Journal of Human Hypertension (2001) 15, 17–25 2001 Macmillan Publishers Ltd All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE Why is plasma renin activity lower in populations of African origin? GA Sagnella Blood Pressure Unit, St George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK Plasma renin activity is significantly lower in black the molecular level suggests that the lower PRA may people compared with whites independent of age and arise from gene variation in the renal epithelial sodium blood pressure status. The lower PRA appears to be due channel. The functional significance of the lower PRA in to a reduction in the rate of secretion of renin but the relation to the different pattern of cardiovascular and exact mechanistic events underlying such differences in renal disease between blacks and whites remains renin release between blacks and whites are still not unclear. Moreover, direct investigations of pre-treat- fully understood. Nevertheless, given the paramount ment renin status in hypertensive blacks in relation to importance of the renin-angiotensin system in the con- blood pressure response have demonstrated that the trol of sodium balance, a most likely explanation is that pre-treatment PRA is not a good index of subsequent the lower renin is a consequence of differences in renal blood pressure response to pharmacological treatment. sodium handling between blacks and whites. The lower Nevertheless, the blood pressure reduction to short PRA does not reflect differences in dietary sodium term sodium restriction is greater in blacks compared intake but the evidence available suggests that the low with whites and, in the black subjects, the greater PRA could be part of the corrective mechanisms reduction in blood pressure to sodium restriction designed to maintain sodium balance in the presence appears to be related, at least in part, to the decreased of an increased tendency for sodium retention in black responsiveness of the renin-angiotensin system. people. While it is possible that several factors may con- Journal of Human Hypertension (2001) 15, 17–25 tribute to the reduced PRA, more recent investigation at Keywords: African origin; plasma renin activity; sodium; renal; genetics Introduction variability in candidate genes likely to influence renin release and activity especially because of early The possibility of differences in the renin-angioten- suggestions that genetic factors may have a strong sin-system between people of African origin (blacks) influence on PRA and urinary aldosterone.2,3 and Caucasians (whites) has been recognised since Indeed, the potential importance of polymorphic the late 1960s. In one of the first studies using a variation at the gene level is highlighted by the newly developed quantitative assay for the measure- identification of polymorphic variants in the angio- ment of plasma renin activity (PRA), Helmer and tensin-converting enzyme (ACE) gene known to 1 Judson reported a much higher frequency of low account for more than 50% of the variability in PRA in black hypertensives (52%) compared with plasma ACE activity4 and in genetic variants of the white hypertensives (31%). renin substrate gene (angiotensinogen) associated The main purpose of this review is to assess the with increased expression of angiotensionogen.5 differences in PRA between blacks and whites, to explore some of the reasons for the low PRA in blacks and, in particular, to examine to what extent Comparison of PRA between blacks and the available evidence supports the widely held whites view that it is a direct result of a greater extracellular Following the early work,1 numerous other investi- fluid volume due to increased renal sodium gators measured PRA in blacks and confirmed the retention. Moreover, in view of recent advances in presence of lower PRA in blacks compared with molecular biology, particular emphasis will also be whites. Some of these studies spanning a period of given to the potential importance of genetic nearly 25 years are summarised in Table 1. As can be seen, on average PRA in blacks is about 50% to that in whites and the differences are similar for Correspondence: GA Sagnella, Blood Pressure Unit, St George’s 15,16 Hospital Medical School, Cranmer Terrace, London SW17 ORE, men and women, however it is also relevant to UK note the wide variability indicating that the PRA in Received 22 June 2000; accepted 17 July 2000 a substantial proportion of blacks is likely to be in Why is PRA lower in populations of African origin? GA Sagnella 18 Table 1 Comparison of PRA in blacks and whites Author Blacks Whites % Levy SB et al (1977)6 normotensives 0.80 ± 0.85(8) 1.60 ± 1.10(13) 50 essential hypertensives 0.70 ± 0.20(7) 