CLIN. AND EXPER. HYPER.-THEORY AND PRACTICE, A12(5), 865-876 (1990)
GENETICS OF HYPERTENSION: WHAT WE KNOW AND DON’T KNOW
ROGER R. WILLIAMS, STEVEN C. HUNT, SANDRA J. HASSTEDT, PAUL N. HOPKINS, LILY L WU, MOMAS D.
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BERRY, BARRY M. STULTS, GARY K. BARLOW, AND HlROSHl KUlDA
CARDIOVASCULAR GENmCS RESEARCH WNIC, UNMRSrrY OF UTAH MEDICAL SCHOOC.SALT LAKE CITY,
UTAH, USA
SUMMARY
Human
hypertenslon Is
arterial
measurable
monogenes,
environment.
Familial
blended
likely
a
multlfactorlal
polygenes,
aggregation
of
shared
trait
family
resulting
from
multlple
environment, and
hypertension and
familial
correlation
pressure appears to be more due to genes than to shared family environment.
Indlvldual
of
blood
Total genetic
heritability of 80% with some recessive major gene effects have been found for several traits assoclated sodium,
with
and
hypertenslon
hypertenslon
Including
sodium-lithium genetics
urinary
countertransport.
Include:
kallikreln Other
non-modulatlon of
excretlon,
interesting
the
renln
intraerythrocytlc
factors anglotensln
regarding system,
intralymphocytlc sodium, ionized calcium, and several genetic markers such as haptoglobin, HIA, and MNS blood type.
Probably the most cllnlcally useful lnformatlon regardlng the
genetics of hypertension Is evolving In several studies reporting a strong associatlon of hypertenslon with dyslipkiemla, diabetes, and obesity.
Key words:
hypertenslongenetlcs-
epldemlology-pathophyslology-blochemls~ry-llplds-famlly history-coronary heart dlsease.
INTRODUCTION
Hypertenslon Is one of the most common chronic diseases and one of the most common reasons for asymptomatlc persons taking prescription medicatlon.
It has consistently been one of the
most prominent risk factors for myocardial lnfarctlon and stroke, the most common causes of death in many countrles.
The large number and expense of studies used to determine belter
865 C o p y r a t 0 1990 by Marcel Dekker, inc.
WILLIAMS ET AL.
866
methods for diagnosing, treating and
preventing arterlal
hypertenslon reflect the
hlgh
prlority of understandlngthis disorder.
Whle numerous studies have found individual pleces in the puzzle of the pathophyufology of hypertension, a clear picture of exactly how they
all M together Is not yet available.
From
all indications, genetic factors must play a very Important rde in this overall picture. While the studles are numerous, and the methods are cornpllcated, e few basic observations illustrate
some
answers
to
important
questions
regarding
the
genetics
of
They also helped to point to other important questions for which answers are
hypertension. Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
consistent
not yet available.
FAMILIAL CORRELATION
Population-based studles of different types of family members have consistently shown that Mood pressure correlates very well in related famlly members and poorly among spouses and adopted children with their parents who share the same environment but do not share the same genes (1-5). Some of the specHIc obsewations are shown in TaMe 1.
Familial correlations can be due to shared family environment or assortatlve mating as genes.
as well
As shown In Table 2, several Important variables shown to be assoclated with
Table 1. Blood Pressure Correlatlons In Familleg Pearson Correlation Famiiv Members
&&)
SBP
Spouse Pairs
(1433)
0.08
0.06
Adoptees Parents
(379)
0.03
0.09
Offspring - Parents
(831)
0.18
0.16
(2618)
0.18
0.14
-
Sibling Pairs
DBP
DZ Twins
(264)
0.25
0.27
Mi! Twins
(248)
0.55
0.58
Combined data from 5 studles: Framingham (l), Tecumseh (2), Evans County (3). Canadian Adoptlon (4). and NHLBI twins (5).
GENETICS OF HYPERTENSION Table 2. Familv Correlations For Non Genetic Variabigg Variables
intraclgss Correlation Coeffi&nts
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Tested
MZ114Q
)-,
Bro1219)
&L@U)
Education
0.57 a
0.55 a
0.40 a
0.47 a
Alcohol
0.70 a
0.24 c
0.40 a
0.50 a
Smoking
0.68 a
0.11
0.16 C
0.31 a
Salt Use
0.38 b
0.20
0.28 a
0.23 a
Exercise
0.41 a
0.12
0.16 C
0.18 a
b = P < 0.01
a = P < 0.001
c = P < 0.05
Results after adjusting for age (and sex within spouse pair), from Utah twins and pedigrees (6). Number of persons indicated in parentheses.
hypertension show excellent correlations in twins, brothers, and spouses.
A higher degree
of correlation among monozygous (MZ) twins when compared to dizygous (DZ) twins is mathematically interpreted as evldence for genetic herltabiilty in many studles.
Following
this reasoning In TaMe 2, one would reach the conclusion that alcohd intake, current smoking status,
and frequency of
vigorous aerobic exercise are all
highly genetically
determined traits since they show significantly higher correlations in MZ twins than in DZ twins.
It is clear that for some environmental variables MZ twlns are more similar than
DZ
twins leading to an overestimation of genetic heritability in most reported twin studies. Shared environment often reflects habits established In childhood.
This likely explains the
observation in Table 2 of significant familial correlations for frequence of salt use among adult relatives not living in the same household. could
reflect
either
current
shared
Current salt use preferences among spouses
environment
or
assortatbe
mating
for
dietary
preferences.
