(Circulation. 2000;102:IV-40.)
© 2000 American Heart Association, Inc.
Special Anniversary Issue |
Genetics of Hypertension, Target-Organ Complications, and Response to Therapy
From the Division of Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minn (S.T.T.), and the Human Genetics Center and Institute of Molecular Medicine, University of Texas–Houston Health Science Center (E.B.).
Correspondence to Stephen T. Turner, MD, Division of Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail turner.stephen{at}mayo.edu
Key Words: blood pressure • cardiovascular diseases • drugs • genetics • hypertension
This issue of
Circulation honors extraordinary achievements in
cardiovascular disease research during the past half century and their
impact on the prevention, evaluation, and treatment of cardiovascular
disorders. One area of particularly noteworthy advancement has been
that of hypertension, the most prevalent risk factor for diseases of
the heart, brain, and kidneys and one of the most common indications
for prescription medications. Because essential hypertension, defined
by systolic blood pressure levels 
140 mm Hg or diastolic blood
pressure levels 90 mm Hg, was the subject of a comprehensive 2-part
review recently published in
Circulation,1 2
this article will focus on 3 frontiers of hypertension research that
are undergoing particularly rapid advancement and are poised to
experience further profound developments with completion of the Human
Genome Project.3
These areas include new understanding of the genetic causes of
hypertension, the genetic susceptibility to target-organ complications,
and the pharmacogenetics of antihypertensive therapy. In each of these
areas, our objectives are to review present knowledge by highlighting
salient findings and to suggest where future advancements are likely to
improve the prevention, evaluation, and treatment of
hypertension.
Genetic Causes of Hypertension
Previous studies have yielded consistent and significant estimates of the genetic contribution to interindividual differences in both systolic and diastolic blood pressure levels. For example, in a sample of 1266 individuals in 278 non-Hispanic white pedigrees, the heritability of systolic blood pressure level (that is, the proportion of interindividual variation attributable to genetic differences among individuals) was estimated to be 0.37.4 Similar values have been reported for diastolic blood pressure level.5 Contemporary genetics research has advanced from the general recognition that "genes are involved" to identifying and characterizing specific contributing genes and gene variants.
Blood pressure levels are controlled by a complex combination of processes that influence cardiac output and peripheral vascular resistance.6 7 Many physiological, biochemical, and anatomic systems contribute to the determination of an individual’s blood pressure level; therefore, multiple genes potentially influence interindividual differences in blood pressure. Because blood pressure control involves a redundancy of traits with balancing pressor and depressor roles, the impact of any one gene may be reduced as its effect is transmitted across intervening levels of biological organization. In addition, the complexity of blood pressure regulation suggests that there is substantial genetic heterogeneity. Hence, individuals with the same blood pressure level do not necessarily have the same genotype at relevant loci, nor do individuals with the same genotype at particular loci necessarily have the same blood pressure level.
Recent studies have demonstrated genetic linkage and
association between marker loci and candidate genes that potentially
influence blood pressure level. For example, both Jeunemaitre and
colleagues8 and
Caulfield and
colleagues9 reported
positive linkage between variants at the angiotensinogen gene locus and
a gene contributing to essential hypertension. Jeunemaitre followed up
this linkage result with an association study between several variant
loci in the angiotensinogen gene and essential
hypertension.8 In
particular, the frequency of an M
T substitution at codon 235 of
angiotensinogen was associated with essential hypertension in 2
separate samples. Associations between the angiotensinogen gene
polymorphism and essential hypertension have been verified by
some,10 but not by
others.11 12 13
It is generally believed that the original association attributed to
the M235T polymorphism was due to its linkage disequilibrium with a
polymorphism at position -6, which is now known to influence
transcription levels of the AGT
gene.14
Even though a role for genetic variation in determining interindividual differences in blood pressure level and diagnostic category is no longer questioned, the identity of the contributing genes and their mechanism of action remain elusive. As already reviewed,1 2 Lifton and colleagues have made spectacular advances in identifying single genes underlying several rare mendelian forms of hypertension.15 16 Although the low frequency in the general population diminishes their public health impact, the contribution of these variants to understanding genetic pathways of blood pressure regulation is considerable. In particular, identification of genetic variants with large effects on pathways of blood pressure control provides direction to novel points for intervention, as exemplified by discovery of LDL-receptor mutations underlying familial hypercholesterolemia17 and the ultimate development of effective statin drugs.18 Despite successes in identifying genes for rare mendelian forms of hypertension, progress toward identifying and characterizing genes contributing to hypertension in the general population has been much more modest.
