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

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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.

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Acknowledgements

We are most grateful to Pfizer Inc for partially funding this study, to AstraZeneca Ltd, Ipsen Ltd and the John Lewis Partnership for their kind donations for the purchase of equipment, to Martin Norin (Biovitrum) for advice on GH structural analysis, to Linda Fryklund (WW Endocrine Care Team, Pfizer Health AB) for her useful suggestions and to Professor Richard Ross (Sheffield) for his generous gifts of HK293hi cells and the STAT 5-responsive luciferase reporter gene construct. We also acknowledge the help of the Welsh Development Agency who funded the purchase of the Real-time PCR system as part of their CETIC program. Philip Bath is the Stroke Association Professor of Stroke Medicine. This study was partly supported by the German Ministry of Science and Education (‘BMBF’) through an NGFN SMP-GEM grant to MK (01GS0426).

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Authors and Affiliations

  1. Institute of Medical Genetics, Cardiff University, Heath Park, CF14 4XN, Cardiff, UK

    Martin Horan, Vicky Newsway, Arti Mahto, David S. Millar, Annie M. Procter & David N. Cooper

  2. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Yasmin & Ian B. Wilkinson

  3. Centre for Endocrine and Diabetes Sciences, Cardiff University, Cardiff, UK

    Mark D. Lewis, Tammy E. Easter, D. Aled Rees & Maurice F. Scanlon

  4. Division of Therapeutics, University Hospital of Nottingham, Nottingham, UK

    Ian P. Hall, Amanda Wheatley & John Blakey

  5. Division of Stroke Medicine, University of Nottingham, Nottingham, UK

    Philip M. W. Bath

  6. Department of Cardiology, Wales Heart Research Institute, Cardiff University, Cardiff, UK

    John R. Cockcroft

  7. Institut für Medizinische Informatik und Statistik, Christian-Albrechts-Universität, Kiel, Germany

    Michael Krawczak

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  1. Martin Horan
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Horan, M., Newsway, V., Yasmin et al. Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum Genet 119, 527–540 (2006). https://doi.org/10.1007/s00439-006-0166-5

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