Impaired P,-adrenergic agonist-induced venodilation in Indians of Asian origin

Objectives: Vascular responsiveness to infusions of vasoactive substances varies between ethnic groups. Indians of Asian origin are a rapidly growing ethnic group in the United States but have not been extensively studied. We sought to determine whether there was any difference in venous responsiveness to a local infusion of vasoactive substances between Indians of Asian origin and white subjects. Methods: We used the dorsal hand vein compliance technique to construct full dose-response curves to the @,-agonist isoproterenol(2 to 270 ng/min) in hand veins preconstricted with phenylephrine in 11 young white subjects and in 11 young Asian Indian subjects. In addition, six subjects in each group were randomly selected to have full dose-response curves to nitroglycerin (0.006 to 1485 ng/min) generated. Results: The maximal response (E,,,) to isoproterenol was smaller in Asian Indians (33.9% +- 41.1% in Asian Indians versus 107.0% + 60.1% in white subjects; p c 0.01). There was no difference in the log of the dose that produced half-maximal venodilation [log(ED,,)] between the two groups (1.10 I?: 0.57 in Asian Indians versus 1.15 f 0.50 in white subjects). However, nitroglycerin infusion produced similar responses for both the E,,, and the log(ED,,) between the two groups. Conclusion: These results indicate that differences may exist in l3-adrenergic responsiveness among white subjects and Indians of Asian origin. Therapy for diseases that use P-adrenergic responses, such as hypertension, must take into account these differential vascular responses because they may affect their efficacy in Asian Indians. (Clin Pharmacol Ther 1996;59:569-76.)

Charanjit Kapoor, MD, Clement Singarajah, MD, Haider Zafar, MD, Kwabena 0. Adubofour, MD, Bruce Takahashi, DO, Zoltan Vajo, MD, and William D. Da&man, MD Phoenix, Ark

Adrenergic receptors play a major role in the control of vascular tone. Vascular tone is regulated through a complex interaction of both neural and non-neural factors.’ Smooth muscle relaxation in- duced by epinephrine (acting on p,-adrenergic re- ceptors), prostaglandins (such as alprostadil [PGE,], PGE,, and epoprostenol [prostacyclin]), and sub- stances whose mechanism of vasodilation is medi- ated through the release of endothelium derived relaxing factor (e.g., acetylcholine and bradykinin) is counterbalanced by vasoconstriction induced by norepinephrine (acting on cx,-adrenergic receptors), angiotensin II, and prostaglandins such as PGF,,.2

Interracial variability in vascular responsiveness

From the Department of Medicine, Maricopa Medical Center. Support by the Maricopa Research Foundation, Phoenix, Ariz. Received for publication July 25, 1995; accepted Dec. 13, 1995. Reprint requests: William Dachman, MD, Department of Med-

icine, Maricopa Medical Center, 2601 E. Roosevelt, Phoenix, AZ 85008.

Copyright 0 1996 by Mosby-Year Book, Inc. 0009-9236/96/$5.00 + 0 13/l/71190

to adrenergic receptors has been shown previously by several investigators.3-8 In addition, in our labo- ratory we have demonstrated differences in vascular responsiveness to isoproterenol and phenylephrine between Mexican Americans, Native Americans, and white Americans (Dachman et al. Unpublished data, April 1994). Investigation into ethnic-specific vascular responsiveness, particularly in black Amer- icans, has led to the development of better treat- ment strategies and drugs in these groups.

Asian Indians are a rapidly growing ethnic group in the United Kingdom, the United States, and Can- ada. However, little is known about how vascular responsiveness in Indians of Asian origin may differ from that of the white population. The aim of this study was to compare venous responsiveness be- tween Asian Indians and white Americans to vaso- active substances: the a,-adrenergic agonist phenyl- ephrine, the &-adrenergic agonist isoproterenol, and nitroglycerin, a vasodilator whose mechanism of action is independent of (Y- and P-adrenergic recep- tors.