As a complement to biological candidate gene studies,
genome-wide linkage analyses are now considered the method of choice
for identifying hypertension susceptibility loci. We have completed the
first genome-wide linkage analyses to identify loci linked to genes
influencing blood pressure levels in the population at
large.19 Multipoint
linkage analyses of the 22 autosomes identified 4 regions showing
significant linkage to genes that influence systolic blood pressure
level. The 4 regions are located on chromosomes 2, 5, 6, and 15. One
region identified by this genome-wide linkage analysis, 5q33 to 5q35,
contains multiple candidate genes, including genes that encode the
ß2-adrenergic receptor, the
1b-adrenergic receptor, and the dopamine
receptor. We have resequenced each of these genes to identify the
spectrum of DNA variation in the population sampled and carried out a
series of association studies to identify which of these positional
candidate genes is influencing interindividual variation in blood
pressure level and diagnostic category (ie, hypertension versus
normotension).20 The
results of these positional candidate gene studies indicate that the
Arg16Gly and Gln27Glu polymorphisms in the
ß2-adrenergic receptor gene
(ADRB2) are influencing blood pressure levels and
diagnostic category in Rochester, Minn. For example, the frequencies of
both the Gly16 and Glu27 alleles were higher in hypertensives than in
normotensives (0.649 versus 0.604 and 0.490 versus 0.429,
respectively), and the odds ratio for the occurrence of hypertension
was 1.80 for the Glu27 allele. Moreover, an ADRB2
knockout mouse has been reported to have elevated blood pressure
level,21 and the
Arg16Gly and Gln27Glu substitutions have been shown to alter
ß2-adrenergic receptor function in
vitro.22
The genome-wide linkage scan discussed above is but an early ripple before a coming tidal wave of studies designed to localize genes for cardiovascular disease and its risk factors, including blood pressure. Sequencing of the human genome by both public and private efforts is rapidly progressing, as is the identification of sequence variation.23 It is therefore imperative that progress be made in placing this flood of genetic information in the context of contemporary medical practice by studying genotype-phenotype relationships.
Genetic Susceptibility to Target-Organ
Damage
A working hypothesis regarding genes that contribute to
development of hypertension-related target-organ diseases is
illustrated in
Figure 1
. First, there may be genes that do not
directly influence blood pressure but that cause primary disease of a
target organ (eg, gene 1). Elevated blood pressure, if present for
other reasons, may simply aggravate or accelerate the effect of such
genes on the primary disease process (dashed arrow in Figure 1). Second,
there may be genes that directly
influence blood pressure, and elevated blood pressure may in turn
directly contribute to the development of target-organ disease (eg,
gene 2). Third, there may be genes that contribute to target-organ
damage both through effects on blood pressure and via pathways separate
from blood pressure (eg, gene 3). The potential for pathogenetic
factors and pathological mechanisms that cause hypertension to also
lead to target-organ complications is emphasized by the observation
that many vasoconstrictor, antinatriuretic, and neuroexcitatory
substances—notably angiotensin II, norepinephrine, and endothelin—not
only raise blood pressure but also stimulate remodeling and
growth,24 2
recognized features of the cardiac and microvascular and macrovascular
complications of
hypertension.25 26
With the exception of cardiac hypertrophy, most of the other
target-organ complications of hypertension are the consequences of
chronic ischemia resulting from atherosclerosis of the conduit arteries
delivering blood to the organ and arteriolosclerosis of the small
muscular resistance arteries within the target organ
(Table).
|
|
Arteriolosclerosis involves small muscular resistance arteries within a target organ,24 whereas atherosclerosis involves larger elastic conduit arteries that supply blood to the organ.27 28 Arteriolosclerosis is characterized by thickening of the media of the vessel due to remodeling, hypertrophy, and/or hyperplasia of smooth muscle,24 whereas atherosclerosis is characterized by hyperplasia and remodeling primarily involving intimal cells.25 27 Research studies are beginning to identify genes that contribute to the cardiac and macrovascular and microvascular complications of hypertension and to characterize whether the effects of these genes are mediated through measures of blood pressure or via mechanisms other than blood pressure.