HERITABILITY ESTIMATES FOR BLOOD PRESSURE
Using mathematical models and formulas, statisticians try to quantitate what proportion of the total variatlon of selected variables can be explained by a Mended combination of ail genes affecting that coulU
bb
trait
explained by
(pdygenes), and what shared
environmental
additional proportion of
factors.
This
statistical
the variation estimation
of
WILLIAMS ET AL.
868
3: Polvaenlc and Fnviro-b
iiitv Fstlmateg
I 2
Variables
Tested
Shared
m J 3 d U rM
(c')
rnironment
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Metabdic: Chdesterol
61% a
42% a
8%
Trigiycerkles
81% a
37% a
6%
HDL-Chd
74% a
45% a
15%
W/HT2
54% b
24% a
0%
Sitting
60% C
22% a
3%
Standing
63%
21% b
3%
Math
44%
23% a
8%
Bicycle
49%
38% a
0%
Hand Grip
50%
17% b
0%
a = P < 0.001
b = P < 0.01
c
=
P < 0.05
Results after adjusting for age and sex for all variables as well as grip strength and workload respecthraly for hand gdp and bicycle Mood pressures. From Utah twins and pedigrees (6).
variability
Is called pdygenlc heritability (h*)
or
envlronmental heritability (cs.
Table
3 presents heritability estimates from 340 Utah twins and 2,500 persons belonging to 98 Utah pedigrees screened at the University of Utah, Cardiovascular Genetics Research Clinic.
it
Is interesting to
note
that
herltabillty estimates
analysis of twins than from pedlgrees.
are
consistently higher from
the
This could be due to failure of the mathemtlcal twln
model to account for MZ twins having more shared gene-gene interactions and greater environmental similarity (see in Table 2). consistently
support
signmcant
polygenlc
However, results from both twlns and pedigrees determination
for
all
sitting
diastolic
pressures and several metabolic variables related to coronary risk and hypertension. estimates of varlance attributable to shared family environment are large sample size wodd be required to obtain statistical signmcance. similar
studies,
80
Mood The
small that a very
From these and other
It seems consistently established that genes rather than shared famlly
GENETICS OF HYPERTENSION
869
environment are responsible for most of the familial aggregation of Mood pressure and associated metabolic factors.
COMPLEX SEGREGATION ANALYSIS IN PEDIGREES
When family correlation studies suggest genetic determination for variables, a l o g l d next step is to test for genetic transmission, and attempt to determine the mode of transmission (recessive,
dominant,
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transmission).
additive,
poiygenlc,
or
polygenlc
mixtures of
and
monogenic
Thls can currently be accomplished with sophisticated statlstlcal formulas
tested using maximum likelihood methods embedded in computer programs. mathematics is complicated, the concept is quite straight forward.
While the
The computer simply looks
at the measured values of a particular trait for each person and asks simple questions such as:
Do all the values seem to fail into a single continuous distribution (supporting
poiygenic traits) or Into two or more discreet distributions (supporting recessive dominant or additive major gene traits)?
Do the values of the children tend to fall halfway between
the parents (supporting polygenic), or do they tend to fall Into one of distributions closer to one of the two parents (supports major gene)?
two
discreet
Do children tend to be
"affected" only when one parent is affected (dominant), or does it almost always occur when only two parents are affected (recessive)?
What percentage of offspring are 'affected' when
no parents are affected. when one parent is affected or when both parents are affected? Mathematical models can be made even more complicated to include factors that may affect the likelihood of an inherited trait being 'penetrant"
or expressed.
For example, the model
could assume 20% of gene carriers will express it under age 20 but 50% will express it over age 40. The model can also assume that among individuals with a particular allele of a monogenic trait, variation within those subjects can be attributed to
pdygenlc effects.
Thls full
mathematical model of genetic transmission In pedigrees Is often referred to as the 'mked model'.
Carrying out these type of calculations for large numbers of obselvations in
pedigrees would be prohlbitive without the beneflt of electronic computers.
Even with their
help, a considerable amount of work Is required for many months to obtain Informative and reliable results.
Table 4 shows the results obtained from pedigree analysis of biochemical
traits associated with human hypertension.
All of them show very high total heritability
estimates, even higher than those seen for well-known genetically influenced traits such as plasma cholesterol level (total heritability 42%).
It
is also interesting to note that all
of the variables shown in Table 4 have both polygenlc and recessive monogenic components.
WILLIAMS ET AL. Table 4. Heritabilltv of Bbchemtcal fraits Assoclata Human Arterlal HvDertensIon
Mode of
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Biochemical Traitg
Herltabllltv fh2)
Transmlssion
J&jQr+&&=m
Urlnary Kallikrein Excretion
Recessive
51%
27%
78%
intraerythrocytlc Sodium
Recessive
29%
55%
84%
Sodium-Lithium Countertransport
Recessive
34%
46%
80%
Lithium Potassium Cotransport
Recessive
14%
33%
47%
Results from several studies of multlgeneratlonal Utah pedigrees (7,8,9).
None of the traits llsted In Table 4 can be consldered as direct causal factors leading to hypertension.
They
are
associated with
hypertension through
studles
showing
that
slgnfflcantly different levels are observed between persons with hypertension versus these
without hypertenslon and/or between normotensive persons with and without a positive family history of hypertenslon.
Moat of these biochemical traits are likely to be quantitative risk factors for hypertenslon llke Mood cholesterol level Is for coronary dlsease.