569

570 I(apooveta1. CLINICAL PHAPJvL4COLOGY 8c ‘THhlW’EUTICS

MAY 1996

We used the dorsal hand vein compliance tech- nique, 9 which is a safe, simple, and minimally inva- sive method used for the study of in vivo responses to vasoactive substances. This technique has been used to compare the responses between several dif- ferent physiologic and pathologic states. The tech- nique has been validated by several investigators, including Alradi and Carruthers,” who found little diurnal, day-to-day, or intrasubject variability in the response to norepinephrine. Vincent et al.‘r found a significant correlation between the blood pressure response to systemically infused phenylephrine and the dose of phenylephrine required to produce half- maximal venoconstriction in the dorsal hand vein, indicating that the response in the hand vein mirrors that of the resistance vessels.

METHODS Study drugs. All study medications were diluted in

normal saline solution. Study drugs were phenyleph- rine hydrochloride (1% injection), isoproterenol hy- drochloride (both from Winthrop Laboratories, New York, N.Y.), and nitroglycerin (DuPont Phar- maceuticals, Manati, Puerto Rico). Phenylephrine was infused in the dosing range from 1 to 6800 ng/min, isoproterenol was infused in the dosing range from 2 to 271 ng/min, and nitroglycerin was infused in the dosing range from 0.006 to 1485 @min. Nitroglycerin was infused with use of non- absorption tubing to avoid interaction between the nitroglycerin and plastic infusion set.

Subjects. Studies were performed on healthy, nonobese normotensive volunteers. Eleven white subjects (eight men and three women; mean age, 31.8 & 5.3 years) and 11 Asian Indians (six men and five women; mean age, 31.2 + 2.6 years; p = NS) were studied. No study volunteers had previously participated in a clinical trial. Demographic data are provided in Table I. White subjects were defined as white Americans of European ancestry. Asian Indi- ans included persons who were born in India of Indian parents and who had immigrated to the United States. Some of the subjects had immigrated first to the United Kingdom and then to the United States, therefore the number of years in either coun- try was considered as having emigrated from India. As expected, the white subject group had a longer number of years in the United States (or the United Kingdom) than the Asian Indian group (31.8 + 5.3 versus 9.1 2 7.1; p < 1 x lo-‘). There were two subjects who were vegetarians in the white subject

group and three subjects who were vegetarians in the Asian Indian group.

The subjects were admitted on the morning of the study to the Drug Evaluation Unit at Maricopa Medical Center (Phoenix, Ariz.). The subjects signed a written informed consent and underwent a complete physical examination, ECG, and routine laboratory tests (SMA-20, complete blood cell count, and urinalysis). Premenopausal female sub- jects were screened for a negative serum pregnancy test within 24 hours before the study period and were studied mid-menstrual cycle. Exclusion criteria included a history of any significant disease state, drug addiction, alcoholism, or chronic use of any medication that could affect the vasculature. All subjects were nonsmokers and were asked to refrain from caffeine for at least 12 hours before the study.

Dorsal hand vein compliance technique. The dorsal hand vein technique was modified slightly from that originally described by Aellig in 1981.9 The technique has the advantage of being able to quantitate responsiveness of the dorsal hand vein to small amounts of vasoactive drugs, often by constructing full dose-response curves, without confounding systemic effects. Studies were con- ducted while each subject was in the supine posi- tion with one arm placed on a padded support sloping upward at an angle of 30 degrees from the horizontal to allow complete emptying of the veins. The temperature of the room was main- tained at 72” + 2” F during the study period. A suitable vein was chosen on the dorsum of the hand and a 23-gauge needle was inserted. A nor- mal saline infusion was started at 0.30 ml/min with a syringe infusion pump. The tripod holding a linear variable differential transformer (LVDT, Shaevitz Engineering, Pennsuaken, N.J.) was mounted on the back of the hand, with the central aperture of the LVDT over the vein under inves- tigation at a distance of 10 mm downstream from the needle. The central aperture of the LVDT contains a freely movable core; vertical movement of the core was directly proportional to the signal output of the LVDT, which was recorded on a strip chart recorder. Recordings of the position of the core located on top of the vein were made both before and after inflation of a sphygmoma- nometer cuff on the arm to 40 mm Hg. This baseline vasodilation during saline infusion with the cuff inflated was defined as 100% relaxation; the recording obtained with the cuff not inflated (and the vein emptied) was defined as 100% con-

CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 59. NUMBER 5 Kupoor et al. 571

Table I. Demographic data from each subject in the white and Asian Indian subject groups Subject Age SenC Years in U.S. Vegetarian

