renin-angiotensin-aldosterone system gene polymorphisms and hypertension in hong kong chinese

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEMGENE POLYMORPHISMS AND HYPERTENSION

IN HONG KONG CHINESE

G. Neil Thomas, Robert P. Young, Brian Tomlinson,Kam Sang Woo*, John E. Sanderson*, and Julian A.J.H. Critchley

Divisions of Clinical Pharmacology and Cardiology*,Department of Medicine and Therapeutics,

The Chinese University of Hong Kong,The Prince of Wales Hospital, Shatin, Hong Kong SAR

ABSTRACT

In Chinese populations, hypertension is common and is a major risk factor forcerebrovascular and coronary heart disease. The renin-angiotensin-aldosteronesystem (RAAS) helps maintain blood pressure and salt homeostasis and ap-pears important in the pathogenesis of hypertension and some forms of vascu-lar disease. We investigated three RAAS gene polymorphisms, the an-giotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen(AGT) M235T and angiotensin II type 1 receptor A1166C polymorphisms in232 hypertensive and 178 normotensive Chinese subjects. The hypertensiveswere generally more obese and dyslipidaemic. No significant differences ingenotype or allele frequencies for any of the polymorphisms were identifiedbetween the groups, nor was there any interactive contribution to blood pres-sure by the ACE and AGT polymorphisms. However, there were large differ-ences in genotype and allele frequencies between the healthy Chinese and pub-lished data for equivalent Caucasian populations. These findings suggest thesepolymorphisms are unlikely to be involved in the pathogenesis of hypertensionin Chinese.

CLIN. AND EXPER. HYPERTENSION, 22(1), 87–97 (2000)

Copyright © 2000 by Marcel Dekker, Inc. www.dekker.com

87

Author for correspondence: GN Thomas, Department of Medicine and Therapeutics, Prince of WalesHospital, Shatin, NT, Hong Kong SAR, Tel: 852 2632 3130, Fax: 852 2637 3929, E-mail:thomas19976cuhk.edu.hk

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

Key Words: renin-angiotensin-aldosterone system, angiotensin-convertingenzyme, angiotensinogen, angiotensin type 1 receptor, Chinese, genetics,hypertension.

INTRODUCTION

Hypertension is an important risk factor in the pathogenesis of vascular dis-ease and in particular cerebrovascular disease, which is a major cause of mortalityand morbidity particularly in Oriental countries. Differences in the demography ofvascular diseases have been seen between racial groups suggesting differencesmay exist in vascular disease pathophysiology, including that in intermediary phe-notypes such as essential hypertension (1).

The renin-angiotensin-aldosterone system (RAAS) is fundamental to bloodpressure regulation and as such each component is potentially involved in the aeti-ology of the polygenic disorder known as hypertension. Furthermore, both an-giotensin-converting enzyme (ACE) inhibitors (2) and angiotensin II (ANGII) an-tagonists (3) may reduce the risks from cardiovascular disease, further implicatingthe involvement of the RAAS in the development of vascular disease.

Plasma angiotensinogen (AGT) levels have been shown to correlate withblood pressure and are elevated in young normotensive adults with a family historyof hypertension (4). Such groups may also have raised plasma renin activity and agenetic predisposition to elevated blood pressure may result from abnormalities inthe RAAS (5). The AGT M235T polymorphism, which influences serum AGT lev-els in Caucasians (6,7), is reputably associated with hypertension (8–10) and car-diovascular disease (11,12) in both Caucasians and Japanese. The association withhypertension has not been consistently found in all studies (13,14), however a re-cent meta-analysis supported this relationship in Caucasians (7) but not in Asiansor Blacks.

ACE is involved in the degradation of the vasodilator bradykinin as well asthe formation of the vasoconstrictor ANGII, whose actions are mediated mainlythrough the ANGII type 1 receptor (AT1R). The ACE insertion/deletion (I/D) poly-morphism has been shown to account for half the variance of plasma ACE levelsin Caucasians and Japanese (15,16), but not in African Americans (15). In USBlacks, Caucasians and Japanese the DD genotype has been associated with hy-pertension, although the findings are inconsistent (17–19). In Japanese and Cau-casians the DD genotype has been associated with cardiovascular disease (19).