Among patients with hypertension, echocardiographic measures of left ventricular mass and geometry are powerful, independent predictors of clinical cardiovascular disease end-point events.29 30 The direct, continuously graded relationship between blood pressure levels and left ventricular mass and the consistent association of hypertension with left ventricular hypertrophy imply that pressure levels are a major determinant of left ventricular mass.31 Presumably, left ventricular hypertrophy is a structural compensatory response to increased mechanical load and wall stress. Other implicated determinants of left ventricular mass have included race, sex, age, body size, dietary sodium intake, blood viscosity, and measures of sympathetic neuron system and renin-angiotensin-aldosterone system activity.31
Left ventricular mass is a complex phenotype influenced by the interacting effects of multiple genetic and environmental factors. Twin and family studies have estimated the heritability of the left ventricular mass as between 22% and 59%.32 33 34 In genetically hypertensive rats, the heritability of left ventricular mass was estimated to be 76%, and 2 quantitative trait loci influencing heart weight were mapped to rat chromosome 1.35 Interestingly, one of these influenced only heart weight, and the other influenced both heart weight and blood pressure level. Thus, genetic variation probably contributes to interindividual differences in the left ventricular mass by virtue of effects on blood pressure level as well as via pathways that are not captured by measurements of blood pressure. It is possible that identification of genes that influence left ventricular mass may enhance the ability to identify genes that influence blood pressure, because left ventricular mass provides a more stable, anatomic measure of the average, integrated effects of blood pressure over a prolonged period of time.36 37
Consistent with the distinctions between atherosclerosis and arteriolosclerosis mentioned above, 2 forms of ischemic cerebrovascular disease are recognized: cortical infarction and subcortical ischemia.38 Subcortical ischemia is far more common than cortical infarction and is readily distinguishable on magnetic resonance imaging (MRI). Ischemic change in the subcortical white matter, referred to as leukoaraiosis, results from impaired blood flow in the long penetrating arterioles, whereas an occlusion in the distribution of the short penetrating arterioles produces lacunar infarction in the deep gray nuclei. Subcortical white matter ischemic change and lacunar infarctions tend to occur in the same persons and are ascribed to similar pathogenetic mechanisms.39
Strong evidence for genetic variance in MRI measures of leukoaraiosis was recently provided by a study of normal elderly male twins.40 Brain MRI scans (1.5 T) were obtained from 74 monozygotic (MZ) and 71 dizygotic (DZ) white male twins who were 68 to 79 years old when scanned. Genetic modeling estimated the heritability of leukoaraiosis volume to be 73%; correction for age and head size reduced the heritability to 71% (95% CI, 66% to 76%). Proband concordance rates for large volumes of leukoaraiosis (ie, >10 cm3) were 61% in MZ twins and 38% in DZ twins, compared with a prevalence of 15% in the entire sample.
Despite considerable literature supporting a genetic contribution to manifestations of atherosclerotic cerebrovascular disease,41 42 few studies have attempted to identify genes that contribute to manifestations of arteriolosclerotic cerebrovascular disease. One case-control study from Japan suggested an association of lacunar infarction with the deletion (D) allele of the insertion/deletion polymorphism of the gene coding for ACE in a small sample.43 Another reported an association with the T677C polymorphism of the methylenetetrahydrofolate reductase gene.44 Intriguingly, mutations in the human Notch3 gene on chromosome 19p13 have been identified to account for the rare mendelian disorder of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).45 Although hypertension is not a feature of the disorder, it is characterized by small-vessel and neuropathic changes reminiscent of those that underlie leukoaraiosis.42
Hypertension may be a consequence as well as a frequent cause of renal dysfunction. Among 332 544 men screened for the Multiple Risk Factor Intervention Trial (MRFIT), there was a graded relationship between levels of both systolic and diastolic blood pressure at baseline and risk of subsequent end-stage renal disease (ESRD), even after other predictors of ESRD risk (age, race, smoking, cholesterol, diabetes, myocardial infarction, and income) had been considered.46 The risk of ESRD is greater among minority populations, particularly among Mexican Americans and blacks.47 48 The most common renal pathological change associated with nonmalignant hypertension is hyalinization and sclerosis of the walls of preglomerular (afferent) arterioles, referred to as hypertensive nephrosclerosis.49
Familial aggregation of ESRD, including hypertensive ESRD, has been documented both in blacks50 51 and in whites.52 In pursuit of human renal failure susceptibility genes, Freedman and colleagues conducted linkage studies in black families affected by ESRD.51 Markers on chromosome 10q spanning the homologous region of the rodent Rf-1 gene did not show evidence for linkage to ESRD; however, 2 adjacent markers on chromosome 10p approached significance in sib pairs with nondiabetic ESRD.53 In other samples, evidence of linkage approached significance for the gene coding for transforming growth factor-ß2,54 and evidence of statistically significant association was found for alleles at the plasma kallikrein gene.55 However, the most direct evidence of renal failure susceptibility genes comes from studies of the fawn-hooded rat.56 Two genes, designated Rf-1 and Rf-2, were determined to contribute substantially to the development of renal impairment. Rf-1 explained 40% of the genetic component of renal impairment but showed no significant linkage or association with blood pressure levels, suggesting that the Rf-1 locus acts through a mechanism other than by increasing blood pressure. The second gene, Rf-2, mapped to a locus that influences blood pressure but also appeared to influence renal damage through a mechanism different from blood pressure.56
Antihypertensive Pharmacogenetics
A variety of mechanisms determine drug response.
