Genetics of Hypertension Study (original) (raw)

Genetics of Essential Hypertension: From Families to Genes

Journal of the American Society of Nephrology, 2002

Family studies demonstrated the contribution of genetic factors to the development of primary hypertension. However, the transition from this phenomenologic-biometric approach to the molecular-genetic one is more difficult. This last approach is mainly based on the Mendel paradigm; that is, the dissection of the poligenic complexity of hypertension is brought about on the assumption that the individual genetic variants underlying the development of hypertension must be more frequent in hypertensive patients than in controls and must cosegregate with hypertension in families. The validity of these assumptions was clearly demonstrated in the so-called monogenic form of hypertension. However, because of the network of the feedback mechanisms regulating BP, it is possible that that the same gene variant may have an opposite effect on BP according to the genetic and environmental backgrounds. Independent groups of observations (acute BP response to saline infusion, incidence of hypertension in a population follow-up of 9 yr, age-related changes on BP) discussed in this review suggest a positive answer to this question. Therefore the impact of a given genetic variant on BP level must be evaluated within the context of the appropriate genetic epistatic interactions. A negative finding or a minor genetic effect in a general population may become a major gene effect in a subset of people with the appropriate genetic and environmental backgrounds.

The Genetic Basis of Hypertension

Journal of medicine and healthcare, 2020

Arterial hypertension as a compounding burden of public health Hypertension (HTN), i.e. increase in blood pressure (ΒΡ) >140/90mmHg is a major risk factor for many manifestations of cardiovascular disease continuum, such as stroke, myocardial infarction, kidney failure and heart failure [1]. Cardiovascular disease is the leading cause of death worldwide, accounting for 17 million deaths. The complications of HTN are responsible for 9 of the 17 million deaths [2] .The incidence of hypertension increases with age, so >2/3 of people over the age of 75 are hypertensive. In a large European survey focusing on primary prevention, BP is regulated in only 38% of hypertensive people receiving medication [3]. This is of interest, as antihypertensive treatment has shown in many studies to be beneficial in reducing cardiovascular morbidity and mortality [4]. Causes of suboptimal BP control The role of the interaction of mechanistic-environmentalgenetic factors There are several reasons for the insufficient regulation of BP in high-risk patients. One of the most important is that the pathogenesis of hypertension is multifactorial since environmental, mechanistic and genetic factors that remain largely unclear are involved in its etiology. From a mechanistic hydrodynamic point of view, BP is expressed by Ohm's law: Pressure = Flow x Resistance The flow depends on the cardiac output (L/min) and the resistance from the peripheral resistances, i.e. the tone of the arterioles and precapillary sphincters. However, the flow depends on environmental factors (e.g. excessive salt intake) and the tone of the vessels depends on the interaction of the autonomic nervous system and the action of hormones [5]. Many other factors, such as age, obesity, smoking, alcohol consumption and physical activity, affect BP levels and make it very difficult to calculate the weight of each factor in BP regulation. Recently, genome testing has begun to be used to detect specific genotypes that underlie the "essential hypertension" phenotype [6].

Epidemiology and genetics of hypertension

Hypertension

The major decline in cardiovascular mortality during the last 20 years may be related to improved hypertension control, but a causal relationship has not been proven. Fundamental epidemiologic associations between age, sex, race, socioecomonic class, and blood pressure (BP) have been well characterized. Risk of coronary heart disease and stroke mortality and morbidity is linearly related to BP or to categorically defined hypertension. Weight is a major correlate of BP at all ages and in most populations. The relationships between hypertension and other nutritionally related factors are not so well defined. The Framingham Study (both cohort and offspring components) provides information about other BP correlates such as heart rate and clinical chemistry values as well as evidence suggesting a genetic influence on BP variability in families. Combined with observations from other studies, it appears that heredity plays a very important role in human hypertension.

Genetic Determinants of Hypertension

Hypertension, 2000

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in Ͼ200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia. (Hypertension. 2000;36:7-13.

Genetics of hypertension FAMILY HISTORY OF HYPERTENSION AND HERITABILITY OF BLOOD PRESSURE

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 pressures compared to normal blood pressure. 23 Untreated, malignant hypertension is associated with a 5-year mortality rate of 95% with 65% dying from congestive heart failure, 14% from renal failure, 11% from myocardial infarction, and just 5% from cerebral hemorrhage. Like premature CAD, hypertension is a familial disease. This was recognized as early as 1923 in Germany. 25 Using historical family data from over 94,000 individuals, we found that the risk of developing hypertension after 1970 in persons under age 50 was approximately doubled for each

The Genetic Basis of Hypertension: An Overview

Avicenna Journal of Pharmaceutical Research

In light of the widespread recognition of the heritability of hypertension (HTN), numerous studies have been conducted to better understand the pathogenesis of different variants of HTN and their interactions. The complexity of crucial HTN makes it difficult to segregate and identify particular genes that influence blood pressure (BP) fluctuation, making the development of single-gene targeted treatments tough. Therefore, finding HTN susceptibility genes will contribute to the understanding of the biology behind the disease. Apart from its potential impact on antihypertensive drug therapy selection, genomic information may also contribute to identifying persons at risk of developing the condition, resulting in new preventative strategies. It is necessary to conduct more replication studies in other populations to confirm that there is a link between certain genetic variations and the varying response to these frequently used antihypertensive medications. Moreover, antihypertensive m...

Genetic Predisposition to Hypertension and Cardiovascular Disease

Progress in Experimental Cardiology, 2003

Sehool if Medicine Summary. Essential hypertension occurs in individuals with a genetic predisposition who respond abnormally to environmental changes. A complex interplay of a number of genetic alterations and environmental factors is involved in the pathogenesis of hypertension. Therefore, hypertension does not follow a clear pattern of inheritance but exhibits familial aggregation of cases. Areverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the complex interplay. To clarify the role of gene polymorphisms in hypertension, we have carried out case-control studies using a candidate gene approach. We mainly focused on gene components of the renin-angiotensin system as candidates, and obtained some suggestive positive results in the association with hypertension, but the estimated relative risk for hypertension was less than 2.0. These results led us to recognize the importance of investigation using a general population with a sufficient number of subjects. We collaborated in two large epidemiological cohort studies and examined the association between genetic factors and the participants' health status in each of them. To deal with a large number of sampies, we established the TaqMan peR method to save time and cost of genotyping. Our investigations revealed a small but significant effect of gene polymorphisms in increasing the risk for hypertension, and suggested interactions with environmental factors such as aging, sex, and salt intake. In this review, we discuss the consensus and controversy of genetic investigations for identification of hypertensive genes and consider the future of tailor-made medicine.