The AT1R present on vascular smooth muscle cells and in the adrenals, me-diates both the vasoconstrictive and salt-conserving actions of ANGII (20). In-creased frequencies of the AT1R A1166C polymorphism have been associatedwith increased blood pressure and arterial stiffness in Caucasian and Japanese sub-jects (20–23). However, the reports are not all affirmative (24,25).

Interethnic differences in vascular disease demography indicate the need toexamine the relationships of candidate genes in specific ethnic groups (1). In thisstudy we investigated the relationship between three RAAS gene polymorphisms

88 THOMAS ET AL.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

and hypertension in Chinese. Investigation of this important ethnic group may helpto establish a genetic basis to account for the observed ethnic differences in the in-cidence and pathogenesis of vascular disease (1,26,27).

METHODS

Subject Recruitment and Ethnic Background

The study protocol was approved by the Clinical Research Ethics Committeeof the Chinese University of Hong Kong. Hypertensive subjects were recruitedfrom the medical out-patient clinic at the Prince of Wales Hospital. Control sub-jects who were normotensive (SBP was ,140 mm Hg and DBP was ,90 mm Hg)and non-diabetic (fasting plasma glucose (FPG) ,6.0 mmol/L) were recruitedfrom hospital staff and their friends. All 410 subjects were unrelated, unpaid andgave written informed consent. They were of Han Chinese origin, without anyknown ancestors of other ethnic origin, and were living in the Hong Kong SpecialAdministrative Region of China at the time of the study. The catchment area of thePrince of Wales Hospital has only been developed since the 1960’s, and serves apopulation of over 1 million. The majority of its inhabitants are a typical socioe-conomic representation of first or second-generation migrants from SouthernChina now living in a Westernized environment.

Measurements and Subject Classification

Seated blood pressure, anthropometric and plasma biochemical parameters,after an overnight fast, were measured. The anthropometric parameters required tocalculate the body mass index and waist-to-hip ratio parameters were measured.Skinfold thickness measurements were taken at the triceps, biceps, iliac crest andsubscapular sites, using digital calipers (Skyndex electronic body fat calculatorsystem, Caldwell Justiss, AZ, USA), from which the percentage body fat wasderived (28).

Subjects were defined as hypertensive, if, after 5 minutes rest, seated SBPwas $140 mm Hg and/or DBP $90 mm Hg on at least two occasions whilst offantihypertensive treatment (after a 4 week washout period) (29). A mean of threereadings taken 1 minute apart was used. No subjects had a history of significant re-nal, hepatic or cardiac disease.

Subjects with impaired fasting glucose and diabetes were diagnosed based onFPG levels. FPG ,6.0 mmol/L was considered normal, a FPG of 6.0–7.0 mmol/Lwas considered impaired fasting glucose and $7.0 mmol/L was indicative of dia-betes (30). Subjects with impaired fasting glucose or type 2 diabetes were excludedfrom the study. Obesity was defined as a body mass index of $25.0 kg/m2 or$27.0 kg/m2 or waist-to-hip ratio $0.85 or $0.90 in females and males, respec-tively (30). Dyslipidaemia was classified as either fasting plasma total cholesterol$6.2 mmol/L or between 5.2 and 6.2 mmol/L with the total cholesterol to HDL-

RAAS GENE POLYMORPHISMS IN CHINESE HYPERTENSIVES 89

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

cholesterol ratio being $5.0,or fasting plasma triglycerides $2.3 mmol/L (31,32).Control subjects were normotensive (SBP was ,140 mm Hg and DBP was ,90mm Hg) and non-diabetic (fasting plasma glucose (FPG) ,6.0 mmol/L) controlswere recruited from hospital staff and their friends.

Genotyping Protocols

DNA was extracted from peripheral blood from 232 essential hypertensivesand 178 normotensive unrelated Chinese. PCR-based protocols were used to iden-tify the ACE gene insertion/deletion (I/D), AGT M235T and AT1R A1166C poly-morphisms (11). The 5% DMSO was included in the reaction mix to improve am-plification of the I allele to prevent the mistyping of ID genotypes as DD (33).Caucasian genotype and allele frequencies for the ACE I/D and AGT M235Tpolymorphisms were obtained from a combination of reports described by Rotimiet al. (34). Those for the AT1R were derived from the control populations describedin those studies referenced in the introduction (20,22–24).

