Geneticism of essential hypertension.

The idea that a person’s genetic constitution is allimportant and that genetic knowledge is sufficiently advanced so that we can make judgments on our past or future health was called geneticism by Medawar.1 He termed geneticism as the application to the human condition of a genetic knowledge or understanding that is assumed to be very much greater than it really is. Proponents of geneticism have promised us that the sequencing of the human genome will offer limitless insights into the pathogenesis of essential hypertension and, moreover, will provide bountiful access to new drug targets and facilitate pharmacological therapy. In terms of citations, only “hypertension and sodium” provokes more “hits” than “hypertension and genetics.” Nevertheless, with a few exceptions, the results appear disappointing. We might pause and reflect on the answers to the question, “Why?” In so doing, we should first examine the genetic differences that separate us from one another. The genetic differences between human beings seem to be of 3 types: those based on single gene mutations, those based on polymorphic genetic differences, and those resulting from a complex interaction of many genes. First, there are the differences that divide us into a great majority and a tiny minority. Essential hypertension clearly does not involve a tiny minority and not yet a great majority; however, this state-of-affairs was lost on early students of the subject. When Weitz first proposed the notion of genetic variance on blood pressure, he concluded that essential hypertension was inherited through the actions of a single gene. Because essential hypertension is common, were Weitz correct, we would expect 2 distinct blood pressure distributions in the population, the haves and the have-nots. Indeed, that very argument occupied Platt and Pickering. Platt studied family histories, measured blood pressure in normotensive probands, hypertensive propositi and their relatives, and argued as Weitz did. Pickering et al, however, studied systolic and diastolic blood pressure distributions from the second to eighth decades in first-degree relatives of normotensive probands and hypertensive propositi.2 They found that the frequency distribution moved upward as age advanced. At no age was there a clear-cut blood pressure distribution into normal and high blood pressures. Moreover, others found subsequently that the relationship between blood pressures of parents and sons was linear for both probands and propositi. As a matter of fact, the relationships were no different than those for height. Pickering concluded that blood pressure is inherited as a graded character over the entire blood pressure range, whether this value is regarded as hypotension, normotension, or hypertension. Nevertheless, disorders that separate us into the great majority and the tiny minority indeed exist. Methods to elucidate these monogenic disorders are at hand and a series of these hypertensive (or hypotensive) disorders have been elucidated.3 However, nearly all of us are lucky enough not to have one of these disorders; the great majority of us are neither carriers of one of these gene mutations nor victims of its action. There are many genetic characteristics that do not divide human beings into a huge majority and a tiny minority. This second form of genetic variability divides us into distinct classes of which none is a huge majority or a tiny minority. Examples are blood groups, A, or B, or AB, or O, or minor blood groups or histocompatibility loci. Variations of this kind are described as “polymorphic.” Polymorphisms are common variants, generally not too important clinically, but not necessarily trivial. Some students of genetics can recall the professor who determined who in the class could taste phenylthiourea. The professor may have also concerned himself with those persons in the room whose urine stank after eating asparagus compared with those whose urine did not. Those of us who were trained in medicine before the advent of proton pump inhibitors will recall that persons with type O blood type have a higher risk for duodenal ulcer, whereas those with type A blood type are more prone to coronary disease. Determining blood group polymorphisms is highly worthwhile before starting a blood transfusion. Polymorphisms do not exist by accident. One possibility is that an advantage exists for the population to be subdivided into 2 or more distinct groups, which depend on and thereby sustain each other. The extreme example might be the sexes. The basis of this polymorphism has been built into our genetic structure for a long time. It would be very “impolitic” for me to argue that one or the other form of this polymorphism is superior. However, negative aspects of the Y chromosome in terms of cardiovascular risk are well known.4 Suffice it to say that the possibility has been raised that the Y polymorphism (the whole chromosome) is likely to die out in the future, leaving the solely X individuals to enjoy the world for themselves.