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.

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 arterial hypertenslon Is likely a multlfactorlal trait resulting from multlple

measurable monogenes, blended polygenes, shared family environment, and Indlvldual

environment. Familial aggregation of hypertension and familial correlation of blood

pressure appears to be more due to genes than to shared family environment. Total genetic

heritability of 80% with some recessive major gene effects have been found for several traits

assoclated with hypertenslon Including urinary kallikreln excretlon, intraerythrocytlc

sodium, and sodium-lithium countertransport. Other interesting factors regarding

hypertenslon genetics Include: non-modulatlon of the renln anglotensln 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.

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866 WILLIAMS ET AL.

methods for diagnosing, treating and preventing arterlal hypertenslon reflect the hlgh

prlority of understandlng this 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 consistent answers to important questions regarding the genetics of

hypertension. They also helped to point to other important questions for which answers are

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 well

as genes. As shown In Table 2, several Important variables shown to be assoclated with

Table 1. Blood Pressure Correlatlons In Familleg

Pearson Cor relation

Famiiv Members &&) SBP DBP

Spouse Pairs (1433) 0.08 0.06

Adoptees - Parents (379) 0.03 0.09

Offspring - Parents (831) 0.18 0.16

Sibling Pairs (2618) 0.18 0.14

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).

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GENETICS OF HYPERTENSION

Table 2. Familv Correlations Fo r Non Ge netic Variab igg

Variables intraclgss Correlation Coeffi&nts

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

a = P < 0.001

Results after adjusting for age (and sex within spouse pair), from Utah twins

and pedigrees (6). Number of persons indicated in parentheses.

b = P < 0.01 c = P < 0.05

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. Current salt use preferences among spouses

could reflect either current shared 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 trait (pdygenes), and what additional proportion of the variation

coulU bb explained by shared environmental factors. This statistical estimation of

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868 WILLIAMS ET AL.

3: Polvae nlc and Fnviro-b I iiitv Fstlma teg

Shared (c') Variables

Tested m J 3 d U M r rnironment

2

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

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).

b = P < 0.01 c = P < 0.05

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 are consistently higher from the

analysis of twins than from pedlgrees. 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). However, results from both twlns and pedigrees

consistently support signmcant polygenlc determination for all sitting diastolic Mood

pressures and several metabolic variables related to coronary risk and hypertension. The

estimates of varlance attributable to shared family environment are 80 small that a very

large sample size wodd be required to obtain statistical signmcance. From these and other

similar studies, It seems consistently established that genes rather than shared famlly

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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 og ld next

step is to test for genetic transmission, and attempt to determine the mode of transmission

(recessive, dominant, additive, poiygenlc, or mixtures of polygenlc and monogenic

transmission). Thls can currently be accomplished with sophisticated statlstlcal formulas

tested using maximum likelihood methods embedded in computer programs. While the

mathematics is complicated, the concept is quite straight forward. 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 two discreet

distributions closer to one of the two parents (supports major gene)? 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.

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WILLIAMS ET AL.

Table 4. Heritab illtv of Bbche mtcal fra its Assoclata

Human Arterlal HvDertens Ion

Mode of Herltabllltv fh2)

Biochemical Traitg 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

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GENETICS OF HYPERTENSION a n

Table 5. Other lnterestina Fac tors Ralardlno HvDertenslon Genetlcg

Factor

Haptoglobln Genotype

HIA Qenotype

MNS Genotype

lonked Calcium

Nonmodulatlon

Renin-Anglotensln

WBC Sodlum

Dysllpldemlc HBP

Diabetes

Obeslty

lnterestino Observa tions

BP Response To Acute Sodium Loadlng

Some HBP Association & Linkage Studies

Some HBP Assoclatlon Studies

Family History of Hypertension (FHx HBP)

Bimodal, Familial, Positive FHx HBP

Be Physiology, DNA Markers Available

FHx HBP and Bicycle BP Reacttvity

FHx HBP, Coronary Risk, Insulin

Heritable Disease with HBP Common

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

I I infuslon ("non-modulation") show signlflcant dlfferences between persons wlth and without

a positive family history of hypertension (12-13). Some studies have used innovative blood

pressures and biochemical tests together. 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. The

challenge Is flnding the right subset of patients and using the right marker. Many experts

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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 analysls for a recessive gene determining sodium-lithium

countertransport. Another would be testing the structural gene for 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. Recent

data suggest the hypothesls that some hypertenslon results from inherited metabolic

abnormalities reinforced by appropriate environmental exposures. A network of physldoglc

lnteractlons that could help explain much of the Inter-relatedness between llpld

abnormalities, diabetes, hypertenslon, and W O M ~ ~ heart disease Is illustrated in Figure

1. 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.

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GENETICS OF HYPERTENSION 07 3

Model Far FDH, CHD, & NIDDM

GENES I ENVIRONMENT I 1

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

associated with hypertension. What Is not known Is how predlctlve will these factors be In

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 factors Involving electrolyte

metabdlsm are slgnlflcant determinants of hypertension rlsk. 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). It Is not yet well established whether or not subsets of

genetlcally susceptlble indlvlduals could show even greater responsiveness to these

lnterventlons while other Individuals In the population are genetically reslstant to even

major changes In dietary electrolyte Intakes.

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874 WILLIAMS ET AL.

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

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 risk associated with hypertension might be attributed to these concomftant

metabolic abnormalities (such as very low HDL-cholesterd) or how much coronary risk from

mild essential hypertenslon would remain even without dysllpklemia present. The main goal

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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GENETICS OF HYPERTENSION a75

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