Statistical Analyses

Differences in the genotype and allele frequencies between the hypertensiveand normotensive populations and between normotensive Chinese and Caucasianpopulations were analysed using the x2 test and odds ratios with Cornfield 95%confidence intervals (EpiInfo Version 5.0,Statcalc, 1990). Differences in anthro-pometric and fasting plasma biochemical parameters between the hypertensive andnormotensive cohorts and between the genotypes were examined using the Stu-dent’s t-test (Statistics Package for the Social Sciences, version 7.5,1996,SPSS Inc,Chicago, Illinois, USA).

RESULTS

The demographic characteristics of the hypertensive and normotensive Chi-nese subjects are described in Table 1. The hypertensive subjects were slightlyolder with a greater proportion of males than the normotensive cohort. Further-more, the hypertensives had a higher heart rate, higher plasma glucose, sodium andurate and were also more obese and dyslipidaemic. RAAS genotype and allele fre-quencies in the 232 essential hypertensives and 178 normotensive Chinese subjectsand in the age and gender-matched cohorts are shown in Tables 2 and 3,respec-tively. Genotype frequencies were all in accordance with the Hardy-Weinbergequilibrium. There was no significant difference in the genotype and allele fre-quencies between either the essential hypertensive and normotensive groups or theage and gender-matched cohorts in this Chinese population. Age-related differ-ences in the distribution of the RAAS genotypes were investigated between the fol-lowing cohorts; subjects over 60 years (n 5 40) were compared to that in those un-

90 THOMAS ET AL.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS


Table 1. Demographic Characteristics of the 232 Hypertensive and 178 Normotensive Chinese.

Cohort Normotensive Hypertensive p value

n 178 232Age (years) 40.6 6 9.7 47.8 6 10.1 ,0.001Gender (%Male) 37.6 49.8 0.022

Systolic blood pressure (mm Hg) 113 6 9 149 6 18 ,0.001Diastolic blood pressure (mm Hg) 66 6 9 89 6 11 ,0.001Mean arterial pressure (mm Hg) 98 6 9 129 6 14 ,0.001Pulse (beats per min) 70 6 9 74 6 12 0.007

Plasma sodium (mmol/L) 140 6 2 142 6 2 ,0.001Plasma potassium (mmol/L) 4.0 6 0.4 4.0 6 0.4 NSPlasma urate (mmol/L) 0.27 (0.26–0.28) 0.33 (0.32–0.34) ,0.001Fasting plasma glucose (mmol/L) 5.0 (5.0–5.1) 5.2 (5.1–5.2) 0.001

Fasting total cholesterol (mmol/L) 5.5 6 1.6 5.7 6 1.4 0.038Fasting HDL-cholesterol (mmol/L) 1.4 6 0.4 1.2 6 0.3 ,0.001Fasting LDL-cholesterol (mmol/L) 3.5 6 1.5 3.7 6 1.3 0.047Fasting triglyceride (mmol/L) 0.96 (0.87–1.06) 1.73 (1.58–1.89) ,0.001

Body mass index (kg/m2) 23.2 6 3.6 25.8 6 3.8 ,0.001Waist-to-hip ratio 0.81 6 0.07 0.87 6 0.07 ,0.001Percent body fat 26.6 6 7.5 29.1 6 6.7 0.003

Percent dyslipidaemia 34.3 55.3 ,0.001Percent obesity 28.8 64.0 ,0.001

Mean 6 SD, Geometric mean (geometric 95% confidence intervals of the mean); NS 5 non-significant

Table 2. Renin-Angiotensin-Aldosterone System Polymorphism Genotype and Allele Frequenciesof Hypertensive and Normotensive Chinese Subjects.

AlleleNumbers Genotype frequencies n (%) frequencies (%)

ACE I/D II ID DD I D

Hypertensive 232 92 (39.7) 110 (47.4) 30 (12.9) 63.4 36.7Normotensive 178 58 (32.6) 95 (53.4) 25 (14.0) 59.3 40.7

AGT M235T MM MT TT M T


AT1R A1166C AA AC CC A C


ACE 5 angiotensin-converting enzyme, AGT 5 angiotensinogen, AT1R 5 angiotensin II type 1receptor.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

der 59 (n 5 369), 49 (n 5 303) and 39 years (n 5 122) and all subjects over 50years (n5106) were compared to those in the under 49 or 39 year age groups. How-ever, in none of these combinations did the genotype distribution differ signifi-cantly. No differences were seen for blood pressure levels between the commonand rare homozygous genotypes and neither was there a difference when the ho-mozygous and heterozygous genotypes carrying the rare allele were combined andcompared with the common homozygous genotype (Table 4). Furthermore, whenthe subjects with the presumed detrimental ACE DD and AGT TT genotypes (n 5

92 THOMAS ET AL.

Table 3. Renin-Angiotensin-Aldosterone System Polymorphism Genotype and Allele Frequenciesin Age and Gender-Matched Hypertensive and Normotensive Chinese Subjects.

