Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

Angiotensin converting enzyme 2 (ACE2), a newly recognized homolog of ACE that converts angiotensin II (Ang II) to angiotensin-1–7 (Ang-(1–7)), is found in vascular smooth muscle cells. Expression of ACE2 may be a local determinant of vascular Ang-(1–7) production and, when increased, may augment the increasingly recognized protective effects of this peptide within injured tissues. We previously showed that treatment with the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan increased aortic ACE2 and Ang-(1–7) in conjunction with improved vascular remodeling in spontaneously hypertensive rats (SHR). In the present study, we investigated balloon injury–related ACE2 in the vasculature by determining the effect of sustained AT1 blockade on ACE2 protein expression in the carotid arteries of 12-week-old male SHR treated with either vehicle (n=5) or 10 mg/kg olmesartan (n=5) in drinking water for 14 days. Olmesartan treatment caused a 61% reduction in the cross-sectional area of the neointima, from 0.27±0.01 mm² in vehicle-treated rats to 0.11±0.01 mm² in olmesartan-treated rats. In contrast, olmesartan treatment had no effect on the medial area of injured or uninjured carotid arteries compared to that in vehicle-treated rats. Quantitative analysis of ACE2 immunostaining intensity in the carotid artery of SHR was significantly greater (p<0.05) in the neointima of olmesartan-treated SHR compared to that in vehicle-treated animals. In contrast, ACE2 immunostaining intensity was not quantitatively different in uninjured carotid arteries of olmesartan and vehicle-treated animals. These studies suggest that changes in ACE2 within the vascular system of SHR are regulated by a factor other than arterial pressure.

Hypertension (HT) and dementia are common disorders in the elderly. HT in the elderly is associated with increased occurrence rates of dementia including Alzheimer's disease (AD) and vascular dementia (VaD). In connection to this, some studies have suggested that HT in old age correlates with the pathogenesis of dementia. Since HT is potentially reversible, a number of randomized trials have examined whether antihypertensive treatment may help in preventing dementia occurrence. We review five studies, all using subjects 60 years or older, which investigated different antihypertensive pharmacological treatments. Data from two trials (Syst-Eur, PROGRESS) open the way toward the prevention of dementia (AD or VaD) by antihypertensive treatments. In the Syst-Eur study, with the dihydropyridine calcium antagonists, a reduction in both types of dementia was demonstrated (risk reduction 55%). The PROGRESS study showed that the use of angiotensin-converting enzyme inhibitors (ACEIs), with or without diuretics, resulted in decrease incidence of stroke-related dementia (risk reduction 19%), but dementia without stroke was not reduced. In contrast, the SHEP trial, treatment with a chlorthalidone-based antihypertensive regimen, did not significantly reduced the incidence of dementia. The SCOPE study (candesartan or hydrochlorothiazide versus placebo) and the HYVET-COG study (indapamide or perindopril versus placebo) found no significant difference between the active treatment and placebo group on the incidence of dementia. We found conflicting results regarding treatment benefits in dementia prevention. Recent clinical trials and studies on animal models suggest that blockades of RAS system could have reduced cognitive decline seen in Alzheimer's disease and vascular dementia. Future trials primarily designed to investigate the effects of antihypertensive agents on impaired cognition are needed.

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