs were then selected based on prior associations with mental health outcomes as determined by a literature search. SNPs identified were added to our list of candidate SNPs. Additional SNPs were selected from seven key genes that are involved in the stress response and mood regulation. These genes code for the corticotropin releasing hormone receptor (CRHR1), the glucocorticoid receptor (NR3C1), the mineralocorticoid receptor (NR3C2), FK506 binding protein 5 (FKBP5), which is part of a receptor complex regulating the sensitivity of the glucocorticoid receptor, the serotonin transporter (SLC6A4), and the enzymes monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT) that control the metabolism of serotonin, dopamine and norepinephrine in the brain. Tag SNPs for these seven genes were identified using the TagSNP function on the SNPinfo web server and the CEU samples from HapMap [19, 20]. Tagging conditions included an r2 threshold of 0.8 and a minor allele frequency (MAF) range of 0.05 to 0.5. This approach provided a broad coverage of functional (derived primarily from the literature) and non-functional SNPs and address most common genetic variations within these genes. All identified tag SNPs were then compared to the PGP database, and SNPs that were found to be associated with preterm birth in this database at p < 0.05 were selected for the candidate gene study. As a result, nine tag SNPs in three different genes – NR3C1, NR3C2 and CRHR1 – were included (Table 1).Fig. 1


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

Christiaens I, Ang QW, Gordon LN, Fang X, Williams SM, Pennell CE, Olson DM - BMC Med. Genet. (2015)

Selection of SNPs. For details, see Methods
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4593185&req=5

Fig1: Selection of SNPs. For details, see Methods
Mentions: Single nucleotide polymorphisms in genes involved in the stress response or mental health were selected using two different strategies (Fig. 1). To address the first part of our aim, a PubMed literature search was conducted to find published reports regarding genetic variants in genes involved in the regulation of the HPA axis and the meso-corticolimbic system and their associations with adverse mental health outcomes, especially major depressive disorder. Candidate SNPs were then selected based on prior associations with mental health outcomes as determined by a literature search. SNPs identified were added to our list of candidate SNPs. Additional SNPs were selected from seven key genes that are involved in the stress response and mood regulation. These genes code for the corticotropin releasing hormone receptor (CRHR1), the glucocorticoid receptor (NR3C1), the mineralocorticoid receptor (NR3C2), FK506 binding protein 5 (FKBP5), which is part of a receptor complex regulating the sensitivity of the glucocorticoid receptor, the serotonin transporter (SLC6A4), and the enzymes monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT) that control the metabolism of serotonin, dopamine and norepinephrine in the brain. Tag SNPs for these seven genes were identified using the TagSNP function on the SNPinfo web server and the CEU samples from HapMap [19, 20]. Tagging conditions included an r2 threshold of 0.8 and a minor allele frequency (MAF) range of 0.05 to 0.5. This approach provided a broad coverage of functional (derived primarily from the literature) and non-functional SNPs and address most common genetic variations within these genes. All identified tag SNPs were then compared to the PGP database, and SNPs that were found to be associated with preterm birth in this database at p < 0.05 were selected for the candidate gene study. As a result, nine tag SNPs in three different genes – NR3C1, NR3C2 and CRHR1 – were included (Table 1).Fig. 1

Bottom Line: High quality maternal DNA was available from saliva samples of 190 cases and 369 controls and compared.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.Multivariate 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.

View Article: PubMed Central - PubMed

Affiliation: Obstetrics and Gynaecology, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. ingechristiaens@doctors.org.uk.

ABSTRACT

Background: 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. 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.

Methods: A 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.

Results: Multivariate 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.

Conclusion: This 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.

Show MeSH
Related in: MedlinePlus