Pharmacokinetic mechanisms that determine the level of the drug in the
blood, and ultimately at its target, include drug absorption,
distribution, excretion, and metabolism. Mechanisms that determine the
fate of the drug itself are distinguished from pharmacodynamic
mechanisms that govern the interaction of the drug with its target and
the subsequent events that occur. Genetic variation that alters the
structure, configuration, or quantity of any of the proteins involved
in any of these mechanisms may contribute to interindividual variation
in drug response. Knowledge of genes that influence the pharmacodynamic
determinants of blood pressure response to antihypertensive medications
has the potential to provide new insights not only into molecular
mechanisms that influence drug response but also into the role that
these genes may play in determining interindividual differences in
blood pressure and the occurrence of hypertension.
Although single-gene polymorphisms with large effects on
drug metabolism have been at the forefront of pharmacogenetic
investigation since its
inception,57 several
factors diminish their relevance to contemporary antihypertensive drug
therapy. First, agents that are metabolized predominantly by known
polymorphic enzymes with large interindividual differences in activity
are no longer widely used (for example, hydralazine and
-methyldopa). Second, for most antihypertensive drugs now in common
use, pharmacodynamic mechanisms play the predominant role in
determining interindividual variation in blood pressure responses. For
example, the dose-response relationships for most modern
antihypertensive drugs are
flat,58 59 60
and the magnitude of blood pressure lowering is similar for drugs
within a
class,61 62 63
despite considerable differences in their pharmacokinetic
properties.64 65 66 67 68
Consequently, there has been major interest in identifying genes that
influence the pharmacodynamic determinants of blood pressure
response.69 70
Cusi and colleagues reported linkage between markers at the
human -adducin locus and a gene contributing to
hypertension71 and
found that a variant allele, characterized by a glycine-to-tryptophan
change at amino acid 460 of -adducin (Trp460), was significantly
more frequent in 477 hypertensive patients than in 332 normotensive
control subjects. Because variants of the -adducin gene are
associated with increased renal tubular reabsorption of sodium and a
volume-expanded sodium-sensitive form of hypertension in
rats,72 the
investigators tested whether the Gly460Trp polymorphism in humans with
essential hypertension was associated with differences in the blood
pressure response to diuretic treatment with furosemide or
hydrochlorothiazide.71
In both protocols, the average blood pressure reduction was >2 times
greater in heterozygotes carrying the Trp460 variant than in Gly460
homozygotes. These findings were confirmed in a subsequent
trial,73 supporting
the contention that the -adducin polymorphism may be useful in
identifying a subset of salt-sensitive hypertensive patients more
responsive to diuretic therapy. These investigations also demonstrate
how a gene that contributes to hypertension via a particular
physiological mechanism (namely, increased renal sodium reabsorption
and volume expansion) can serve as a candidate gene to influence blood
pressure response to an antihypertensive agent that targets this
mechanism.
For many traits, there may be no known polymorphic candidate gene, or the list of possible candidates may be so extensive as to make investigation of all of them impractical. In this circumstance, a genome scanning approach can be used to first identify the chromosomal regions of genes that influence the trait, followed by positional cloning of candidate gene(s) within the linked regions.74 75 Because no prior knowledge or assumptions are required about gene function, the attractive feature of this method is the possibility of identifying new genes previously unsuspected to influence the trait. To the best of our knowledge, the only published genome-wide search for a pharmacogenetic trait locus used a rodent model of genetic hypertension to identify a region on rat chromosome 2 containing a gene that influences blood pressure response to a dihydropyridine calcium channel blocker (PY108-068).76
Future Developments
As a consequence of the Human Genome Project, complete
mapping and sequencing of all 50 000 to 100 000 genes in the human
genome77 are
expected to be completed before the year
2003.3 Among the many
methodological and technological advancements spawned by these
accomplishments, several are likely to expand the role of genetics in
hypertension-related research.