AlleleNumbers Genotype frequencies n (%) frequencies (%)

ACE I/D II ID DD I D


AGT M235T MM MT TT M T


AT1R A1166C AA AC CC A C


ACE 5 angiotensin-converting enzyme, AGT 5 angiotensinogen, AT1R 5 angiotensin II type 1receptor.

Table 4. Systolic and Diastolic Blood Pressures Associated with Renin-Angiotensin-Aldos-terone System Polymorphism Genotypes.

ACE I/D II (n $ 150) DD (n $ 55)

Systolic blood pressure (mm Hg) 134 6 23 129 6 21Diastolic blood pressure (mm Hg) 80 6 16 76 6 15

AGT M235T MM/MT (n $ 107) TT (n $ 303)


AT1R A1166C AA (n $ 355) AC/CC (n $ 51)


No significant differences in blood pressure between the genotypes was encountered

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

34) were compared to those carrying the AGT M allele and the ACE II genotype(n 5 42) there was no interactive contribution, with blood pressure levels beingsimilar in both cohorts.

When the genotype and allele frequency distribution in the normal Chinesesubjects were compared with Caucasian control populations that had been previ-ously used to report ethnic differences with Black populations (34), there were sig-nificant differences for all three polymorphisms. The ACE I/D DD genotype(33.0% vs. 14.0%, p ,0.0001) and D allele frequencies (56.0% vs. 40.7%, p,0.0001) were lower in the Chinese populations. The differences between the Chi-nese and Caucasian control populations were much greater for the AGT M235Tpolymorphism with the T allele (41.8% vs. 83.4%, p ,0.0001) being more thantwice as common in the Chinese. Furthermore, for the AT1R A1166C polymor-phism the frequency of the C allele was significantly lower in the Chinese controlsubjects (6.6% vs. 29.0% p ,0.0001) compared to those reported in equivalentCaucasian subjects (20,22–24). The CC genotype was not identified in our Chinesepopulation.

DISCUSSION

As found in previous studies the hypertensives were generally more obeseand dyslipidaemic than the normotensive controls (35–37). As the hypertensiveswere also slightly older with a greater proportion of males, some of the differencesin anthropometric and biochemical parameters seen between the cohorts may be at-tributed to these differences in age and gender, but it is unlikely that this would ac-count for them entirely.

The RAAS is clearly involved in the maintenance of blood pressure (2–5,20)and as such mutations in the genes of RAAS components might be expected to con-tribute to the pathogenesis of hypertension. On the whole, the literature supportsthe association of the T allele of the AGT M235T polymorphism with hypertension(7–10) and the ACE I/D polymorphism with a predisposition to the developmentof vascular disease rather than to hypertension in Caucasian and Japanese popula-tions (19). A recent systematic review of the ACE I/D polymorphism suggested anexcess risk of hypertension with the D allele in Orientals (19). This conclusion wasdrawn from only three studies, two of which were in Japanese populations. Fur-thermore, in Chinese, previous reports describing the involvement of the AGTpolymorphism in hypertension have been conflicting (38,39), indicating that fur-ther studies in Asian populations are still necessary. In this, the first study in Chi-nese to examine all three polymorphism in the same cohort of subjects, we foundno association between hypertension and these gene polymorphisms in either thetotal population or in age and gender-matched cohorts. Furthermore, unlike in asmaller study of Caucasian subjects (40), there was no age-related decline in theprevalence of the ACE DD genotype. We also investigated for a possible interac-tion between the AGT and ACE gene polymorphisms in their contribution to hy-pertension, however none were identified. This suggests that modulation of the


Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

RAAS by these mutations, or those with which they are in linkage disequilibrium,may not play a major role in hypertension in this population.

The genotype and allele frequencies of the normotensive Chinese controlpopulation were significantly different from those previously reported in equiva-lent Caucasian populations. The interethnic differences in the prevalence of the al-lele frequencies of these polymorphisms are larger than those reported in positiveassociation studies between control and affected cohorts within the same ethnicgroup. These large differences in the polymorphism allele frequencies have led tothe hypothesis that they may be important in ethnic variations in cardiovasculardisease demography (27).