White subjects 1 28 2 33 3 32 4 3.5 5 19 6 28 7 31 8 35 9 36

10 35 11 38

Mean ? SD 31.8 2 5.3

Asian Indian subjects 1 31 2 27 3 29 4 35 5 29 6 32 7 34 8 29 9 35

10 31 11 32

Mean 2 SD 31.2 i 2.6

*p < 1 X lo-’ compared with white subjects.

striction. The difference between the two posi- tions of the core gives a measure of the diameter change of the vein under the given congestion pressure. Baseline recordings were obtained dur- ing normal saline infusion after approximately 30 minutes to allow for equilibrium of the vein after the initial vasoconstriction produced by insertion of the needle. Phenylephrine, an a,-selective ag- onist, was used to produce vasoconstriction of the hand vein. A dose-response curve to phenyleph- rine was performed in each subject (dose range, 2 to 6800 ng/min), and the dose of phenylephrine that produced 80% constriction was determined. This dose was then infused at a constant rate during the subsequent performance of the vasodi- latory dose-response curve. Response to each con- centration of the drug was recorded after infusing for at least 5 minutes, which allows sufficient time to reach the maximum effect at each infusion rate. Blood pressure and heart rate were regularly monitored in the opposite arm throughout the study period and did not change appreciably in any study subject. Isoproterenol dose-response

Female Male Male Female Female Male Male Male Male Male Male

Male Female Female Male Female Male Male Female Male Female Male

28 33 32 35 19 28 31 35 36 35 38

31.8 + 5.3

19 2 2 4 5 4

21 6

18 7

10 9.1 ? 7.1*

No No No No Yes No No No No Yes No

No No Yes No Yes No Yes No No No No

curves were performed in each of the volunteers in both groups. Six white subjects and six Asian Indians subjects were randomly selected to return on a second study day to have nitroglycerin dose- response curves generated in phenylephrine pre- constricted hand veins in the same manner as described above.

Data analysis. Individual dose-response curves were analyzed with a sigmoid E,,, model with use of the computer program, MKMODEL.‘* This iter- ative nonlinear curve-fitting program provides an estimate of the maximal response (E,,) and the infusion rate producing half-maximal response (ED,,). A log-transformation was performed on in- dividual ED,, values to obtain geometric means. An unpaired two-tailed t test was used to compare the individual ED,, values (after log-transformation) and the E,,, values for the subject groups. A cor- relation was sought between the effect of living out- side of India on the response to isoproterenol in Asian Indians. A value ofp -C 0.05 was considered to be significant. All mean values are given as mean + SD.

572 IGzpoor et al. CLINICAL PHARMACOLOGY & THERAPEUTICS

MAY 1996

120 - 0

0 White Caucasian subject

100 --

+ Asian Indian subject

0 I 1 I I I

0.1 1 10 100 1000

ISOPROTERENOL INFUSION RATE (nglmin)

Fig. 1. Dose-response curves generated from isoproterenol infusion into dorsal hand veins obtained from a typical white subject (open squares) and from a typical Asian Indian subject (solid squares). Vasodilation is expressed as a percentage of baseline (prephenylephrine) vein diameter.

RESULTS Dose-response curves to isoproterenol were gen-

erated in each subject, and the E,, and log dose that produced half-maximal response [log(ED,,)] to isoproterenol were determined. Infusion of isopro- terenol resulted in a larger maximal venodilatory response in white subjects than in Asian Indians (107.0% + 60.1% versus 33.9% 5 41.1%;~ < O.Ol), whereas there was no difference in the log(ED,,) between the two groups (1.2 t- 0.5 [16 ng/min] for white subjects and 1.1 t 0.6 [13 ng/min] for Asian Indians; Fig. 1 and Table II).

We wanted to investigate whether factors other than race may have contributed to the diminished venodilatory response to isoproterenol in the Asian Indian group. Therefore a correlation was sought between the number of years the Asian Indian sub- jects had lived outside of India and the response to isoproterenol. There was no correlation between the log(ED,,) or the E,,, for the isoproterenol re- sponse and the number of years the Asian Indian subjects had lived outside of India (Y = -0.33;~ = NS). To exclude the possibility that a vegetarian diet may have influenced our results, we performed a separate analysis in which the small number of veg-