One capability that will facilitate the discovery of genes that influence the human hypertension-related phenotypes described above is the ability to perform genome-wide association studies using single-nucleotide polymorphisms (SNPs). Association studies that use biallelic SNPs measured in biologically unrelated individuals not only are inherently more powerful but also require fewer study subjects and thus are the only practical study design for genetic analyses of many hypertension-related phenotypes—in particular, antihypertensive drug responses. Dense SNP maps have the potential to reduce a genome-wide search for a gene that influences a hypertension-related phenotype to a relatively straightforward series of comparisons of allele frequencies between groups of unrelated individuals selected from opposite extremes of the phenotypic distribution.78
Collection and analysis of genotype information is likely to become a routine part of large clinical trials, especially those designed to assess blood pressure lowering and reduction in clinical cardiovascular disease events, such as myocardial infarction, stroke, and progression of renal disease. Genotyping of study participants can be viewed as a logical extension of the usual covariate information (such as race, sex, age, and body size).79 One can envision testing the effects of variation in known candidate genes as well as scanning the entire genome to identify loci harboring new genetic variants that influence blood pressure, development of target-organ complications, and responses to antihypertensive drug therapy.81 82 83 84 85
The ultimate goal of genetic knowledge is to advance beyond our current "one-size-fits-all" approaches to more individualized prevention, evaluation, and treatment of hypertension and its target-organ complications. The anticipated mapping and sequencing of all genes in the human genome3 implies that all of the genetic factors that contribute to interindividual variation in these phenomena will be discovered. The challenge will be to ascertain the functions of newly discovered genes, to assess the extent and impact of their polymorphisms, including gene-gene and gene-environment interactions, and to identify those pathways of effect that are valid targets for intervention.81 86 87 Discovery of genes that influence the development and progression of disease and discovery of genes that influence responses to antihypertensive therapy are reciprocal processes, inasmuch as disease genes become candidates to influence response to therapeutic interventions and response genes become candidates to influence disease activity.88 Knowledge of genes that contribute to the disease process and genes that influence therapeutic responses should also facilitate the development of novel preventive and diagnostic approaches that are based on a deeper understanding of the molecular determinants of the disease in individual patients. Certainly, the collection and analyses of unprecedented amounts of genetic information in the coming years have the potential to revolutionize the approaches to the prevention, evaluation, and treatment of hypertension and its associated target-organ diseases.
Acknowledgments
This work was supported by grants R01-HL53330, R01-HL54464, R01-HL51021, and R01-HL54481 from the US Public Health Service and National Heart, Lung, and Blood Institute and by funds from the Mayo Foundation.
References
1.
Carretero
O, Oparil S. Essential hypertension, I: definition and
etiology. Circulation. 2000;101:329–335.
2.
Carretero
O, Oparil S. Essential hypertension, II: treatment.
Circulation. 2000;101:446–453.
3.
Collins
F. Shattuck lecture. Medical and societal consequences of the human
genome project. N Engl J Med. 1999;341:28–37.
4.
Perusse
L, Moll P, Sing C. Evidence that a single gene with gender- and
age-dependent effects influences BP determination in a population-based
sample. Am J Human Genet. 1991;49:94–105.
5.
Ward R.
Familial aggregation and genetic epidemiology of blood pressure. In:
Laragh J, Brenner B, eds. Hypertension: Pathophysiology,
Diagnosis, and Management. New York, NY; Raven Press;
1995:67–88.
6.
Ferrannini
E. Metabolic abnormalities of hypertension: a lesson in complexity.
Hypertension. 1991;18:636–639.
7.
Guyton
A. BP control: special role of the kidneys and body fluids.
Science. 1991;252:1813–1816.
8.
Jeunemaitre
X, Soubrier F, Kotelevtsev Y, et al. Molecular basis of human
hypertension: role of angiotensinogen. Cell. 1992;71:169–180.
9.
Caulfield
M, Lavender P, Farrall M, et al. Linkage of the angiotensinogen gene to
essential hypertension. N Engl J Med. 1994;330:1629–1633.
10.
Jeunemaitre
X, Charru A, Chatellier G, et al. M235T variant of the human
angiotensinogen gene in unselected hypertensive patients.
J Hypertens. 1993;11:S80–S81.
11.
Fornage
M, Turner ST, Sing CF, et al. Variation at the M235T locus of the
angiotensinogen gene and essential hypertension: a population-based
case-control study from Rochester, Minnesota. Hum
Genet. 1995;96:295–300.
12.
Rotimi
C, Morrison L, Cooper R, et al. Angiotensinogen gene in human
hypertension: of an association lack of the 235T allele among
African-Americans. Hyperetension. 1994;24:591–594.
13.
Province
M, Boerwinkle E, Chakravarti A, et al. Lack of association of the
angiotensinogen-6 polymorphism with blood pressure levels in the
comprehensive NHLBI Family Blood Pressure Program. J
Hypertens. 2000;18:867–876.