Whlle on the average persons with
dlsease have hlgh rlsk values and persons without the dlsease have lower risk values. hlgh
rlsk values for some traits are seen in some persons without disease, and low risk values are seen In some persons with disease.
Also llke coronary risk factors, no slngle trait likely
predlcts hypertenslon in any given lndivldual.
A battery of several quantitative traits such
as those llsted In Table 4 may help predlct future hypertension just as a battery of risk
factora are now used to help predict coronary disease. OTHER INTERESTING FACTORS Many Interesting factors have been examined In studies of persons with and without a family history of hypertension or In sibshlps or other famly groups where hypertension
Is found.
Only a few of them are llsted In Table 5 (10-16) with longer lists presented in other reviews (17-19).
Slnce sodlum intake remains one of the most interesting environmental variables
thought to be involved In the pathophysldogy of hypertension, several of these factors are
an
GENETICS OF HYPERTENSION Table 5. Other lnterestina Factors Ralardlno HvDertenslon Genetlcg
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Factor
lnterestino Observations
Haptoglobln Genotype
BP Response To Acute Sodium Loadlng
HIA Qenotype
Some HBP Association & Linkage Studies
MNS Genotype
Some HBP Assoclatlon Studies
lonked Calcium
Family History of Hypertension (FHx HBP)
Nonmodulatlon
Bimodal, Familial, Positive FHx HBP
Renin-Anglotensln
Be Physiology, DNA Markers Available
WBC Sodlum
FHx HBP and Bicycle BP Reacttvity
Dysllpldemlc HBP
FHx HBP, Coronary Risk, Insulin
Diabetes
Heritable Disease with HBP Common
Obeslty
Carries a lot of Weight In Most HBP Studies ~
Multiple studies (10-16) discussed In prior revlews (17-19).
InValVed
In
sodium and
electrolyte metaboilsm.
Different alleles
of
the
haptoglobin
genotype were significantly associated with different Mood pressure responses to acute sodlurn loading (10). Commonly studied genetic markers such as HLA tissue type and MNS blood type have been shown in some studies to be associated or genetically linked to presence of hypertension (11).
Some traits such as ionized calcium and blunted response to angiotensln
II infuslon ("non-modulation") show signlflcant dlfferences between persons wlth and without a positive family history of hypertension (12-13). pressures and biochemical tests together.
Some studies have used innovative blood
In one such study, high lntralymphocytic sodium
concentratton was associated wlth a positive family history of hypertension and even more dramatically associated with a subset of
indtviduats who had exaggerated increases In
dlastollc blood pressure in response to bicycle exercise (14).
The fleld of molecular biology Is rapidly providing tods for even more sophisticated genetic studies.
For speclflc hormones such as renln, angiotensln, and kallikreln, DNA markers are
being developed for structural genes allowing the possibility of genetic linkage studies testing for abnormalities of these genes being associated wlth risk of hypertension. challenge Is flnding the right subset of patients and using the right marker.
The
Many experts
872
WILLIAMS ET AL.
advise uslng the 'candidate gene approach" in which a specific marker is selected based on
some medical or physioioglcai evidence of abnormality in the subjects for which malor gene
effects are suggested.
For example, persons with very high LDL cholesterd levels with
domlnant inheritance are thought to
have familial hypercholesterdemia and make Meal
candidates for DNA marker studles of the LDL receptor.
A "candldate gene approach' for
hypertension could Include testing the sodlum-hydrogen transporter gene In pedigrees with evidence
from
segregation
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countertransport.
Another
analysls would
for
a
recessive
be testing the
gene
structural
determining gene
for
sodium-lithium
kalllkreln versus
urlrmy kailikreln excretion levels in pedlgrees showlng major gene segregation of this trait.
HYPERTENSION: A METABOLIC DISEASE?
Llpid abnormalities, diabetes. and obesity are commonly associated with hypertension. data suggest
the
hypothesls that
some
hypertenslon results from
abnormalities reinforced by appropriate environmental exposures. lnteractlons that abnormalities, 1.
could
diabetes,
help
explain
hypertenslon, and
much
of
W O M ~ ~
the
inherited
Recent metabolic
A network of physldoglc
Inter-relatedness
between
llpld
heart disease Is illustrated in Figure
Developing unpublished data in Utah suggests that between 2540% of famllles with early
coronary disease occurring before age 55 have evidence of familial aggregatlon of metabolic abnormalities shown in Figure 1.
While the exact cause and genetic relationships of these
metabolic abnormalitles remains to be determined, practical benefit can be gained from even the general notion of the assoclatlons shown In Figure 1.
Because some hypertension is
associated with ltpid abnormalities, it is useful to measure cholesterd, triglycerlde and HDL cholesterol levels In persons with hypertension, especially if they have a family history of hypertension or early coronary disease.
Much of the risk of coronary disease In persons
with diabetes may also be associated with these metabolic abnormalities, emphasizing the need to search for hypertenslon and lipid abnormalities among persons with diabetes. Recognlzlng the potential adverse effects of some antihypertensbe medications on blood lipids and glucose tolerance can help clinicians choose the appropriate medications that will be most helpful and least harmful to persons who may also have the metabolic abnormalities shown in Figure 1.