Although the efficacy of drugs such as ACE inhibitors suggests a role for theRAAS in the maintenance of blood pressure there was no evidence to suggest thatthese gene polymorphisms modulate blood pressure or are involved in the patho-genesis of hypertension in this Chinese population.

ACKNOWLEDGEMENTS

This work was supported by the Hong Kong Research Grants Council grantsCUHK 237/94M and CUHK 426/95M. Current address of Dr RP Young: Depart-ment of Medicine, University of Auckland, Auckland Hospital, Park Rd, Auck-land, New Zealand

REFERENCES

1. Schriver MD. Ethnic variation as a key to the biology of human disease. Ann InternMed 1997;127:401–403.

2. Swales JD, Dzau VJ. ACE inhibition: research advances and clinical implications.Am Heart J 1992;123:1412–1414.

3. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC,Snavely DE, Chang PI, on behalf of ELITE study investigators. Randomised trial oflosartan versus captopril in patients over 65 with heart failure (Evaluation of Losar-tan In The Elderly Study, ELITE). Lancet 1997;349:747–752.

4. Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV, Davidson HR, Connor JM,Lever AF, Fraser R. Abnormalities of glucocorticoid metabolism and the renin-an-giotensin system: a four-corners approach to the identification of genetic determi-nants of blood pressure. J Hypertens 1992;10:473–482.

5. Harrap SB, Davidson HR, Connor JM, Soubrier F, Corvol P, Fraser R, Foy CJ, WattGC. The angiotensin I converting enzyme gene and predisposition to high blood pres-sure. Hypertension 1993;21:455–460.

6. Jeunemaitre X, Charru A, Chatellier G, Dumont C, Sassano P, Soubrier F, Menard J,Corvol P. M235T variant of the human angiotensinogen gene in unselected hyper-tensive patients. J Hypertens [Suppl] 1993;11:80–81.

7. Staessen JA, Kunzetsova T, Wang JG, Emelianov D, Vlietinck R, Fagard R. M235Tangiotensinogen gene polymorphism and cardiovascular renal risk. J Hypertens1998;17:9–17.

94 THOMAS ET AL.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

8. Hata A, Namikawa C, Sasaki M, Sato K, Nakamura T, Tamura K, Lalouel JM. An-giotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 1994;93:1285–1287.

9. Caulfield M, Lavender P, Newell-Price J, Farrall M, Kamdar S, Daniel H, Lawson M,De Freitas P, Fogarty P, Clark AJ. Linkage of the angiotensinogen gene locus to hu-man essential hypertension in African Caribbeans. J Clin Invest 1995;96:687–692.

10. Kunz R, Kreutz R, Beige J, Distler A, Sharma AM. Association between the an-giotensinogen 235T-variant and essential hypertension in whites: a systematic reviewand methodological appraisal. Hypertension 1997;30:1331–1337.

11. Katsuya T, Koike G, Yee TW, Sharpe N, Jackson R, Norton R, Horiuchi M, Pratt RE,Dzau VJ, McMahon S. Association of angiotensinogen gene T235 variant with in-creased risk of coronary heart disease. Lancet 1995;345:1600–1603.

12. Ishigami T, Umemura S, Iwamoto T, Tamura K, Hibi K, Yamaguchi S, Nyuui N,Kimura K, Miyazaki N, Ishii M. Molecular variant of angiotensinogen gene is asso-ciated with coronary atherosclerosis. Circulation 1995;91:951–954.

13. Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJ. Link-age of the angiotensinogen gene to essential hypertension. N Engl J Med 1994;330:1629–1633.

14. Fornage M, Turner ST, Sing CF, Boerwinkle E. Variation at the M235T locus of theangiotensinogen gene and essential hypertension: a population-based case-controlstudy from Rochester, Minnesota. Hum Genet 1995;96:295–300.

15. Bloem LJ, Manatunga AK, Pratt JH. Racial difference in the relationship of an an-giotensin I-converting enzyme gene polymorphism to serum angiotensin I-convertingenzyme activity. Hypertension 1996;27:62–66.

16. Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hi-ramori K. Deletion polymorphism of the angiotensin-converting enzyme gene is as-sociated with serum ACE concentration and increased risk for CAD in the Japanese.Circulation 1994;90:2199–2202.