2.80 ± 4.67(18) 25 Sever et al (1978)7 essential hypertensives 0.34 ± 0.56(23) 0.97 ± 1.10(77) 35 Mitas JA et al (1979)8 normotensives 0.76 ± 0.11(14) 1.58 ± 0.48(15) 48 essential hypertensives 0.95 ± 0.26(9) 1.23 ± 0.16(27) 77 Veterans (1987)9 essential hypertensives 0.69 ± 0.82(407) 1.35 ± 1.27(216) 51 Hohn AR et al (1983)10 children 2.40 ± 1.70(36) 4.76 ± 2.8(33) 50 children with family history of hypertension 1.98 ± 1.50(18) 4.62 ± 3.5(41) 43 James GD et al (1986)11 normotensives 2.10 ± 1.60(112) 2.80 ± 2.0(124) 75 He F et al (1998)12 essential hypertensives 0.48 ± 0.46(33) 1.08 ± 0.76(71) 44 He J et al (1999)13 population-based study 0.92 ± 1.36(110) 1.26 ± 1.35(183) 73 Kotchen et al (2000)14 essential hypertensives 1.10 ± 1.07(29) 1.80 ± 1.15(33) 61 Values are means ± s.d. (n); PRA activity (ng/ml/hr); supine and for subjects on their normal sodium intake. % (ratio of PRA in blacks/whites expressed as %). the range found in whites. Moreover, PRA distri- renin hypertension’ in blacks. However, ‘low renin butions are not normal, although there is no evi- hypertension’ is clearly an arbitrary definition and dence for a bimodal distribution in blacks. A lower the actual frequency in blacks has ranged widely plasma PRA has also been observed in some10,17 but depending on the cut-off value taken to delimit the not in every study18,19 of black children compared state of ‘low PRA’. Furthermore, suppressed PRA is with white children, however, it is apparent that the also present in both normotensive and hypertensive difference between black and white children blacks even when on a low salt diet6,12 and in becomes more pronounced with increasing age even response to loss of sodium as induced by admini- over an age range of 8–14 years.17 Interestingly, stration of diuretics.23,24 slightly lower PRA has also been reported in black The low PRA in blacks is also associated with a neonates.20 lower plasma angiotensin II independent of ACE While a lower PRA was originally defined in activity.12 Given the potent cardiovascular and renal relation to hypertension in blacks, lower PRA has effects of angiotensin II (Figure 1) this has led to also been found in normotensives6,8,9,11,13 suggesting that the lower PRA is not simply a consequence of the high blood pressure, at least in individuals with- out malignant hypertension and renal failure. That the lower PRA is a characteristic feature of blacks as a group is also supported by a lack of difference in PRA between normotensive and hypertensive blacks from rural African regions.21,22 A major criticism of some of the earlier studies was that they were limited by small numbers in clinic-based designs. However, lower PRA has also been found in popu- lation-based studies of blacks and whites in the absence of significant differences in blood pressure between the two groups.7,9,13 Nevertheless, in both whites and blacks, a weak but statistically signifi- cant inverse association between PRA and both sys- tolic and diastolic blood pressure has been reported even after adjusting for age and gender13 (−2.4 mm Hg/1.24 ng/ml/hr renin for systolic and −1.5 mm Hg/1.24 ng/ml/hr renin for diastolic blood pressure, respectively). The regression coefficients were slightly higher for the blacks and this could Figure 1 Systemic, renal and other effects of Angiotensin II (AT1 account for the apparently higher frequency of ‘low receptor). (See Taal and Brenner25 for further details). Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 19 speculations about the functional significance of the Renin-angiotensinogen reaction lower PRA in blacks in relation to the physiological role of renin in the control of sodium balance; to the In humans, the concentration of angiotensinogen in pathophysiological significance for cardiovascular/ the plasma is less than that required for full satu- renal disease and to the treatment of hypertension ration and therefore even small changes in plasma in blacks. levels can influence the amount of angiotensin I pro- duced.27 There is little information on the kinetics of the renin-angiotensinogen reaction in plasma from Possible reasons for lower PRA in black people, nor on the presence of endogenous blacks inhibitors of renin activity. But any effects are likely to be small as a lower PRA in blacks was also asso- The control of renin release into the circulation is ciated with a lower plasma concentration of renin.28 under the influence of many neural, haemodynamic A number of polymorphic variants have recently and hormonal factors.26 Renin release depends on been identified within the renin gene raising the both renal perfusion pressure and on tubular func- possibility that these variants might influence renin tion.