Genetics of hypertension

Abstract

Hypertension is the most prevalent cardiovascular disorder. In the 1999 to 2000 NHANES survey, the prevalence of hypertension progressively increased from 7.2% in those aged 18 to 39 to 30.1% in 40 to 59 year olds and 65.4% in those 60 and older. 1 Risk of both coronary atherosclerosis and stroke increase exponentially as blood pressure rises (see Fig. 1). 2 Although the relative risk for stroke increases more rapidly than coronary disease, at any pressure, the absolute risk for coronary disease is considerably greater than for stroke. An insight into this finding comes from autopsy studies that show that the carotid and intracerebral vascular beds are relatively protected from atherosclerosis as compared to the coronary circulation, particularly at lower blood pressures (see Fig. 2). 3,4 Probably the major means whereby hypertension accelerates atherosclerosis is through pressure-driven convection of LDL and other atherogenic particles into the arterial intima. 5-8 Indeed, without at least arterial pressures, atherosclerosis does not exist in the vascular tree 9 even in patients with homozygous familial hypercholesterolemia. 10,11 Increased turbulence (a rare occurrence in the human circulatory system) does not increase atherosclerosis. Rather, higher sheer stress is a strong stimulus for release of nitric oxide that locally decreases risk of atherosclerosis. Focal areas of low sheer stress are at inherently increased risk of atherosclerotic disease (such as the coronary arteries where flow stops during each systole). 12 Interestingly, in most studies, stroke risk has been affected little by serum total cholesterol, 13,14 although some recent studies identify clear associated risk. 15 At least some association with all standard cardiovascular risk factors should be expected, not only because thromboembolic stroke may be caused by carotid tree atherosclerosis, but because aortic plaques have been strongly implicated as an embolic source for ischemic stroke. 16 -18 Hypertension is not just a risk factor for atherosclerosis. High blood pressure can have direct adverse effects on arteries, arterioles, and the heart, resulting in potentially severe consequences beyond the more common manifestations of myocardial infarction and atherothrombotic stroke. Even modestly elevated blood pressure is a major risk factor for congestive heart failure. 19,20 Hypertension is a major contributor to left ventricular hypertrophy, a major risk factor for sudden death independent of other risk factors. 21,22 Hypertension can lead progressively to arterial and arteriolar hypertrophy, arteriosclerosis and arteriolosclerosis, and with very high pressures to fibrinoid change and fibrinoid necrosis in arterioles. These latter changes can result in lumen compromise of arterioles resulting in lacunar stroke, Charcot-Bouchard aneurysms, glomerulosclerosis and nephrosclerosis, and ultimately malignant hypertension in the kidney and retinal ischemia and blindness. Risk of intracerebral hemorrhage is increased 33-fold at stage 3 or higher pre...

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

“…This allows the classification of subjects as "affected" within a family tree in the absence of clinical symptoms when only a specific abnormality at the molecular biochemical level is present. Complexity is obviously greater in a polygenic multifactorial disease like primary hypertension (76). Defining the causal sequence in humans is impossible without the availability of an appropriate animal model (109,154).…”

Pharmacogenomics and nutrigenomics: synergies and differences

“…Many other genes have been investigated for a possible role in hypertension, but none has been 536 firmly established. As for other chronic diseases and risk factors, a simple view of the genetics of hypertension is likely to be over-optimistic because so many different biological mechanisms are 549 involved.…”

“…The authors of the second paper argue that too much emphasis on genetic factors is a distraction from the more relevant issue of identifying and reducing the preventable causes of hypertension. There are some rare genetic disorders which lead to severe hypertension at an early age, however 536 many complex mechanisms affect blood pressure in most people. The most studied gene for common hypertension is the angiotensinogen gene (AGT), which plays a role in the biological system which stimulates thirst and appetite for salt.…”

The Confluence of Population Genetics with Molecular Pharmacology at the Angiotensin II Receptor: Dawn of a New Era or Just a New Wrinkle?: Fig. 1.

“…Molecular genetics opened the door for investigators to start analyzing gene sequences in search of polymorphisms, and the angiotensin system was one of the first to be probed. Single nucleotide polymorphisms (SNPs) were identified in angiotensinogen, angiotensin-converting enzyme, and the AT 1 receptor genes and population geneticists undertook association studies to test relationships of these SNPs to different cardiovascular disorders, including hypertension (Hopkins and Hunt, 2003). The initial results were chaotic; inconsistency in replication became the initial resounding message (Jeunemaitre and Gimenez-Roqueplo, 2002;Koopmans et al, 2003;Zhu and Cooper, 2003).…”