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LETTERS TO THE EDITOR |
Division of Hypertension, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
It was a pleasure to read the editorial by Dimsdale (1) describing his wide-ranging and innovative research on ethnic physiological and behavioral phenotypic variation. It was also interesting to see the sodium hypothesis given increasing attention. The sodium hypothesis exemplifies the ideas and principles of darwinian medicine (2), and it is important for these ideas to move into the mainstream of medical research.
I would like to offer some comments on the discussion of the sodium sensitivity hypothesis. The suggestion by Grim (3) that intense selection pressure occurred during the Middle Passage is intriguing, yet as Dimsdale points out, the similarity of genotype frequencies for the renin-angiotensin system are similar for West Africans and African Americans in the United States, although they would be expected to have shifted over the time period when slave ships were traveling the Atlantic.
I have suggested that selection for sodium sensitivity among Africans is not a recent event but rather has been ongoing from the time the earliest hominids roamed the African savannah, at the very least a couple of million years (4): "During the Pleistocene, Africa was a homogeneous economy; its inhabitants all hunted on the savannah. Man’s sodium intake was most likely comparable to what the Bushmen obtain today from their natural diet ... [about 175 mg of Na per day]. Perhaps this was adequate for early man most of the time. However, it is reasonable to postulate a small but constant selection pressure from sodium depletion heat exhaustion against those individuals who lost more sodium in their sweat during a hunt. Selection would be more intense during sudden, sporadic heat waves, before the homeostatic salt-saving mechanisms could be mobilized to their maximum. Women would be particularly stressed during periods of pregnancy and lactation."
If indeed selection for sodium sensitivity occurred slowly throughout the Pleistocene, then the Africans who came over on the slave ships already were a sodium-sensitive population. We should then expect to see differences in allelic frequencies between Africans (and African Americans) on one hand and populations of European descent on the other hand. Two molecular variants of the angiotensinogen (AGT) gene are of interest and have been found to differ across a number of African and African-derived populations (5). The frequency of the T allele of the M235T variant of the AGT gene is about twice as common in African Americans and African Caribbeans (83% and 81%, respectively) as it is in Caucasians (42%). It is even higher in Nigerians (91%). The difference between Africans and African Americans reasonably reflects admixture with Caucasians (6). Similarly, the frequency of the T allele of the T174M variant of the AGT gene is highest in Nigerians (96%) and somewhat lower in African Americans and African Caribbeans (94% and 92%, respectively, again probably due to admixture); the frequency in Caucasians is significantly lower (85%). In a study of Nigerian adults, those who were homozygous for the 235T allele had significantly higher plasma AGT levels, and AGT levels were significantly higher among hypertensives (7). However, as these authors note, there was no direct association between the molecular variant and hypertension status, which does not allow for any statements of causality.
How can we account for these differences in gene frequency? Rotimi et al. (7) note that the association between the 235T allele and increased plasma AGT levels suggests that the AGT gene variants may be of pathophysiological relevance and may provide an opportunity to further understand salt sensitivity in North American blacks. The fact that the frequency of the T allele differs markedly between Africans and Caucasians suggests the operation of natural selection over a long period of time, most reasonably in the area of sodium metabolism. It is a reasonable hypothesis that different local ecological conditions create selection pressures that over time shift gene frequencies in adaptive directions. With single mendelian traits, such as the sickle cell gene, it was easier to discover how a particular genotype, in this case the sickling heterozygote, enhanced survival in a malarial environment. Inasmuch as hypertension is a disorder whose etiology is considered multifactorial, it is more difficult to discern the role of any given quantitative trait in a metabolic pathway. In any event, the clear black-white differences in the allelic frequencies of the AGT gene does urge further investigation into how these alleles are functionally manifested as intermediate phenotypes in these two ethnic groups.
REFERENCES
Editor-in-Chief, Psychosomatic Medicine, Department of Psychiatry, University of California, San Diego, La Jolla, California
I appreciate Professor Gleiberman’s letter concerning the genetics of hypertension (1). She points out that sodium sensitivity may not be a recently appearing characteristic in African Americans, at least as shown by allelic frequencies of the angiotensinogen gene. I offer a tentative response because genetics is such a rapidly moving field that by the time this correspondence is published, my reply may be out of date.
This is a curious time for genetics. Although the human genome is virtually mapped, the fact remains that we do not know where to look on this map. It is as if we have entered a vast library filled with books written in an unfamiliar language, although we do know the alphabet. Finding something in this library is further aggravated by the absence of an identifiable card catalog. How do you read these books? How do you locate a specific book once you have learned how to read this foreign language? More to the case at hand, where do we start to look for genes that may be relevant to hypertension and ethnicity?
We start, as Gleiberman suggests, with genes that are known to be relevant to salt and blood pressure. The angiotensinogen gene is a logical first place to begin. The fact that it has not proven instructive concerning the blood pressure burden borne by African Americans means that one must move on to scrutinize other genes. Given the number of genes, the likelihood that multiple genes are involved, and the certainty that the influences of these genes are modified by the social environment, it is likely that we will be searching for a while. Ars longa, vita brevis. ("Life is short, the art long, opportunity fleeting, experience treacherous, judgment difficult.")—Hippocrates, Aphorisms.
REFERENCES
This article has been cited by other articles:
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  C. J. Hilmert, C. D. Schetter, T. P. Dominguez, C. Abdou, C. J. Hobel, L. Glynn, and C. Sandman Stress and Blood Pressure During Pregnancy: Racial Differences and Associations With Birthweight Psychosom Med, January 1, 2008; 70(1): 57 - 64. [Abstract] [Full Text] [PDF]
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L. Gleiberman and J. E. Dimsdale Salt, Hypertension, Evolution Response Psychosom Med, March 1, 2001; 63(2): 325 - 327. [Full Text] [PDF]
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