14.
Inoue
I, Nakajima T, Williams C, et al. A nucleotide substitution in the
promoter of human angiotensinogen is associated with essential
hypertension and affects basal transcription in vitro. J
Clin Invest. 1997;99:1786–1797.
15.
Lifton
R. Molecular genetics of human blood pressure variation.
Science. 1996;272:676–680.
16.
Geller
D, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor
mutation in hypertension exacerbated by pregnancy.
Science. 2000;289:119–123.
17.
Goldstein
J, Hobbs H, Brown M. Familial hypercholesterolemia. In: Scriver C,
Beaudet A, Sly W, et al, eds. Metabolic and molecular bases of
inherited disease. New York, NY; McGraw-Hill Inc.;
1995:1981–2030.
18.
Alberts
A, MacDonald J, Till A, et al. Lovastatin. Cardiovasc Drug
Res. 1989;7:89.
19.
Krushkal
J, Xiong M, Ferrell R, et al. Linkage and association of adrenergic and
dopamine receptor genes in the distal portion of the long arm of
chromosome 5 with systolic blood pressure variation. Hum Mol
Genet. 1998;7:1379–1383.
20.
Bray
M, Krushkal J, Li L, et al. Positional genomic analysis identifies the
ß2-adrenergic receptor gene as a
susceptibility locus for human hypertension.
Circulation. 2000;101:2877–2882.
21.
Rohrer
D, Bernstein D, Chruscinski A, et al. The development and physiological
consequences of disrupting genes encoding 1 and 2 adrenoceptors.
Adv Pharmacol. 1998;42:499–501.
22.
Turki
J, Pak J, Green S, et al. Genetic polymorphisms of the
ß2-adrenergic receptor in nocturnal and
nonnocturnal asthma. J Clin Invest. 1995;95:1635–1641.
23.
Halushka
M, Fan J, Bentley K, et al. Patterns of single-nucleotide polymorphisms
in candidate genes for blood-pressure homeostasis. Nat
Genet. 1999;22:239–247.
24.
Berk
B, Alexander R. Biology of the vascular wall in hypertension. In:
Brenner B, ed. The Kidney. Philadelphia, Pa; WB
Saunders Co; 1996:2049–2070.
25.
Ross
R. Atherosclerosis: an inflammatory disease. N Engl J
Med 1999; 340:115–126.
26.
Heagerty
A, Aalkjaer C, Bund S, et al. Small artery structure in hypertension:
dual processes of remodeling and growth. Hypertension. 1993;21:391–397.
27.
Chobanian
A. 1989 Corcoran lecture: adaptive and maladaptive responses of the
arterial wall to hypertension. Hypertension. 1990;15:666–674.
28.
Zanchetti
A, Sleight P, Birkenhager W. Evaluation of organ damage in
hypertension. J Hypertens. 1993;11:875–882.
29.
Casale
P, Devereux R, Milner M, et al. Value of echocardiographic measurement
of left ventricular mass in predicting cardiovascular morbid events in
hypertensive men. Ann Intern Med. 1986;105:173–178.
30.
Koren
M, Devereux R, Casale P, et al. Relation of left ventricular mass and
geometry to morbidity and mortality in uncomplicated essential
hypertension. Ann Intern Med. 1991;114:345–352.
31.
Frohlich
E, Apstein C, Chobanian A, et al. The heart in hypertension.
N Engl J Med. 1992;327:998–1008.
32.
Post
W, Larson M, Myers R, et al. The heritability of left ventricular mass:
the Framingham Heart Study. Hypertension. 1997;30:1025–1028.
33.
Adams
T, Yanowitz F, Fisher G, et al. Heritability of cardiac size: an
echocardiographic and electrocardiographic study of monozygotic and
dizygotic twins. Circulation. 1985;71:39–44.
34.
Harshfield
G, Grim C, Hwang C, et al. Genetic and environmental influences on
echocardiographically determined left ventricular mass in black twins.
Am J Hypertens. 1990;3:538–543.
35.
Innes
B, McLaughlin M. Independent genetic susceptibility to cardiac
hypertrophy in inherited hypertension. Hypertension. 1998;31:741–746.
36.
Post
W, Larson M, Levy D. Cardiac structural precursors of hypertension.
Circulation. 1994;90(suppl
I):I-614.
37.
Iso H,
Kiyama M, Doi M, et al. Left ventricular mass and subsequent blood
pressure changes among middle-aged men in rural and urban Japanese
populations. Circulation. 1994;89:1717–1724.
38.