etarians were excluded from each subject group. The results were similar to the original analysis. The nonvegetarian group of white subjects (n = 9) had a larger E,,, than the nonvegetarian group of Asian Indians (n = 8; 93.3 t 40.9 versus 38.5 + 46.5;~ =C O.OS), while maintaining a similar log(ED& (1.1 ? 0.5 versus 1.2 -t 0.4). We also wanted to investigate whether the small number of female subjects in each subject group may have influenced our results. Therefore we compared the responses to isoproter- enol between the male subjects alone in each subject group. The results were similar to the analysis per- formed with the female subjects included. The male white subjects (n = 8) had a larger E,, to the infusion of isoproterenol than the male Asian In- dian subjects (n = 6; 113.3 f 65.7 versus 39.6 + 54.5; p < 0.05), while maintaining a similar log(ED,,) (1.3 2 0.5 versus 1.4 +- 0.6).

To investigate whether the diminished response to isoproterenol in Asian Indians was due to a gen- eralized inability to venodilate or specifically due to an inability to venodilate to a P-adrenergic agonist, we studied the venodilatory response to nitroglyc- erin. Nitroglycerin dose-response curves were gen- erated in six white subjects and six Asian Indian

CLINICAL PHARMACOLOGY & THEBAPEUTICS VOLUME 59, NUMBER 5 Kapoor et al. 573

Table II. Responsiveness of the dorsal hand vein to the infusion of phenylephrine, isoproterenol, and nitroglycerin in white subjects and in Asian Indian subjects

Subject

Phenylephrine Isoproterenol Nitroglycerin

log(ED,d lodEW E WED,,) E (nglmin) (nglmin) (% reYp?nse) (nglmin) (7% reYp?nse)

White subjects 1 2 3 4 5 6 7 8 9

10 11

Mean t SD

Asian Indian subjects 1 2 3 4 5 6 7 8 9

10 11

Mean 2 SD

1.77 0.90 140.4 2.87 2.02 80 3.27 0.51 110 2.87 1.08 43.9 3.87 0.47 86.3 3.87 1.15 106 1.67 1.00 66.4 2.27 1.35 124.9 2.57 1.88 28.4 2.87 1.46 250.4 2.57 0.83 140

2.7 k 0.72 1.15 -c 0.50 107.0 ? 60.1

2.87 1.50 36.4 3.87 1.08 40.1 3.87 0.43 49.3 3.57 0.89 9.5 3.87 0.38 6 2.87 1.95 148 3.87 2.17 10 3.57 1.00 5 2.27 0.76 5.6 2.87 0.86 35 2.57 1.12 28.3

3.27 5 0.60 1.10 +- 0.57 33.9 ? 41.1%

- -

1.62 1.35 1.74 -

1.61 -

0.83

2T2 1.68 2 0.69

1.52 2.54 2.20

- 2.11 - -

2.37 1.90

2.10 t 0.36

- 60

140 96 - 78 - 40 - 50

77.3 ? 36.7

153 36 20 - -

64 -

71.6 77

70.3 ? 46.1

log(ED,,,), Log of the dose of phenylephrine used to produce 80% vasoconstriction; log(ED,,), log dose that produced half-maximal response; E,,,, maximal response.

*p < 0.01 compared with white subjects.

subjects. No difference was noted in the E,,, (70.3% ? 46.1% in Asian Indians versus 77.3% t- 36.7% in white subjects) or in the logED,, (2.1 + 0.4 [126 ng/min] in Asian Indians versus 1.7 5 0.7 [50 ng/min] in white subjects) between the two groups (Fig. 2 and Table II).

In addition, we compared the log of the dose of phenylephrine that was used to produce 80% vaso- constriction (log(ED,,)) between the two subject groups. There was no difference in log(ED,,) be- tween white subjects (2.7 -+ 0.7) and Indians of Asian origin (3.3 5 0.6; p = NS). There was no difference in baseline hand vein diameter between the two subject groups (data not shown).

DISCUSSION Our study revealed a diminished pharmacody-

namic response to isoproterenol between Indians of Asian origin and white American subjects. Asian

Indians had a significantly smaller maximal relax- ation (E,,,) to isoproterenol. The diminished ability to venodilate to isoproterenol represents a specific P,-adrenergic response and not a generalized inabil- ity to venodilate because there was no difference in vascular response shown to the infusion of the non- P-adrenergic vasodilator (nitroglycerin) between the two subject groups. To our knowledge, this is the first such study to compare the vascular responsive- ness of Indians of Asian origin to white subjects.