07 3
GENETICS OF HYPERTENSION
Model Far FDH, CHD, & NIDDM
1 I
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GENES
I
ENVIRONMENT
Figure1. A pathophysiologic model is suggested for shared metabolic factors promoting familial dysli idemic hypertension (FDH),,coronary heart disease (CHD , and non-insulin dependent Jabetes mellitus (NIDDM). Other abbreviations used include: FCHL (familial combined hyperli idemla), HBP (high blood pressure), meds (medications), and HDL, LDL, and VLDL Tor hig!, low, and ve low density lipoprotein cholesterol. Single arrows suggest one factor influences the next. Souble arrows suggest both factors influence each other.
WHAT WE STILL DON’T KNOW
It
IS dear
that genetic factors play an important factor in determining the rlsk of future
hypertenslon.
Even speclflc biochemical tests have been shown to be both hlghly genetic and What Is not known Is how predlctlve will these factors be In
associated with hypertension.
predicting future hypertension and how useful they will be as a risk factor battery like coronary risk factors.
Data consistently
suggest
both
genetic
and
environmental
metabdlsm are slgnlflcant determinants of hypertension rlsk.
factors
Involving electrolyte
Sodium reduction and calcium
or potasslum supplernentatlon have been associated with a net drop in dlastolic blood pressure of about 2-3 mmHg (20-21). genetlcally
susceptlble
lnterventlons while other
It Is not yet well established whether or not subsets of
indlvlduals
could
show
Individuals In the
major changes In dietary electrolyte Intakes.
even
greater
population are
responsiveness
genetically
to
reslstant to
these even
WILLIAMS ET AL.
874
Consistent data associate hypertension with genetically lntiuenced abnormalities in energy
metabdlsm
(lipids,
obesity,
Insulin).
lnterventlon studies
show
a
net
decrease
In
diastolic Mood pressure of 5-10 mmHg in response to weight reductlon or aerobic exercise
(22-23). It Is not known whether or not some lndlvlduals are especially susceptible to these non-pharmacdoglc interventions and show even more dramatlc improvement In blood pressure
Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
whlle other indivMuais would show iMe or no benefichi change In Mood pressure even in response to good compliance with these healthy behaviors.
it Is also not known how much of
coronary
attributed to
risk
associated with
hypertension might
be
these
concomftant
metabolic abnormalities (such as very low HDL-cholesterd) or how much coronary risk from The main goal
mild essential hypertenslon would remain even without dysllpklemia present.
of this overview has been to encourage other Investigators to gain an Interest In asking these
same questions and searchlng for the answers.
REFERENCES
1. Feinleib M:
CR, eds.
Genetics and famlilai aggregatlon of blood pressure.
Onesti G, Kllrnt
In:
Hypertension determinants, complications, and Interventlon.
New York:
Grune
-& Strgtton, 1979: 35.
2. Johnson BC, Epsteln FH, Kjelsberg MO:
Distribution and famlllal studies of blood
pressure and serum cholesterol levels in a total communlty-Tecumseh,
Mlchlgan.
J
Chronic Dls 1965: 18:147.
3. Hayes CG, Tyrder HA, Cassei JC, Hlil C:
Famlly aggregatlon of Mood pressure In Evans
County, Georgia. Arch Intern Med 1971; 128:965-75. 4.
Bimn P, Mongeau JG, Bertrand D:
Familial aggregatlon of blood pressure In 558 adopted
children. Can Med Assoc J 1976: 15773-4.
5.
Felnlelb
M, Garrison RJ, Fabskz R, et
al:
The NHLBl twln study of cardlovascular disease
risk factors: Methodology and summary of results. Am J EpMernld 1977; 106:284-95.
6.
Hunt SC, Hasstedt SJ, Kulda H, Stuits EM. Hopklns PN, Williams RR:
Genetlc heritability
and common envlronmental components of resting and stressed blood pressures, IipMs, and body mass index in Utah pedigrees and twins. Am J Epldemld 1989; 129:625-638.
a75
GENETICS OF HYPERTENSION 7.
Berry TD, Hasstedt SJ, Hunt SC, Wu
LL, Smith JB, Ash KO, Kukla H, Williams RR:
high urinary kaiiikrein may protect against hypertension in Utah klndreds.
A gene for
Hypertension
1989; 13336.
8.
Hasstedt SJ, Wu LL, Ash KO, Kuida H, Williams RR: countertransport in Utah pedigrees:
Hypertension and sodium-lithium
Evklence for major locus Inheritance.
Am J Hum
Genet 1988; 43:14-22.
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9. .Has@edt SJ, Hunt SC, Wu
LL
Williams RR:
The inheritance of intraerythrocytic sodium
level. Am J Med Genet 1988; 29:193-203.
10. Weinberger MH,
Mlller JZ, Fineberg NS, W t FC, Grim CE, Christian JC:
Sodlurn
SensitMty and resistance of blood pressure are associated with different haptoglobin phenotypes. Hypertension 1987; 10:443-6.
11. Wllllams RR: Will gene markers predict hypertension? Hypertension (In press 1989).
12. Hunt SC, McCarron DA, Smith JB, Ash KO, Brlstow MR, Williams RR: The relationship of
plasma Ionized
calcium to
cardiovascular disease
endpoint and
family
history of
hypertension. Clin & Exp Hypertens 1984; 6:1397-1414.
13. Ufton RP, Hopkins PN, Williams RR, Hdienberg NK, Williams GH, Dluhy
RG: Evidence for
heritability of non-modulatingessential hypertension. Hypertension 1989; 13:8&4-889.
14. Arnbrosionl E. Costa
FV, Montebugnoli 1, et at:
IntraIyrnphocytic sodium concentration:
A sensitive index to identify young subjects at risk of hypertension.