Phillips
S, Whisnant J. Hypertension and stroke. In: Laragh J, Brenner B,
eds. Hypertension. New York, NY; Raven Press;
1995:465–480.
39.
Roman
G. From UBOs to Binswanger’s disease: impact of magnetic resonance
imaging on vascular dementia research. Stroke. 1996;27:1269–1273.
40.
Carmelli
D, Park M, DeCarli C, et al. Genetic variability of brain parenchyma
and white-matter hyperintensity volume in elderly male twins.
Neurology. 1998;50(suppl
4):A439.
41.
Boerwinkle
E, Doris P, Fornage M. Field of needs: the genetics of stroke.
Circulation. 1999;99:331–333.
42.
Alberts
M. Genetics of Cerebrovascular Disease. New York, NY:
Futura Publishing Co; 1999.
43.
Doi Y,
Yoshinari M, Yoshizumi H, et al. Polymorphism of the
angiotensin-converting enzyme (ACE) gene in patients with thrombotic
brain infarction. Atherosclerosis. 1997;132:145–150.
44.
Notsu
Y, Nabika T, Park H, et al. Evaluation of genetic risk factors for
silent brain infarction. Stroke. 1999;30:1881–1886.
45.
Joutel
A, Corpechot C, Ducros A, et al. Notch3 mutations in cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL), a mendelian condition causing stroke and vascular dementia.
Ann N Y Acad Sci. 1997;826:213–217.
46.
Klag
M, Whelton P, Randall B, et al. Blood pressure and end-stage renal
disease in men. N Engl J Med. 1996;334:13–18.
47.
Chiapella
A, Feldman H. Renal failure among male Hispanics in the United States.
Am J Public Health. 1995;85:1001–1004.
48.
Klag
M, Whelton P, Randall B, et al. End-stage renal disease in
African-American and white men. J AMA. 1997;277:1293–1298.
49.
Fogo
A, Breyer J, Smith M, et al. Accuracy of the diagnosis of hypertensive
nephrosclerosis in African Americans: a report from the African
American study of kidney disease (AASK) trial. Kidney
Int. 1997;51:244–252.
50.
Bergman
S, Key B, Kirk K, et al. Kidney disease in the first-degree relatives
of African-Americans with hypertensive end-stage renal disease.
Am J Kidney Dis. 1996;27:341–346.
51.
Freedman
B, Bowden D, Rich S, et al. Genetic initiation of hypertensive and
diabetic nephropathy. Am J Hypertens. 1998;11:251–257.
52.
Spray
B, Attassi N, Tuttle A, et al. Familial risk, age at onset, and cause
of end-stage renal disease in white Americans. J Am Soc
Nephrol. 1995;5:1806–1810.
53.
Yu H,
Sale M, Rich S, et al. Evaluation of markers on human chromosome 10,
including the homologue of the rodent Rf-1 gene for linkage to
end-stage renal disease in blacks. Am J Kidney
Dis. 1999;33:1–8.
54.
Freedman
B, Yu H, Spray B, et al. Genetic linkage analysis of growth factor loci
and end-stage renal disease in African Americans. Kidney
Int. 1997;51:819–825.
55.
Yu H,
Bowden D, Spray B, et al. Linkage analysis between loci in the
renin-angiotensin axis and end-stage renal disease in
African-Americans. J Am Soc Nephrol. 1996;7:2559–2564.
56.
Brown
D, Provoost A, Daly M, et al. Renal disease susceptibility and
hypertension are under independent genetic control in the fawn-hooded
rat. Nat Genet. 1996;12:44–51.
57.
Weber
W. Pharmacogenetics. New York, NY: Oxford University
Press; 1997.
58.
Israili
Z. Correlation of pharmacological effects with plasma levels of
antihypertensive drugs in man. Ann Rev Pharmacol
Toxicol. 1979;19:25–52.
59.
Von
Bahr C, Collste P, Frisk-Holmberg M, et al. Plasma levels and effects
of metoprolol on blood pressure, adrenergic beta receptor blockade, and
plasma renin activity in essential hypertension. Clin Pharmacol
Ther 1976;20;130–137.
60.
Beermann
B, Groschinsky-Grind M. Antihypertensive effect of various doses of
hydrochlorothiazide and its relation to the plasma level of the drug.
Eur J Clin Pharmacol. 1978;13:195–201.
61.
Materson
B, Reda D, Cushman W, et al. Single-drug therapy for hypertension in
men: a comparison of six antihypertensive agents with placebo.
N Engl J Med. 1993;328:914–921.
62.