It is unlikely that environmental factors such as diet or the length of time the Asian Indian subjects had lived outside of India influenced the results. Although our study was not designed to test the hypothesis that diet may influence the response to isoproterenol, there was no difference in the results when we compared the combined group of vegetar- ian and nonvegetarian Asian Indians with vegetar- ian and nonvegetarian white subjects than when the

574 Kapoov et al. CLINICAL PHARMACOLOGY & THERAPEUTICS

MAY 1996

oWhite Caucasian subject

10

0

0.01 0.1 1 10 100 1000 10000

NITROGLYCERIN INFUSION RATE (nglmin)

Fig. 2. Dose-response curves generated from nitroglycerin infusion into dorsal hand veins obtained from a typical white subject (open squares) and from a typical Asian Indian subject (solid squares). Vasodilation is expressed as a percentage of baseline (prephenylephrine) vein diameter.

analysis included solely nonvegetarians. However, the number of vegetarians in the Asian Indian group was lower than we expected, and we were unable to investigate the influence of a vegetarian diet within the Asian Indian group. In addition, we found that there was no correlation between the number of years the Asian Indian subjects had lived away from India and the response to isoproterenol, lending further credence to the fact that genetic factors and not environmental factors influenced the response to isoproterenol.

Indians of Asian origin represent 0.3% of the population of the Unites States.13 However, little is known about cardiovascular disease or coronary heart disease risk factors in this group in the United States. A survey of Asian Indian physicians and U.S.-born physicians indicated that the immigrant group had higher total cholesterol levels and de- pressed high-density lipoprotein-cholesterol sub- fractions.14 In other Western countries, such as in the United Kingdom, immigrants from the Indian subcontinent have higher morbidity and mortality from coronary heart disease than the England and Wales average irrespective of regional, cultural, or religious differences.i5-l8 Similar increased mortality

from coronary heart disease has been found in im- migrant Asian Indians in other parts of the world.‘9Y20 including Trinidad in the Western Hemi-

Given the high morbidity rate from coronary heart disease in Asian Indians in other Western countries, one may expect a similar trend as the population grows in the United States. In Trinidad, for example, the prevalence of coronary heart dis- ease in people of Asian Indian ancestry was three times greater than other ethnic groups.22 In En- gland, the relative rate of a first myocardial infarc- tion at Northwick Park Hospital was 4.9 times greater in the Asian Indian population that the white population, and the mean age for the first myocardial infarction was S/2 years younger.23 In addition, in Leicester, England, Asian Indians were found to be 2.2 times more likely than other ethnic groups to receive a diagnosis of myocardial infarc- tion.24 Therefore it is important to gain an under- standing of how Indians of Asian origin may re- spond differently to vasoactive drugs.

Race has previously been described as an im- portant factor in P-adrenergic responsiveness,25,26 and ethnicity, as in our study, may play a key role

CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME. 59. SL’MBER 5 Kupoor et al. 575

as well. Zhou et a1.7 found a greater sensitivity to propranolol on heart rate and blood pressure in Chinese men than in white subjects7 Darmansjah and Muchtar described differences in pharmaco- kinetic metabolism of drugs among various ethnic groups. Several drugs have been initially marketed in Indonesia at the same doses prescribed for Europeans and Americans. As a consequence, a larger number of side effects have been observed. One class of agents in which a large number of side effects have been described are B-blockers. Reductions in the dosing of atenolol from 100 mg/day to 50 mg/day for Indonesians (compared with white subjects) has resulted in a smaller num- ber of adverse effects while the same level of blood pressure control was maintained.4 Although these observations may support the notion of al- tered pharmacokinetic metabolism in different population groups, it is unclear whether pharma- codynamic differences also exist.

To be most effective for the population at large, clinical trials should not be confined to only one racial group. Drug trials in developing countries tend to be less rigorous than trials in developed nations. They are directed toward introduction of the drug, rather than determination of the efficacy of the drug in these populations.4 Clinical trial out- comes for one racial group are then used to treat other groups in a similar fashion, despite different genetic, nutritional, and climactic settings.4,27,28

Racial variability in the response to vasoactive substances is a prime consideration in determination of initial therapy for diseases such as hypertension. For example, black Americans respond more favor- ably to calcium channel blockers and diuretics for optimal control of high blood pressure.29 On the basis of our findings, we can anticipate that Indians of Asian origin may also respond differently to an- tihypertensive therapy. However, further investiga- tion needs to be done with an eye toward the devel- opment of drug therapy and treatment strategies tailored to this specific population.