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1981; 3575-91.
15. Wnliams RR, Hunt SC, Hopkins PN, Stults BM, Wu U, Hasstedt SJ, Barlow GK. Stephenson SH,
Lalouel JM, Kuida H:
Familial dyslipklemlc hypertension:
Evidence from 58 Utah families
for a syndrome present in approximately 12% of patients with essential hypertension. JAMA 1988; 259:35793586.
16. Hunt SC, Wu LL, Hopklns PN, Stub
Apolipoproteln,
low
density
BM, Kulda H, Ramirez ME, Lalouel JM, WHllams RR:
llpoproteln
subfraction,
and
insulin associations with
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familial comblned hyperlipidemla:
Study of
Utah patients with familial dyslipidemlc
hypertension. Arteriosclerosis 1989; 9:335-344.
17. Wlhms RR, Hunt SC, Hasstedt SJ, Jorde LB, Wu
H:
The genetics of hypertension:
LL, Barlow GK, Ash KO, Stults BM, Kuida
An unsolved p U e with many pieces.
In:
Human
Qenetics (Vogel F, Sperllng K, Eds). Berlin: Sprlnger-Verlag1987; pp. 311325.
18. Dluhy
RG, Hopkins P, Hollenberg NK, Willlams GH, Willtams RR:
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of the renin-angiotensin-aldosterone
Herliable abnormalities
system in essential hypertenslon.
J Cardiovasc
Pharmacd 1988; 12(Suppl3):S149-s154.
19. Wllihms RR, Hunt SC, Hasstedt SJ, Hopkins PN, Wu LL, Berry TD, Stults BM, Barlow GK,
Kuida H: in:
Inherited blmodal traits and susceptibility to hypertension in Utah pedigrees.
Salt and Hypertension (Rettlg R, Ganten D, Luff FC, Eds).
Heidelberg, FRG:
Sprlnger-Verlag1989; 139-155.
20. Chalmers JP, Doyle AE, Hopper JL, Howe PRC, Matthews PG, Mathews J, Morgan TO, Moulds RFW,
Nestel P, Scogglns BA, Smith SA. Tonkin A, Whitworth JA, Wing LMH: Fall in blood pressure wlth modest reductton In dletary salt intake in mild hypertension.
Lancet 1989; 1 : s
402.
21. McCarron DA, Morris
CD: Blood pressure response to oral calcium in persons with mild to
moderate hypertension. Annals Int Med 1985; 103:825-831.
22. MacMahon SW, Wiicken DEL, Macdonald GJ: ventricular mass:
The effect of weight reduction on left
A randomized controlled trkl
In young,
overwelght hypertensbe
ptlents. New Engl J Med 1986; 314334-9.
23. Duncan JJ. Farr JE, Upton SJ, Hagan RD, Oglesby ME, Blair SN:
The effects of aerobk
exercise on plasma catecholamines and Mood pressure In patients with mild essential hypertenslon. JAMA 1985; 254:2609-2613.
GENETICS OF HYPERTENSION: WHAT WE KNOW AND DON’T KNOW
ROGER R. WILLIAMS, STEVEN C. HUNT, SANDRA J. HASSTEDT, PAUL N. HOPKINS, LILY L WU, MOMAS D.
Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
BERRY, BARRY M. STULTS, GARY K. BARLOW, AND HlROSHl KUlDA
CARDIOVASCULAR GENmCS RESEARCH WNIC, UNMRSrrY OF UTAH MEDICAL SCHOOC.SALT LAKE CITY,
UTAH, USA
SUMMARY
Human
hypertenslon Is
arterial
measurable
monogenes,
environment.
Familial
blended
likely
a
multlfactorlal
polygenes,
aggregation
of
shared
trait
family
resulting
from
multlple
environment, and
hypertension and
familial
correlation
pressure appears to be more due to genes than to shared family environment.
Indlvldual
of
blood
Total genetic
heritability of 80% with some recessive major gene effects have been found for several traits assoclated sodium,
with
and
hypertenslon
hypertenslon
Including
sodium-lithium genetics
urinary
countertransport.
Include:
kallikreln Other
non-modulatlon of
excretlon,
interesting
the
renln
intraerythrocytlc
factors anglotensln
regarding system,
intralymphocytlc sodium, ionized calcium, and several genetic markers such as haptoglobin, HIA, and MNS blood type.
Probably the most cllnlcally useful lnformatlon regardlng the
genetics of hypertension Is evolving In several studies reporting a strong associatlon of hypertenslon with dyslipkiemla, diabetes, and obesity.
Key words:
hypertenslongenetlcs-
epldemlology-pathophyslology-blochemls~ry-llplds-famlly history-coronary heart dlsease.
INTRODUCTION
Hypertenslon Is one of the most common chronic diseases and one of the most common reasons for asymptomatlc persons taking prescription medicatlon.
It has consistently been one of the
most prominent risk factors for myocardial lnfarctlon and stroke, the most common causes of death in many countrles.
The large number and expense of studies used to determine belter
865 C o p y r a t 0 1990 by Marcel Dekker, inc.
WILLIAMS ET AL.
866
methods for diagnosing, treating and
preventing arterlal
hypertenslon reflect the
hlgh
prlority of understandlngthis disorder.
Whle numerous studies have found individual pleces in the puzzle of the pathophyufology of hypertension, a clear picture of exactly how they
all M together Is not yet available.