The
Treatment of Mild Hypertension Research Group. The treatment of mild
hypertension study: a randomized, placebo-controlled trial of a
nutritional-hygienic regimen along with various drug monotherapies.
Arch Intern Med. 1991;151:1413–1423.
63.
Materson
B, Reda D, Preston R, et al. Response to a second single
antihypertensive agent used as monotherapy for hypertension after
failure of the initial drug. Arch Intern Med. 1995;155:1757–1762.
64.
Hall
W, Reed J, Flack J, et al. Comparison of the efficacy of
dihydropyridine calcium channel blockers in African American patients
with hypertension. Arch Intern Med. 1998;158:2029–2034.
65.
Zusman
R. Are there differences among angiotensin receptor blockers?
Am J Hypertens. 1999;12:231S–235S.
66.
Burnier
M, Brunner H. Comparative antihypertensive effects of angiotensin II
receptor antagonists. J Am Soc Nephrol. 1999;10:S278–S282.
67.
Wahl
J, Turlapaty P, Bramah N, et al. Comparison of acebutolol and
propranolol in essential hypertension. Am Heart
J. 1985;109:313.
68.
Leonetti
G, Cuspidi C. Choosing the right ACE inhibitor: a guide to selection.
Drugs. 1995;49:516–535.
69.
Bianchi
G, Swales J. Do we need more anti-hypertensive drugs? Lessons from the
new biology. Lancet. 1995;345:1555–1557.
70.
Ferrari
P. Pharmacogenomics: a new approach to individual therapy of
hypertension? Curr Opin Nephrol Hypertens. 1998;7:217–222.
71.
Cusi
D, Barlassina C, Azzani T, et al. Polymorphisms of a-adducin and salt
sensitivity in patients with essential hypertension.
Lancet. 1997;349:1353–1357.
72.
Manunta
P, Barlassin C, Bianchi G. Adducin in essential hypertension.
FEBS Lett. 1998;430:41–44.
73.
Glorioso
N, Manunta P, Filigheddu F, et al. The role of
74.
Collins
F. Positional cloning: let’s not call it reverse anymore. Nat
Genet. 1992;1:3–6.
75.
Collins
F. Positional cloning moves from perditional to traditional.
Nat Genet. 1995;9:347–350.
76.
Vincent
M, Samani N, Gauguier D, et al. A pharmacogenetic approach to blood
pressure in Lyon hypertensive rats. J Clin
Invest. 1997;100:2000–2006.
77.
Fields
C, Adams M, White O, et al. How many genes in the human genome?
Nat Genet. 1994;7:345–346.
78.
Collins
F, Guyer M, Chakravarti A. Variations on a theme: cataloging human DNA
sequence variation. Science. 1997;278:1580–1581.
79.
Schork
N, Weder A. The use of genetic information in large-scale clinical
trials: applications of Alzheimer research. Alzheimer Dis Assoc
Disord. 1996;10:22–26.
81.
Dutton
G. Computational genomics: medicine of the future? Ann Intern
Med. 1999;131:801–804.
82.
Persidis
A. Biotechnologies to watch: which technologies promise to make
significant contributions to biotechnology’s drug pipeline?
Nat Biotechnol. 1997;15:1409.
83.
Persidis
A. The business of pharmacogenomics: considered the heir apparent to
functional genomics, pharmacogenomics promises to redefine basic
notions of what constitutes a disease. Nat Biotechnol. 1998;16:209–210.
84.
Dorey
E. Millennium exploits retained right with new venture. Nat
Biotechnol. 1997;15:614.
85.
Marshall
A. Phase II results in rheumatoid arthritis encouraging for Immunex.
Nat Biotechnol. 1997;15:829–830.
86.
Grahame-Smith
D. How will knowledge of the human genome affect drug therapy?
Br J Clin Pharmacol. 1999;47:7–10.
87.
Wiley
S. Genomics in the real world. Curr Pharm Design. 1998;4:417–422.
88.
Evans
W, Relling M. Pharmacogenomics: translating functional genomics into
rational therapeutics. Science. 1999;286:487–491.
-adducin polymorphism
in blood pressure and sodium handling regulation may not be excluded by
a negative association study. Hypertension. 1999;34:649–654.
This Article 
Extract
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Permissions Citing Articles
Citing Articles via Google Scholar
Google Scholar
Articles by Turner, S. T.
Articles by Boerwinkle, E.
Search for Related Content
PubMed
PubMed Citation
Articles by Turner, S. T.
Articles by Boerwinkle, E.
Related Collections
Cardiovascular Pharmacology
Cerebrovascular disease/stroke
Genomics
Genetics of Stroke
Genetics of cardiovascular disease