Glucocorticoid receptor-9beta polymorphism is associated with systolic blood pressure and heart growth during early childhood. The Generation R Study
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.
References (28)
- et al.
DNA regulatory elements for steroid hormones
J Steroid Biochem
(1989) - et al.
The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function
J Biol Chem
(1996) - et al.
Endocrine and metabolic programming during intrauterine development
Early Hum Dev
(2005) - et al.
Impaired growth and increased glucocorticoid-sensitive enzyme activities in tissues of rat fetuses exposed to maternal low protein diets
Life Sci
(1998) - et al.
Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings
Am J Cardiol
(1986) - et al.
Usefulness of the pediatric electrocardiogram in detecting left ventricular hypertrophy: results from the Prospective Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) multicenter study
Am Heart J
(2003) - et al.
Antiinflammatory action of glucocorticoids — new mechanisms for old drugs
N Engl J Med
(2005) - et al.
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
(1998) - et al.
Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition
Recent Prog Horm Res
(2004) - et al.
Primary structure and expression of a functional human glucocorticoid receptor cDNA
Nature
(1985)
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
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2022, Journal of EthnopharmacologyCitation Excerpt :In general, most cell types and tissues in vivo express GRs. In contrast, only selective tissues, including the cardiomyocytes, vascular endothelium, and kidney epithelial cells, express MRs (Geelhoed et al., 2011). Thus, the direct effects of glucocorticoids in the heart can be amplified, as MR depicts a higher affinity for glucocorticoids than GR, and glucocorticoids can signal through GR or MR (Giordano et al., 2012).
The clinical significance of the glucocorticoid receptors: Genetics and epigenetics
2021, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :Selectively, the A3669G polymorphism elevates the GRβ stability at mRNA and protein levels, resulting in the prevention of transcriptional activity of the GR and GC-resistance. It impacts the transrepression activity of the GR and is associated with an elevated inflammatory state, reduced central obesity, cardiovascular disease (CVD), primary myelofibrosis, and rheumatoid arthritis [41–43]. The N363S polymorphism is associated with a hypersensitivity to GCs, a lower density of bone, obesity [44], an increase in body mass index (BMI), waist-to-hip ratio, and insulin response to dexamethasone, the CAD [45–48].
Generalized and tissue specific glucocorticoid resistance
2021, Molecular and Cellular EndocrinologyCitation Excerpt :In patients with long-term remission of Cushing's syndrome, the GR-9β polymorphism was associated with higher systolic blood pressure (Roerink et al., 2016). Actually, in a prospective Dutch cohort study, which evaluated individuals from fetal life until young adulthood, the GR-9β polymorphism was associated with higher systolic blood pressure and higher left ventricular mass at the age of 24 months (Geelhoed, 2011). Likewise, in a large population-based prospective Dutch cohort, the A3669G GR-9β polymorphism was associated with increased risk of myocardial infarction and coronary heart disease, higher levels of C-reactive protein and IL-6, and increased carotid intima-media thickness (van den Akker et al., 2008).
Impact of glucocorticoid receptor polymorphisms on glucocorticoid action
2018, Encyclopedia of Endocrine DiseasesCardiac GR and MR: From development to pathology
2016, Trends in Endocrinology and MetabolismCitation Excerpt :Genetic evidence in humans also supports an association between GR and heart disease. A common GR gene haplotype linked to relative GC resistance is associated with systolic dysfunction and heart failure in adults [53–55], and with increased systolic blood pressure and heart growth in childhood [56]. Transgenic models tell us what is possible, not necessarily what happens in a physiological or pathophysiological setting.
Glucocorticoid signaling in the heart: A cardiomyocyte perspective
2015, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :Later studies performed nearly 50 years ago described a reduction in contractile force generation by the heart papillary muscle in adrenalectomized rats with glucocorticoid insufficiency [14]. More recent evidence that insufficient glucocorticoid signaling is detrimental to the heart has come from epidemiological studies focused on a polymorphism (A3669G) in exon 9 of the GR gene that has been associated with glucocorticoid resistance [15–17]. People with this polymorphism were found to have an increased risk of coronary artery disease, enlarged hearts, systolic dysfunction, and heart failure.