Hypertension in US-born vs. foreign-born African-Americans

In this issue of the Journal Brown et al.[1] report that African-Americans have nearly twice the prevalence of hypertension of blacks born outside the United States. Analyzing data in the National Health and Nutrition survey, they found that 42.8% of US-born blacks but only 27.4% of foreign-born blacks had hypertension. Among foreign-born blacks, length of US residency was not significantly associated with odds of hypertension. In discussing their findings, the authors cited socioeconomic conditions, chronic stress, racial discrimination and mental health distress as reasons for the higher prevalence of hypertension among US-born blacks. However, they noted that there was no significant difference in the prevalence of having health insurance between the groups (71.1 vs. 75.4%), and that longer US residence was associated with more hypertension despite a higher proportion of higher income. In the Racial, Ethnic and Geographic Differences in Stroke study, blacks were more likely to have their hypertension diagnosed, more likely to have it treated and more likely to have it treated more intensively, but less likely to have their blood pressure (BP) controlled. Thus, socioeconomic conditions seem unlikely to be a major factor. The authors mentioned the African Diaspora hypothesis [2,3], with natural selection for salt and water retention conferring a survival advantage during the conditions of heat and privation between decks on the slave ships during the Atlantic crossing, and also for survival in the early years of enslavement. The genetic background on which such natural selection could be based was not discussed. My interest in hypertension in blacks arose from my experience with the descendants of escaped slaves who came to Canada via the Underground Railroad. I opened my hypertension clinic in 1977, by using stimulated plasma renin activity [4] to guide therapy, as suggested by Laragh et al.[5]. Near London, Ontario, in North Buxton, was one of four settlements established in the nineteenth century for escaped slaves coming to Canada. Although it might be said ‘what would a Canadian know about hypertension in blacks?; he hardly sees any black patients’, it was precisely because so few of my patients were black (∼1%) that it quickly became apparent that they were biologically different. Among patients with resistant hypertension and very low stimulated plasma renin levels (<1 ng/ml per h), we performed iodocholesterol scans before and after dexamethasone suppression to try to identify patients with unilateral adrenocortical adenomas as a potentially curable cause of hypertension. By 1983 we had performed 100 such scans; not a single one showed a unilateral hot adrenal. Some scans (∼20%) were normal; they may have represented variants of Liddle syndrome that we could not diagnose as in those days we did not have access to plasma aldosterone levels. The rest all showed bilateral hot adrenal glands [6]. By the time Biglieri et al.[7] first described his first four cases of primary aldosteronism due to bilateral adrenal hyperplasia in 1984, I already had 10 patients whose hypertension was so severe and uncontrollable that my surgical colleagues had performed adrenalectomies; first removing the larger and hotter adrenal, and in some cases, going back to remove part of the remaining adrenal. Among the first 10 such cases, four were black – a huge disproportion. Three were from North Buxton, perhaps suggesting a founder effect; the fourth was from Swaziland. I described this experience at a Festschrift for John Laragh in 1999, suggesting that black patients were more likely to have primary aldosteronism due to bilateral hyperplasia [8]. There is some support for this in the literature. As reviewed in 2010 [9], ‘Primary aldosteronism increasingly recognized as being due to bilateral hyperplasia [10], and thus less likely to be treated surgically [10] accounts for 20% of resistant hypertension in the United States [11], and a higher proportion among blacks [12,13]’. Apart from hyperaldosteronism (high-plasma aldosterone with low stimulated renin activity), black patients are more sensitive to aldosterone [14,15]. This may relate to the function of the renal sodium channel. As reviewed in this Journal [16], black hypertensive patients retain salt and water, and tend to have what may be called a Liddle phenotype, with low plasma aldosterone and low stimulated renin. The genetic background for that originated in Africa. Among mainly Caribbean blacks in London, UK, McGregor's group found that 5% had a T594M variant of the renal sodium channel (ENac, SCNBB1) and were particularly responsive to amiloride [17], a specific antagonist of ENac. Rayner's group in Cape Town found that among the Khoi San people of the Kalahari (thought to be candidates for the original Homo sapiens), 20% had a different variant, R563Q. Significantly, although resident in the hot dry Kalahari, far from sources of salt, persons with that variant were not hypertensive; however, they become hypertensive when they move to Cape Town. ‘Among hypertensive patients in Cape Town and Johannesburg, this variant was present in 9.1% of Nguni-Zulu, 6.4% of Sotho, 6.3% of Nguni-Xhosa, 4.1% of mixed ancestry, and 5.9% of all patients’, but was not present in West Africans [16]. Lest readers think this is important only in Africa, a Liddle phenotype was found in 6% of patients attending a Veteran's Administration Hospital in Louisiana [18]. (Unfortunately, the authors could not tell me if the Liddle phenotype was more common among black patients.) It is now apparent that a Liddle phenotype may be attributable not only to variants of ENac itself, but also to variants that affect the function of ENac. Laffer et al.[19] reported that a variant of CYP4A11, which activates ENac, was resistant to spironolactone, but responsive to amiloride. A number of other variants affect the function of ENac. In a study of resistant hypertension in Africa we sequenced candidate genes for two phenotypes: CYP11B2 (aldosterone synthase) among patients with a primary aldosteronism phenotype (high aldo/low renin), and SCNN1B, NEDD4L, GRK4, UMOD and NPPA among those with a Liddle phenotype (low aldo/low renin). We found many variants, and a number of those variants were present in all patients sequenced [20]. The article by Brown et al. seems to support the African Diaspora hypothesis, as US-born blacks had a greater prevalence of hypertension. That hypothesis should be further tested by comparing the frequency of the variants discussed above, among African-Americans born in the United States vs. foreign-born blacks (or vs. persons still residing in Africa). Why does all this matter? Although it may take many more years to diminish the effects of racial discrimination, psychosocial stress and socioeconomic disparities, it is possible now to improve BP control in blacks by employing physiologically individualized therapy based on aldosterone/renin phenotyping. I suggested in 2006 [21] that much of the two-fold disparity in stroke risk of African-Americans could be eliminated in this way. A recent controlled trial in Africa [22] now provides evidence. In patients with uncontrolled hypertension in clinics in Nigeria, Kenya and South Africa, we allocated patients to usual care vs. physiologically individualized therapy (PhysRx) based on aldo/renin phenotyping. The algorithm used to guide therapy in PhysRx is shown in Table 1. Although this approach was not effective in the clinic in Kenya (perhaps for reasons of noncompliance and affordability of medication), ‘When only the sites in Nigeria and South Africa were considered, systolic control was obtained in 15.0% of UC vs. 78.6% of PhysRx (P < 0.0001), diastolic control in 45.0 vs. 71.4% (P = 0.04), and control of both in 15.0 vs. 66.7% (P = 0.0001). If only the Nigerian site (where patients were randomized to the two treatment strategies and conditions were more similar to US clinics) is considered, systolic control was obtained in 15% of UC vs. 85% of PhysRx (P = 0.0001), diastolic control in 45 vs. 75% (P = 0.11) and control of both systolic and diastolic pressure in 15 vs. 75% (P < 0.0001) even though the renal function was worse at that site.’ This approach should be tested in the United States.TABLE 1: Physiologically individualized therapya based on renin/aldosterone profileACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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