From
all indications, genetic factors must play a very Important rde in this overall picture. While the studles are numerous, and the methods are cornpllcated, e few basic observations illustrate
some
answers
to
important
questions
regarding
the
genetics
of
They also helped to point to other important questions for which answers are
hypertension. Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
consistent
not yet available.
FAMILIAL CORRELATION
Population-based studles of different types of family members have consistently shown that Mood pressure correlates very well in related famlly members and poorly among spouses and adopted children with their parents who share the same environment but do not share the same genes (1-5). Some of the specHIc obsewations are shown in TaMe 1.
Familial correlations can be due to shared family environment or assortatlve mating as genes.
as well
As shown In Table 2, several Important variables shown to be assoclated with
Table 1. Blood Pressure Correlatlons In Familleg Pearson Correlation Famiiv Members
&&)
SBP
Spouse Pairs
(1433)
0.08
0.06
Adoptees Parents
(379)
0.03
0.09
Offspring - Parents
(831)
0.18
0.16
(2618)
0.18
0.14
-
Sibling Pairs
DBP
DZ Twins
(264)
0.25
0.27
Mi! Twins
(248)
0.55
0.58
Combined data from 5 studles: Framingham (l), Tecumseh (2), Evans County (3). Canadian Adoptlon (4). and NHLBI twins (5).
GENETICS OF HYPERTENSION Table 2. Familv Correlations For Non Genetic Variabigg Variables
intraclgss Correlation Coeffi&nts
Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
Tested
MZ114Q
)-,
Bro1219)
&L@U)
Education
0.57 a
0.55 a
0.40 a
0.47 a
Alcohol
0.70 a
0.24 c
0.40 a
0.50 a
Smoking
0.68 a
0.11
0.16 C
0.31 a
Salt Use
0.38 b
0.20
0.28 a
0.23 a
Exercise
0.41 a
0.12
0.16 C
0.18 a
b = P < 0.01
a = P < 0.001
c = P < 0.05
Results after adjusting for age (and sex within spouse pair), from Utah twins and pedigrees (6). Number of persons indicated in parentheses.
hypertension show excellent correlations in twins, brothers, and spouses.
A higher degree
of correlation among monozygous (MZ) twins when compared to dizygous (DZ) twins is mathematically interpreted as evldence for genetic herltabiilty in many studles.
Following
this reasoning In TaMe 2, one would reach the conclusion that alcohd intake, current smoking status,
and frequency of
vigorous aerobic exercise are all
highly genetically
determined traits since they show significantly higher correlations in MZ twins than in DZ twins.
It is clear that for some environmental variables MZ twlns are more similar than
DZ
twins leading to an overestimation of genetic heritability in most reported twin studies. Shared environment often reflects habits established In childhood.
This likely explains the
observation in Table 2 of significant familial correlations for frequence of salt use among adult relatives not living in the same household. could
reflect
either
current
shared
Current salt use preferences among spouses
environment
or
assortatbe
mating
for
dietary
preferences.
HERITABILITY ESTIMATES FOR BLOOD PRESSURE
Using mathematical models and formulas, statisticians try to quantitate what proportion of the total variatlon of selected variables can be explained by a Mended combination of ail genes affecting that coulU
bb
trait
explained by
(pdygenes), and what shared
environmental
additional proportion of
factors.
This
statistical
the variation estimation
of
WILLIAMS ET AL.
868
3: Polvaenlc and Fnviro-b
iiitv Fstlmateg
I 2
Variables
Tested
Shared
m J 3 d U rM
(c')
rnironment
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Metabdic: Chdesterol
61% a
42% a
8%
Trigiycerkles
81% a
37% a
6%
HDL-Chd
74% a
45% a
15%
W/HT2
54% b
24% a
0%
Sitting
60% C
22% a
3%
Standing
63%
21% b
3%
Math
44%
23% a
8%
Bicycle
49%
38% a
0%
Hand Grip
50%
17% b
0%
a = P < 0.001
b = P < 0.01
c
=
P < 0.05
Results after adjusting for age and sex for all variables as well as grip strength and workload respecthraly for hand gdp and bicycle Mood pressures. From Utah twins and pedigrees (6).
variability
Is called pdygenlc heritability (h*)
or
envlronmental heritability (cs.
Table
3 presents heritability estimates from 340 Utah twins and 2,500 persons belonging to 98 Utah pedigrees screened at the University of Utah, Cardiovascular Genetics Research Clinic.
it
Is interesting to
note
that
herltabillty estimates
analysis of twins than from pedlgrees.
are
consistently higher from
the
This could be due to failure of the mathemtlcal twln
model to account for MZ twins having more shared gene-gene interactions and greater environmental similarity (see in Table 2). consistently
support
signmcant
polygenlc
However, results from both twlns and pedigrees determination
for
all
sitting
diastolic
pressures and several metabolic variables related to coronary risk and hypertension. estimates of varlance attributable to shared family environment are large sample size wodd be required to obtain statistical signmcance. similar
studies,
80
Mood The
small that a very
From these and other
It seems consistently established that genes rather than shared famlly
GENETICS OF HYPERTENSION
869
environment are responsible for most of the familial aggregation of Mood pressure and associated metabolic factors.
COMPLEX SEGREGATION ANALYSIS IN PEDIGREES
When family correlation studies suggest genetic determination for variables, a l o g l d next step is to test for genetic transmission, and attempt to determine the mode of transmission (recessive,
dominant,
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transmission).
additive,
poiygenlc,
or
polygenlc
mixtures of
and
monogenic
Thls can currently be accomplished with sophisticated statlstlcal formulas
tested using maximum likelihood methods embedded in computer programs. mathematics is complicated, the concept is quite straight forward.
