Journal of Human Hypertension (1999) 13, 225–229 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Genetic epidemiology of essential hypertension I Gavras1, A Manolis1,2 and H Gavras1 1Hypertension and Atherosclerosis Section of the Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 2Tzanio Hospital, Piraeus, Greece This review article is intended to introduce the unini- heritable anthropometric, clinical or biochemical tiated clinician to the basic concepts, aims and early characteristics; and some applications of genetic epi- findings of the genetic epidemiology of hypertension. It demiologic techniques, such as linkage and association separates the rare monogenic ‘Mendelian’ hypertensive studies of certain gene polymorphisms with hyperten- disorders from the vast majority of patients with essen- sion using affected sibling pairs and large sibships or tial hypertension, which is a complex, polygenic, multi- wide genomic screens comparing affected and unaffec- factorial disorder resulting from interaction of several ted populations. Although so far there is no genotypic genes with each other and with the environment. It high- variation proven to be causally related to essential lights some clinical strategies used to enhance hypertension, its intermediate phenotypes or any of its searches for ‘candidates genes’, such as subgrouping complications, it is hoped that new, more efficient of populations into relatively homogenous groups or methods of genetic analysis will yield clinically mean- ‘intermediate phenotypes’ according to presumably ingful information. Keywords: gene polymorphisms; candidate genes; monogenic disorders; intermediate phenotypes; polygenic multifactorial traits Hypertensive phenotypes the interaction of several genes with each other and with the environment result in different phenotypes. Essential hypertension results from the interaction Hypertension is often associated with insulin of hereditary and environmental factors and is one resistance ranging from borderline fasting of the leading causes of premature cardiovascular hyperglycaemia/hyperinsulinaemia to clinically morbidity and mortality. Blood pressure levels are overt diabetes mellitus type II. The frequent coexist- highly correlated among family members, a fact ence of the two conditions has suggested a common attributable to either common genetic background or aetiologic background.4 If left untreated, hyperten- shared environment and lifestyle habits, or both. sion results in target organ complications, such as Studies of familial aggregation and rates of concord- congestive heart failure, stroke and renal failure, all ance among monozygotic and dizygotic twins sug- of which can be prevented to various extents by gest that genes may contribute as much as 40% of 1 optimal blood pressure control. Coronary artery dis- the risk to this disorder. High blood pressure, ease is also a frequent complication of both hyper- defined as systolic pressure у140 mm Hg and dia- у tension and diabetes, but appears to be less prevent- stolic 90 mm Hg, is characterised by a high but able by optimal blood pressure control.5 For these variable prevalence rate of 15–25% among popu- reasons, it is now accepted that arterial blood press- lations.2 But blood pressure does not have a bimodal ure elevation per se is only one of the factors con- distribution into normal and abnormal groups. tributing to target organ damage and does not con- Rather, it is a quantitative trait with wide pheno- sistently predict the occurrence or severity of typic variation and a continuous distribution, where hypertensive complications. In other words, hyper- an arbitrary cutoff line at some point of the Gaussian curve separates normal from abnormal. This indi- tension is too broad a phenotype. Over the years several efforts have been made to cates that hypertension is a complex trait, ie, a 5 phenotype that does not follow the classic Mendel- classify essential hypertensive into subtypes or ian rules of dominant or recessive inheritance ‘intermediate phenotypes,’ ie, subgroups homo- attributable to a single gene locus.3 More likely, it is geneous for one or more traits that might have diag- a polygenic and multifactorial disorder, in which nostic or prognostic significance. Various clinical or biochemical characteristics have been chosen in an effort to better define patients at risk of compli- cations. An early such effort was the classification Correspondence: Dr Haralambos Gavras, Chief, Hypertension & into renin subgroups (ie, patients with high, normal Atherosclerosis Section, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA or low plasma renin activity in relation to their Received 15 October 1998; revised 16 