Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke

Abstract

An increased prevalence of both hypertension and cerebrovascular stroke is apparent in growth hormone (GH) deficiency whilst hypertension is a frequent complication in acromegaly. This has suggested a possible link between GH, stature and arterial function. Since the risk of both hypertension and stroke also appears to be inversely correlated with adult height, we have instigated an exploratory study to assess whether inter-individual variation in the genes encoding human growth hormone (GH1) and the GH receptor (GHR) might be associated with an increased risk of hypertension and stroke. GH1 promoter haplotypes were found to differ significantly not only between hypertensive patients (n = 111) and controls (n = 121) but also between stroke patients (n = 155) and controls (n = 158). Intriguingly, the association between GH1 promoter haplotype and risk of hypertension was much greater in females than in males. An inverse correlation between height and central systolic blood pressure was apparent in both hypertensive patients and normal controls but was much stronger in individuals carrying at least one GH1 promoter risk haplotype. The GH1 genotype therefore constitutes a risk factor for hypertension that interacts with stature. A strong association was found between the presence of at least one GH1 risk haplotype and a family history of stroke at an early age (odds ratio: 9.07, 95% confidence interval: 1.14-72.22). Three novel GH variants (Arg16His, Phe176Cys, Cys189Arg) were identified during the course of this study. Although two exhibited markedly reduced biological activity in vitro, their clinical significance remains unclear. No association was found between GHR genotype and either hypertension or stroke, nor was any interaction noted between GHR and GH1 genotypes in terms of a disease association. However, an association between GHRd3 genotype and hypertension was observed among stroke patients, particularly females. Elevated HDL was found to be a risk factor for hypertension in individuals lacking a copy of the GHRd3 allele. Weak associations with GHR genotype were also noted for peripheral systolic and diastolic blood pressure in hypertensive patients. Although the underlying mechanisms are still unclear, our findings are consistent with a complex relationship between height, hypertension, GH1 promoter haplotype, GHR polymorphism and the risk of stroke.

Growth Hormone (GH) Receptor C.1319 G>T Polymorphism, But Not Exon 3 Retention or Deletion Is Associated With Better First-Year Growth Response to GH Therapy in Patients With GH Deficiency

“…The extended DNA fragments were spotted onto a 384-element silicon chip (SpectroCHIP, Sequenom), and then analyzed by a Bruker Biflex III MALDI-TOF Spectro-READER mass spectrometer (Sequenom). Genotyping of d3-GHR was done according to the method developed by Pantel et al (11) with modifications (12,13). For a given sample, we separately amplified full-length GHR isoforms and exon 3-deleted isoforms by two different PCRs using primer pairs G1:G3 and G1:G2, respectively.…”

Significance of the disulphide bonds of human growth hormone

“…A C182R substitution has been reported in a patient with hypertension in a study that also found an inverse correlation between adult height and central hypertension [19]. Unfortunately, the height of the patient carrying the C182R mutation was not reported.…”

Analysis of candidate genes of QTL and chromosomal regions for essential hypertension in the rat model

“…Gigante B et al [52] reported that F2R genetic [53], including Npr1 and Npr3. Another of the candidate genes, growth hormone receptor (GHR), has been linked to hypertension in two independent studies [19,54]. In "The Québec Family Study", a study of genome-wide linkage analysis for systolic and diastolic blood pressure, Rice et al [55] found an association between polymorphisms of corticotrophin releasing hormone gene (CRH) and hypertension.…”