We thank Dr. Pat Palumbo for his helpful advice and comments regarding the manuscript. We would also like to thank Debra Smith, RN, for her help with the subjects. We also thank Tom Kedziora and Joe Vise110 for their help in preparing the drug infusions.

References 1. Hamilton CA, Vincent J, Reid JL. cY-Adrenoceptors

and neural control of the circulation: studies in exper-

imental animals. In: Zanchetti A, Tarazi RC, editors. Handbook of hypertension; vol 8: pathophysiology of hypertension-regulatory mechanisms. Amsterdam: Elsevier Science BV, 1986:125-50.

2. Vanhoutte PM. Introductory remarks: (Y- and B-adrenergic receptors and the cardiovascular system. J Cardiovasc Pharmacol 1981;3(suppl l):Sl-13.

3. Eichler HG, Blaschke TF, Hoffman BB. Decreased responsiveness of superficial hand veins to phenyleph- rine in black normotensive males. J Cardiovasc Phar- macol 1990;16:177-81.

4. Darmansjah I, Muchtar A. Dose response variation among different populations. Clin Pharmacol Ther 1992;52:449-52.

5. Yurenev AP, Parfyonova EV, Krasnikova TL, Ari- pova NA. Alteration of beta-adrenoceptor function in hypertensive patients with different degrees of left ventricular hypertrophy. Am J Hypertens 1992;5(6 pt 2):164S-8s.

6. Stein M, O’Malley K, Kilfeather S. Ethnic differences in cyclic AMP accumulation: effect on (Y*, &, and prostanoid receptor responses. Clin Pharmacol Ther 1990;47:360-5.

7. Zhou H, Koshakji RP, Silberstein DJ, Wilkinson GR, Wood AJJ. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American Whites. N Engl J Med 1989;329:565- 70.

8. Vincent J, Elliot HL, Meredith PA, Reid JL. Racial differences in drug responses-a comparative study of trimazosin and alpha-l responses in normotensive Caucasians and West Africans. Br J Clin Pharmacol 1986;21:401-8.

9. Aellig WH. A new technique for recording compli- ance of human hand veins. Br J Clin Pharmacol 198; 11:237-43.

10. Alradi AO, Carruthers SG. Evaluation and applica- tion of the linear variable differential transformer technique for the assessment of dorsal hand vein alpha-receptor activity. Clin Pharmacol Ther 1985;38: 495-502.

11. Vincent J, Blaschke TF, Hoffman BB. Vascular reac- tivity to phenylephrine and angiotensin II: compari- son of direct venous and systemic responses. Clin Pharmacol Ther 1992;51:68-75.

12. Holford NHG. MKMODEL-a mathematical mod- elling tool for the PROPHET system. In: Perry HM, editor. PROPHET public proceedings procedures notebook. Cambridge: Bolt, Beranek and Newman, 1985:4.89-4.126.

13. United States Bureau of the Census, Department of Commerce. 1990 Census of population and housing. Washington: US Government Printing Office, 1990.

14. Thomas I, Gupta S, Sempos C, Cooper R. Serum lipids of Indian physicians living in the U.S. compared to U.S.-born physicians. Atherosclerosis 1986;61:99-106.

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1.5. McKeigue PM, Adelstein AM, Shipley MJ, et al. Diet and risk factors for coronary heart disease in Asians in Northwest London. Lancet 1985;2:1086-90.

16. Balarajan R, Bulusu L, Adelstein AM, Shukla V. Patterns of mortality among migrants to England and Wales from the Indian subcontinent. Br Med J 1984; 289:1185-g.

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20. Danaraj TJ, Acker MS, Danaraj LMS, Ong WH, Yam TB. Ethnic group differences in coronary heart dis- ease in Singapore: an analysis of necropsy records. Am Heart J 1959;58:516-26.

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22. Miller GJ, Alexis SD, Beckles GLA, Byam NTA. Serum lipoproteins and susceptibility of men of In- dian descent to coronary heart disease. Lancet 1982; 2:200-3.

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