17. O’Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer EJ, My-ers RH, Levy D. Evidence for association and genetic linkage of the angiotensin-con-verting enzyme locus with hypertension and blood pressure in men but not women inthe Framingham Heart Study. Circulation 1998;97:1766–1772.

18. Fornage M, Amos CI, Kardia S, Sing CF, Turner ST, Boerwinkle E. Variation in theregion of the angiotensin-converting enzyme gene influences interindividual differ-ences in blood pressure levels in young white males. Circulation 1998;97:1773–1779.

19. Staessen JA, Wang JG, Ginocchio G, Petrov V, Saavedra AP, Soubrier F, VlietinckR, Fagard R. The deletion/insertion polymorphism of the angiotensin converting en-zyme gene and cardiovascular-renal risk. J Hypertens 1997;15:1579–1592.

20. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E, Tiret L, Cam-bien F, Corvol P, Soubrier F. Angiotensin II type 1 receptor gene polymorphisms inhuman essential hypertension. Hypertension 1994;24:63–69.

21. Miyamoto Y, Yoshimasa T, Itoh H, Igaki T, Harada M, Yamashita J, Chun T, Doi K,Ishikawa M, Hori Y, Kuwahara K, Inoue M, Masuda I, Saito Y, Nakao K. Associa-tion of angiotenin II type 1 receptor gene polymorphism with essential hypertension.J Hypertens 1996;14(Suppl 1):S29.

22. Tiret L, Bonnardeaux A, Poirer O, Ricard S, Marques-Vidal P, Evans A, Arveiler D,Luc G, Kee F, Ducimetiere P, Soubrier F, Cambien F. Synergistic effects of an-giotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphismson risk of myocardial infarction. Lancet 1994;344:910–913.


Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

23. Benetos A, Topouchian J, Ricard S, Gautier S, Bonnardeaux A, Asmar R, Poirier O,Soubrier F, Safar M, Cambien F. Influence of angiotensin II type 1 receptor poly-morphism on aortic stiffness in never-treated hypertensive patients. Hypertension1995;26:44–47.

24. Castellano M, Muiesan ML, Beschi M, Rizzoni D, Cinelli A, Pasini G, Porteri E, Bet-toni G, Salvetti M, Agabiti-Rosei E. Angiotensin II type 1 receptor A to C1166 poly-morphism: relationships with 24-hour blood pressure and cardiovascular structure. JHypertens 1996;14:S30.

25. Bai H, Saku K, Jimi S, Liu R, Takeda Y, Liu K, Nii T, Shirai K, Arakawa K. An-giotensinogen II type 1 receptor gene polymorphisms in both hypertensives and coro-nary heart disease patients. J Hypertens 1996;14:S26.

26. Labarthe DR. Geographic patterns of hypertension and stroke. Hypertension Primer.Dallas: American Heart Association, 1989:145–149.

27. Young RP, Thomas GN, Critchley JAJH, Tomlinson B, Woo KS, Sanderson JE. In-terethnic differences in coronary heart disease mortality in 25 populations: associa-tion with the angiotensin-converting enzyme DD genotype frequency. J CardiovascRisk 1998;5:303–307.

28. Durnin JVGA, Womersley J. Body fat assessed from total body density and its esti-mation from skinfold thickness: measurements on 481 men and women aged from 16to 72 years. Brit J Nutr 1974;32:77–97.

29. JNC-VI. The sixth report of the Joint National Committee on prevention, detection,evaluation and treatment of high blood pressure. Ann Intern Med 1997;157:2413–2446.

30. The Expert Committee on the Diagnosis and Classification of Diabetes mellitus. Re-port of the Expert Committee on the Diagnosis and Classification of Diabetes melli-tus. Diabetes Care 1997;20:1183–1197.

31. Guide to plasma lipids and lipoproteins for Hong Kong doctors. J Hong Kong CollCardiol 1996;4:81–89.

32. Expert panel on detection evaluation and treatment of high blood cholesterol inadults. Summary of the second report of the National Cholesterol Education Program(NCEP) Expert panel on detection, evaluation and treatment of high blood cholesterolin adults. JAMA 1993;269:3015–3023.