November 1998; accepted blood pressure and state of sodium balance). It was 10 December 1998 shown in both retrospective and prospective surveys Genetic epidemiology of essential hypertension I Gavras et al 226 that high-renin patients are at increased risk of myo- partly responsible for these findings, it is felt that cardial infarction,6,7 a finding in agreement with the genetically determined characteristics play an equal demonstration that excess angiotensin II of exogen- or more important role.11–14 Differences in the bio- ous or endogenous origin can produce myocardial chemical and endocrine profiles of black hyperten- infarcts.8,9 sives suggest different pathophysiologic mech- A trait deemed to be useful for classification into anisms than in white hypertensives.15 A prime subgroups that would enhance subsequent genetic example of such a biological difference is the analysis, should be pathogenically meaningful and increased frequency and magnitude of salt sensi- show evidence of heritability. Because essential tivity (ie, magnitude of blood pressure rise in hypertension is a complex disorder, in which many response to a sodium load), which is encountered different genes at various loci are likely to be in about three-quarters of hypertensive black involved, it is expected that phenotypically different patients.16 Salt sensitivity is associated with dimin- subjects may present with different constellations of ished ability to excrete a sodium load, and hence gene mutations. Thus, searching for underlying gen- tendency to retain salt, which is attributable to a var- etic causes might be more likely to be fruitful in sub- iety of mechanisms, including alterations in cation populations classified according to intermediate transport across cell membranes, abnormal renal phenotypes. Presumably heritable clinical charac- haemodynamics, and decreased generation of intra- teristics, that have been used to subdivide the hyper- renal natriuretic substances such as kinins, atrial tensive population, include obesity (defined by the natriuretic peptides, prostaglandins and dopamine. body mass index), abdominal adiposity (defined by Black hypertensives also tend to exhibit differences the waist-to-hip ratio), early onset of hypertension in other endocrine characteristics, such as low (eg, before age 50 years), excessive severity of hyper- plasma renin activity, higher levels of endothelin,17 tension (eg, requiring triple drug regimen), hyperres- augmented alpha-adrenergic receptor reactivity, ponsiveness to adrenergic stimuli, salt sensitivity, higher levels of plasma vasopressin (AVP) and etc. Biochemical traits include elevated fasting glu- accentuated hypotensive response to an antivaso- cose and insulin levels, elevated circulating levels pressor AVP antagonist.18 It has also been proposed, of pressor hormones such as renin, catecholamines but not uniformly accepted, that black subjects have and vasopressin, altered characteristics of alpha- relative insulin resistance.15 Of particular interest is adrenergic receptors, decreased activity of the kal- the fact that some of these racial differences have likrein-kinin system, different hormonal responses been observed not only in black hypertensives but to salt loading, etc. Several of these traits have been also in black normotensives compared to age and shown (or are predicted) to coexist in the same indi- gender-matched Caucasians. For example, in a nor- vidual. For example, low-renin individuals are motensive population, lower levels of urinary kal- likely to have low kallikrein excretion and high cir- likrein were reported not only in black vs Caucasian culating vasopressin. Other biochemical parameters, adults19 but also in children.20 In fact, it is possible such as angiotensin-converting enzyme and angio- that low levels of kallikrein might be one reason for tensinogen levels, lipid profile, etc, have also been lack of a local renoprotective effect of kinins and reported to differ among hypertensive populations increased propensity of black hypertensives to renal and possibly contribute to cardiovascular risk. damage, even under good blood pressure control. A common intermediate phenotype is the so- There is strong clinical evidence suggesting that, called metabolic syndrome X. This consists of a con- although salt-sensitivity tends to increase with age, stellation of clinical and biochemical character- it has a large heritable component.21 The high preva- istics, including hypertension, abdominal adiposity lence of salt-sensitivity described in African Amer- (‘apple shape’), hyperlipidaemia, hyperglycaemia icans appears to be also present in native Africans, and hyperinsulinaemia.4 Each one of these charac- as