Endocrine Abstracts (2006) 11 P379

Chromosome 1p shows significant linkage to steroid metabolism in hypertension in the British Genetics of Hypertension Study

S Padmanabhan1, R Fraser1, M Ingram1, E Davies1, PB Munroe2, R Dobson2, M Brown3, N Samani4, D Clayton3, M Farrall5, J Webster6, M Lathop7, M Caulfield2, AF Dominczak1 & JM Connell1

1BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; 2Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London Medical School, London, United Kingdom; 3Clinical Pharmacology and Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom; 4Department of Cardiology, University of Leicester, Leicester, United Kingdom; 5Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom; 6Clinical Pharmacology Unit, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; 7Centre National de Genotypage, Evry, France.

Background: Glucorticoids can affect blood pressure in humans, as demonstrated most strikingly in Cushing’s syndrome. We have previously reported that total cortisol metabolite excretion is raised in obese subjects, while other investigations have identified genetically determined changes in glucocorticoid receptor function as contributors to hypertension. Furthermore, in essential hypertension, vasoconstrictor sensitivity to glucocorticoids is increased. Such raised sensitivity could represent the primary stimulus leading to HTN and has been invoked in a fetal programming process that could underlie raised BP later in life. We performed a genome wide scan on the severely hypertensive Caucasian BRIGHT population to identify chromosomal loci affecting cortisol secretion and metabolism that might contribute to the genetic risk of developing hypertension.

Methods: We had complete urinary steroid profile on 119 sibling pairs from the BRIGHT population which comprise 2142 severely hypertensive Caucasian affected sibling pairs. A 10 cM genome wide scan was performed using (THF+THE+aTHE) adjusted for age which is a measure of total cortisol metabolite excretion, as a quantitative trait. Linkage analysis was performed using MERLIN QTL.

Results: Significant linkage was observed for (THF+THE+aTHE) on chromosome 1 at 106.5 cM near marker D1S230 (LOD score 4.3, P<10−6). The candidate gene encoding sterol carrier protein SCPX lies near locus for (THF+THE+aTHE).

Conclusions: We have shown evidence for linkage to cortisol metabolite excretion to a region in chromosome 1p in a cohort of hypertensive sibling pairs. This suggests that corticosteroids provide a useful an intermediate phenotype for hypertension; the genetic determinants for cortisol secretion in hypertensive subjects may lie in chromosome 1p.