33. Fogarty DG, Maxwell AP, Doherty CC, Hughes AE, Nevin NC. ACE gene typing.Lancet 1994;343:851.

34. Rotimi C, Puras A, Cooper R, McFarlane-Anderson N, Forrester T, Ogunbiyi O,Morrison L, Ward R. Polymorphisms of renin-angiotensin genes among Nigerians,Jamaicans, and African Americans. Hypertension 1996;27:558–563.

35. Després JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regionaldistribution of body fat, plasma lipoproteins and cardiovascular disease. Arterioscle-rosis 1990;10:497–511.

36. Havlik RJ, Hubert HB, Fabsitz RR, Feinleib M. Weight and hypertension. Ann InternMed 1983;98:855–859.

37. Haffner SM, Mitchell BD, Valdez RA, Hazuda HP, Morales PA, Stern MP. Eight-year incidence of hypertension in Mexican-Americans and non-Hispanic whites. TheSan Antonio Heart Study. Am J Hypertens 1992;5:147–153.

38. Cheung BM, Leung R, Shiu S, Tan KC, Lau CP, Kumana CR. M235T polymorphismof the angiotensinogen gene and hypertension in Chinese. J Hypertens 1998;16:1137–1140.

96 THOMAS ET AL.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

39. Chiang FT, Hsu KL, Tseng CD, Hsiao WH, Lo HM, Chern TH, Tseng YZ. Molecu-lar variant M235T of the angiotensinogen gene is associated with essential hyperten-sion in Taiwanese. J Hypertens 1997;15:607–611.

40. Morris BJ, Zee RY, Schrader AP. Different frequencies of angiotensin-converting en-zyme genotypes in older hypertensive individuals. J Clin Invest 1994;94:1085–1089.

Submitted: 03/29/99Revised: 05/21/99Accepted; 06/08/99


Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

Order now!

Reprints of this article can also be ordered at

http://www.dekker.com/servlet/product/DOI/101081CEH100100064

Request Permission or Order Reprints Instantly!

Interested in copying and sharing this article? In most cases, U.S. Copyright Law requires that you get permission from the article’s rightsholder before using copyrighted content.

All information and materials found in this article, including but not limited to text, trademarks, patents, logos, graphics and images (the "Materials"), are the copyrighted works and other forms of intellectual property of Marcel Dekker, Inc., or its licensors. All rights not expressly granted are reserved.

Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly. Simply click on the "Request Permission/Reprints Here" link below and follow the instructions. Visit the U.S. Copyright Office for information on Fair Use limitations of U.S. copyright law. Please refer to The Association of American Publishers’ (AAP) website for guidelines on Fair Use in the Classroom.

The Materials are for your personal use only and cannot be reformatted, reposted, resold or distributed by electronic means or otherwise without permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the limited right to display the Materials only on your personal computer or personal wireless device, and to copy and download single copies of such Materials provided that any copyright, trademark or other notice appearing on such Materials is also retained by, displayed, copied or downloaded as part of the Materials and is not removed or obscured, and provided you do not edit, modify, alter or enhance the Materials. Please refer to our Website User Agreement for more details.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y T

he U

nive

rsity

of

Man

ches

ter

on 1

2/21

/14

For

pers

onal

use

onl

y.

http://www.copyright.gov/fls/fl102.html

http://www.publishers.org/conference/copyguide.cfm

http://www.dekker.com/misc/useragreement.jsp

http://www.dekker.com/misc/useragreement.jsp

http://s100.copyright.com/AppDispatchServlet?authorPreorderIndicator=N&pdfSource=Dekker&publication=CEH&title=RENIN-ANGIOTENSIN-ALDOSTERONE+SYSTEM+GENE+POLYMORPHISMS+AND+HYPERTENSION+IN+HONG+KONG+CHINESE&offerIDValue=18&volumeNum=22&startPage=87&isn=1064-1963&chapterNum=&publicationDate=01%2F19%2F2000&endPage=97&contentID=10.1081%2FCEH-100100064&issueNum=1&colorPagesNum=0&pdfStampDate=07%2F28%2F2003+09%3A57%3A44&publisherName=dekker&orderBeanReset=true&author=G.+Neil+Thomas%2C+G+N+Thomas%2C+Robert+P.+Young%2C+Brian+Tomlinson%2C+Kam+Sang+Woo%2C+John+E.+Sanderson%2C+Julian+A.J.H.+Critchley&mac=T$tamJT87NI8TV9E$zns1A--

renin-angiotensin-aldosterone system gene polymorphisms and hypertension in hong kong chinese

Documents