Glucocorticoid receptor-9beta polymorphism is associated with systolic blood pressure and heart growth during early childhood. The Generation R Study

doi:10.1016/j.earlhumdev.2010.11.006

Early Human Development

Volume 87, Issue 2, February 2011, Pages 97-102

https://doi.org/10.1016/j.earlhumdev.2010.11.006 Get rights and content

Abstract

Background

Glucocorticoid receptor-9β polymorphism (rs6198) is associated with the susceptibility for cardiovascular disease.

Aim

To examine whether the GR-9β variant is also associated with blood pressure and heart growth in early childhood.

Study design

This study was embedded in a population-based prospective cohort study from fetal life onwards. Analyses were based on 857 children.

Outcome measures

Left cardiac structures (aortic root diameter, left atrial diameter and left ventricular mass), shortening fraction and heart beat were measured postnatally at the ages of 1.5, 6 and 24 months. Blood pressure was measured at 24 months of age.

Results

The distribution of the GR-9β genotype showed 75.1% homozygous reference, 23.5% heterozygous and 1.4% homozygous variant subjects. No differences in cardiovascular outcomes were observed at the ages of 1.5 and 6 months. At the age of 24 months, homozygous variants showed an increased systolic blood pressure of 2.65 mm Hg (95% CI: 0.16, 5.14), an increased heart rate of 9.10 beats per minute (95% CI: 1.28, 16.7) and an increased left ventricular mass of 4.99 g (95% CI: 1.33, 8.65) compared to homozygous references. This means an increase of 2.6%, 8.6% and 16%, respectively. GR-9β polymorphism was significantly associated with left ventricular mass growth during the first 2 years.

Conclusion

Our findings suggest that genetically determined differences in cortisol exposure affect cardiovascular development in early life.

Introduction

Glucocorticoids are important regulators of cardiovascular function and metabolism. High levels of glucocorticoids result in unfavorable cardiovascular risk factors, such as visceral obesity, steroid-induced diabetes and hypercholesterolemia [1]. The effects of these hormones are mediated by glucocorticoid receptors, which show a large interindividual variation in their sensitivity [2]. Genetic variants in the glucocorticoid receptor gene (GR or NR3C1) seem to contribute to this difference in sensitivity [3].

In humans, two isoforms of the glucocorticoid receptor exist: hGRα and hGRβ [4]. hGRα resides in the cytoplasm, can bind glucocorticoids, and can alter gene transcription by binding to glucocorticoid response elements [5]. hGRβ does not bind hormone and is transcriptionally inactive [6]. In vitro studies have shown that it can act as a dominant negative inhibitor of hGRα's transactivation properties [7]. A polymorphism in the glucocorticoid receptor gene, the GR-9β variant (rs6198), has been identified that is associated with cortisol sensitivity. A few studies demonstrated associations of the GR-9β variant with a reduced risk of bacterial colonization with Staphylococcus aureus in the nose [8] and an increased susceptibility to rheumatoid arthritis and a more aggressive disease course in multiple sclerosis [9], [10]. Recently, it was demonstrated in a middle-aged population-based cohort in The Netherlands that this polymorphism of the glucocorticoid receptor gene is associated with the risk of myocardial infarction and coronary heart disease [11]. Variation in cortisol sensitivity may not only harm glucocorticoid treatment of immune related diseases, but may also directly affect cardiovascular growth and development in the fetus and subsequently increase the risk of cardiovascular disease in adulthood [12], [13]. It was shown in sheep fetus that cortisol treatment resulted in an increase in cardiac mass without myocyte enlargement, indicating that cortisol stimulates hyperplastic growth of cardiomyocytes but not hypertrophic growth [14]. It is unknown what the effect is of variation in cortisol levels on fetal and early postnatal cardiovascular growth and development. The relative effect of variants of the glucocorticoid receptor gene on blood pressure and cardiac structures might be larger in childhood, when the effect of various environmental factors, such as life style habits, is limited.

We hypothesize that the GR-9β variant of the glucocorticoid receptor gene affects blood pressure and cardiac growth in early life. These early cardiovascular changes may predispose the individual to cardiovascular disease in adulthood. Therefore, we studied in a prospective cohort study from fetal life onwards the effects of the GR-9β polymorphism of the glucocorticoid receptor gene on blood pressure and left cardiac structures and function during the first two years of life.

Section snippets

Design

This study was embedded in the Generation R Study, a prospective cohort study from fetal life until young adulthood in Rotterdam, The Netherlands [15], [16]. Assessments in pregnancy included physical examinations, fetal ultrasounds, biological samples and questionnaires. More detailed assessments of fetal and postnatal growth and development are conducted in a subgroup, the Focus cohort [15], [16]. The study has been approved by the Medical Ethics Committee of the Erasmus Medical Center,

Results

Table 1 presents the baseline characteristics of infants who participated in the postnatal echocardiogram studies. The percentage of boys was 52%. The overall median ages (95% range) in infants at their visits were 1.5 months (1.0–2.9), 6.3 months (5.5–8.3) and 25.1 months (23.6–28.3). At all ages, aortic root diameter, left ventricular diameter and left ventricular mass were larger in boys than in girls.

Table 2 shows that systolic blood pressure at the age of 24 months was higher in children with

Discussion

In our prospective cohort study we found that the GR-9β polymorphism (rs6198), which has previously been shown to be related to myocardial infarction and coronary heart disease, is associated with higher systolic blood pressure and higher left ventricular mass at the age of 24 months. No associations were found for the other cardiac measurements.

The major strengths of our study are its prospective design from early fetal life and the size of the cohort. Furthermore, the relative effect of

Conflict of interest statement

None declared.

Funding sources

The first phase of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and The Netherlands Organization for Health Research and Development (ZonMw).

Ethical statement

The study has been approved by the Medical Ethics Committee of the Erasmus Medical Center, Rotterdam. Written informed consent was obtained from all participants.

Acknowledgements

The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR), Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam.

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This article is part of a Special Issue entitled ‘Steroid Perspectives’.

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Glucocorticoid receptor-9beta polymorphism is associated with systolic blood pressure and heart growth during early childhood. The Generation R Study

Abstract

Background

Aim

Study design

Outcome measures

Results

Conclusion

Introduction

Section snippets

Design

Results

Discussion

Conflict of interest statement

Funding sources

Ethical statement

Acknowledgements

J Steroid Biochem

J Biol Chem

Early Hum Dev

Life Sci

Am J Cardiol

Am Heart J

Antiinflammatory action of glucocorticoids — new mechanisms for old drugs

N Engl J Med

Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals

J Clin Endocrinol Metab

Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

Recent Prog Horm Res

Primary structure and expression of a functional human glucocorticoid receptor cDNA

Nature

Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans

J Clin Invest

Staphylococcus aureus nasal carriage is associated with glucocorticoid receptor gene polymorphisms

J Infect Dis

A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis

J Rheumatol

A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis

J Clin Endocrinol Metab