Dynamic linkage of the angiotensin II type I receptor gene locus in essential hypertension: a study of hypertensive families of french-canadian origin

Abstract

The goal of the present study was to evaluate the involvement of the angiotensin II type I receptor (AT1R) gene in the development of essential hypertension as well as cardiac hypertrophy in hypertensive families of French-Canadian origin. Twenty-four-hour ambulatory blood pressure, 9 echocardiography and 15 impedance cardiography parameters were collected during a posture test in 186 sib-pairs originating from 114 hypertensive families. The posture test, defined as 60 min being in a supine position, 10 min standing and 30 min sitting, was followed by a mathematical stress test. The families were selected from a geographically-isolated population of French-Canadian origin on the basis of having at least two siblings affected by early onset (<55 years) hypertension and dyslipidemia. The AT1R gene locus was investigated using a microsatellite and two single nucleotide polymorphisms (A1166C, T573C). Quantitative sibpair linkage analysis was performed with SIBPAL software from the S.A.G.E package. We also performed dynamic linkage analysis, which consisted of a time series of 25 linkage analyses of impedance cardiography parameters during the posture and mathematics stress tests. Sib-pair analysis demonstrated significant linkage of the AT1R locus with night systolic blood pressure (p=0.007), night mean blood pressure (p=0.005), posterior wall thickness (p=0.03) and inter-ventricular septal thickness (p=0.006). The results of dynamic linkage study showed that the effect of the AT1R gene locus becomes apparent immediately after a change of posture and mental stress, pointing to rapid humoral regulation such as neuromodulator activation, downstream of the renin angiotensin system. Sibpair linkage analysis indicates that, in French-Canadian hypertensive families, the AT1R gene locus plays a significant role in the control of blood pressure, myocardial contractility and cardiac size. To our knowledge, this is the first report of a dynamic linkage study and it demonstrates potential for pathway discoveries downstream of the effector allele. Supported by NIH SCOR and CIHR grants (MT-14654).