While the
The computer simply looks
at the measured values of a particular trait for each person and asks simple questions such as:
Do all the values seem to fail into a single continuous distribution (supporting
poiygenic traits) or Into two or more discreet distributions (supporting recessive dominant or additive major gene traits)?
Do the values of the children tend to fall halfway between
the parents (supporting polygenic), or do they tend to fall Into one of distributions closer to one of the two parents (supports major gene)?
two
discreet
Do children tend to be
"affected" only when one parent is affected (dominant), or does it almost always occur when only two parents are affected (recessive)?
What percentage of offspring are 'affected' when
no parents are affected. when one parent is affected or when both parents are affected? Mathematical models can be made even more complicated to include factors that may affect the likelihood of an inherited trait being 'penetrant"
or expressed.
For example, the model
could assume 20% of gene carriers will express it under age 20 but 50% will express it over age 40. The model can also assume that among individuals with a particular allele of a monogenic trait, variation within those subjects can be attributed to
pdygenlc effects.
Thls full
mathematical model of genetic transmission In pedigrees Is often referred to as the 'mked model'.
Carrying out these type of calculations for large numbers of obselvations in
pedigrees would be prohlbitive without the beneflt of electronic computers.
Even with their
help, a considerable amount of work Is required for many months to obtain Informative and reliable results.
Table 4 shows the results obtained from pedigree analysis of biochemical
traits associated with human hypertension.
All of them show very high total heritability
estimates, even higher than those seen for well-known genetically influenced traits such as plasma cholesterol level (total heritability 42%).
It
is also interesting to note that all
of the variables shown in Table 4 have both polygenlc and recessive monogenic components.
WILLIAMS ET AL. Table 4. Heritabilltv of Bbchemtcal fraits Assoclata Human Arterlal HvDertensIon
Mode of
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Biochemical Traitg
Herltabllltv fh2)
Transmlssion
J&jQr+&&=m
Urlnary Kallikrein Excretion
Recessive
51%
27%
78%
intraerythrocytlc Sodium
Recessive
29%
55%
84%
Sodium-Lithium Countertransport
Recessive
34%
46%
80%
Lithium Potassium Cotransport
Recessive
14%
33%
47%
Results from several studies of multlgeneratlonal Utah pedigrees (7,8,9).
None of the traits llsted In Table 4 can be consldered as direct causal factors leading to hypertension.
They
are
associated with
hypertension through
studles
showing
that
slgnfflcantly different levels are observed between persons with hypertension versus these
without hypertenslon and/or between normotensive persons with and without a positive family history of hypertenslon.
Moat of these biochemical traits are likely to be quantitative risk factors for hypertenslon llke Mood cholesterol level Is for coronary dlsease.
Whlle on the average persons with
dlsease have hlgh rlsk values and persons without the dlsease have lower risk values. hlgh
rlsk values for some traits are seen in some persons without disease, and low risk values are seen In some persons with disease.
Also llke coronary risk factors, no slngle trait likely
predlcts hypertenslon in any given lndivldual.
A battery of several quantitative traits such
as those llsted In Table 4 may help predlct future hypertension just as a battery of risk
factora are now used to help predict coronary disease. OTHER INTERESTING FACTORS Many Interesting factors have been examined In studies of persons with and without a family history of hypertension or In sibshlps or other famly groups where hypertension
Is found.
Only a few of them are llsted In Table 5 (10-16) with longer lists presented in other reviews (17-19).
Slnce sodlum intake remains one of the most interesting environmental variables
thought to be involved In the pathophysldogy of hypertension, several of these factors are
an
GENETICS OF HYPERTENSION Table 5. Other lnterestina Factors Ralardlno HvDertenslon Genetlcg
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Factor
lnterestino Observations
Haptoglobln Genotype
BP Response To Acute Sodium Loadlng
HIA Qenotype
Some HBP Association & Linkage Studies
MNS Genotype
Some HBP Assoclatlon Studies
lonked Calcium
Family History of Hypertension (FHx HBP)
Nonmodulatlon
Bimodal, Familial, Positive FHx HBP
Renin-Anglotensln
Be Physiology, DNA Markers Available
WBC Sodlum
FHx HBP and Bicycle BP Reacttvity
Dysllpldemlc HBP
FHx HBP, Coronary Risk, Insulin
Diabetes
Heritable Disease with HBP Common
Obeslty
Carries a lot of Weight In Most HBP Studies ~
Multiple studies (10-16) discussed In prior revlews (17-19).
InValVed
In
sodium and
electrolyte metaboilsm.
Different alleles
of
the
haptoglobin
genotype were significantly associated with different Mood pressure responses to acute sodlurn loading (10). Commonly studied genetic markers such as HLA tissue type and MNS blood type have been shown in some studies to be associated or genetically linked to presence of hypertension (11).
Some traits such as ionized calcium and blunted response to angiotensln
II infuslon ("non-modulation") show signlflcant dlfferences between persons wlth and without a positive family history of hypertension (12-13). pressures and biochemical tests together.
Some studies have used innovative blood
In one such study, high lntralymphocytic sodium
concentratton was associated wlth a positive family history of hypertension and even more dramatically associated with a subset of
indtviduats who had exaggerated increases In
dlastollc blood pressure in response to bicycle exercise (14).
The fleld of molecular biology Is rapidly providing tods for even more sophisticated genetic studies.
For speclflc hormones such as renln, angiotensln, and kallikreln, DNA markers are
being developed for structural genes allowing the possibility of genetic linkage studies testing for abnormalities of these genes being associated wlth risk of hypertension. challenge Is flnding the right subset of patients and using the right marker.
The
Many experts
872
WILLIAMS ET AL.
advise uslng the 'candidate gene approach" in which a specific marker is selected based on
some medical or physioioglcai evidence of abnormality in the subjects for which malor gene
effects are suggested.
For example, persons with very high LDL cholesterd levels with
domlnant inheritance are thought to
have familial hypercholesterdemia and make Meal
candidates for DNA marker studles of the LDL receptor.
A "candldate gene approach' for
hypertension could Include testing the sodlum-hydrogen transporter gene In pedigrees with evidence
from
segregation
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countertransport.
Another
analysls would
for
a
recessive
be testing the
gene
structural
determining gene
for
sodium-lithium
kalllkreln versus
urlrmy kailikreln excretion levels in pedlgrees showlng major gene segregation of this trait.
HYPERTENSION: A METABOLIC DISEASE?
Llpid abnormalities, diabetes. and obesity are commonly associated with hypertension. data suggest
the
hypothesls that
some
hypertenslon results from
abnormalities reinforced by appropriate environmental exposures. lnteractlons that abnormalities, 1.
could
diabetes,
help
explain
hypertenslon, and
much
of
W O M ~ ~
the
inherited
Recent metabolic
A network of physldoglc
Inter-relatedness
between
llpld
heart disease Is illustrated in Figure
Developing unpublished data in Utah suggests that between 2540% of famllles with early
coronary disease occurring before age 55 have evidence of familial aggregatlon of metabolic abnormalities shown in Figure 1.
While the exact cause and genetic relationships of these
metabolic abnormalitles remains to be determined, practical benefit can be gained from even the general notion of the assoclatlons shown In Figure 1.
Because some hypertension is
associated with ltpid abnormalities, it is useful to measure cholesterd, triglycerlde and HDL cholesterol levels In persons with hypertension, especially if they have a family history of hypertension or early coronary disease.
Much of the risk of coronary disease In persons
with diabetes may also be associated with these metabolic abnormalities, emphasizing the need to search for hypertenslon and lipid abnormalities among persons with diabetes. Recognlzlng the potential adverse effects of some antihypertensbe medications on blood lipids and glucose tolerance can help clinicians choose the appropriate medications that will be most helpful and least harmful to persons who may also have the metabolic abnormalities shown in Figure 1.
07 3
GENETICS OF HYPERTENSION
Model Far FDH, CHD, & NIDDM
1 I
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GENES
I
ENVIRONMENT
Figure1. A pathophysiologic model is suggested for shared metabolic factors promoting familial dysli idemic hypertension (FDH),,coronary heart disease (CHD , and non-insulin dependent Jabetes mellitus (NIDDM). Other abbreviations used include: FCHL (familial combined hyperli idemla), HBP (high blood pressure), meds (medications), and HDL, LDL, and VLDL Tor hig!, low, and ve low density lipoprotein cholesterol. Single arrows suggest one factor influences the next. Souble arrows suggest both factors influence each other.
WHAT WE STILL DON’T KNOW
It
IS dear
that genetic factors play an important factor in determining the rlsk of future
hypertenslon.
Even speclflc biochemical tests have been shown to be both hlghly genetic and What Is not known Is how predlctlve will these factors be In
associated with hypertension.
predicting future hypertension and how useful they will be as a risk factor battery like coronary risk factors.
Data consistently
suggest
both
genetic
and
environmental
metabdlsm are slgnlflcant determinants of hypertension rlsk.
factors
Involving electrolyte
Sodium reduction and calcium
or potasslum supplernentatlon have been associated with a net drop in dlastolic blood pressure of about 2-3 mmHg (20-21). genetlcally
susceptlble
lnterventlons while other
It Is not yet well established whether or not subsets of
indlvlduals
could
show
Individuals In the
major changes In dietary electrolyte Intakes.
even
greater
population are
responsiveness
genetically
to
reslstant to
these even
WILLIAMS ET AL.
874
Consistent data associate hypertension with genetically lntiuenced abnormalities in energy
metabdlsm
(lipids,
obesity,
Insulin).
lnterventlon studies
show
a
net
decrease
In
diastolic Mood pressure of 5-10 mmHg in response to weight reductlon or aerobic exercise
(22-23). It Is not known whether or not some lndlvlduals are especially susceptible to these non-pharmacdoglc interventions and show even more dramatlc improvement In blood pressure
Clin Exp Hypertens Downloaded from informahealthcare.com by McMaster University on 11/28/14 For personal use only.
whlle other indivMuais would show iMe or no benefichi change In Mood pressure even in response to good compliance with these healthy behaviors.
it Is also not known how much of
coronary
attributed to
risk
associated with
hypertension might
be
these
concomftant
metabolic abnormalities (such as very low HDL-cholesterd) or how much coronary risk from The main goal
mild essential hypertenslon would remain even without dysllpklemia present.
of this overview has been to encourage other Investigators to gain an Interest In asking these
same questions and searchlng for the answers.
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CR, eds.
Genetics and famlilai aggregatlon of blood pressure.
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Hypertension determinants, complications, and Interventlon.
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-& Strgtton, 1979: 35.
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8.
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Am J Hum
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