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109 | 2010
Annuaire du Collège de France 2008-2009
Résumé des cours et travaux 109e année
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Cours du Professeur B. Harrap

Stephen B. Harrap
p. 1037-1045

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1. Applying epidemiological principles to clinical trials – lessons in stroke and diabetes

  • 1 Lawes C.M.M., Vander Hoorn S., Rodgers A., “Global burden of blood-pressure-related disease, 2001”, (...)

1Cardiovascular disease is now endemic worldwide and no longer limited to economically developed countries 1. In developed countries, cardiovascular disease accounts for about 35% of all deaths. Similar rates, but among younger age groups, are now being seen in developing countries such as Tanzania and India. Strategies to combat this growing burden are logically directed at cardiovascular risk factors, in particular blood pressure.

  • 2 Kearney P.M., Whelton M., Reynolds K., Muntner P., Whelton P.K., He J., “Global burden of hypertens (...)

2It has been estimated that worldwide in 2001, 7.6 million premature deaths were attributable to high blood pressure 2. By the year 2025, hypertension is expected to increase in prevalence by 60%, affecting 1.56 billion people, with an 80% increase (from 639 million to 1.15 billion) in economically developing nations. In terms of cardiovascular disease, high blood pressure accounted for 54% of stroke and 47% of ischemic heart disease globally. This makes high blood pressure the most important cardiovascular risk factor. It was also noted that half of this burden was in people with hypertension; the remainder was in those with lesser degrees of high blood pressure.

  • 3 Rose G., “Strategy of prevention : lessons from cardiovascular disease”, Br. Med. J., 282, 1981,184 (...)
  • 4 Stamler J., Stamler R., Neaton J.D., “Blood-pressure, systolic and diastolic, and cardiovascular ri (...)

3The late Geoffrey Rose made the point that there is a continuous relationship between blood pressure and cardiovascular risk 3 Even people with average levels of blood pressure have higher risks than those with the lowest pressures. If one multiplies the number of people with average pressure by the risk associated with such a pressure, one finds that average pressure accounts for more cardiovascular deaths than can be attributed to the fewer individuals with the highest pressure levels 4 Herein lies a paradox. The medical profession identifies and treats only patients with hypertension. Population “treatment” has been the domain of public health where dietary and lifestyle measures are promoted population-wide to reduce blood pressure generally. Why don’t doctors extend their treatments to people with normal blood pressures if it is this group that most cardiovascular deaths occur?

4The answer depends on assessing the balance of risks – that of blood pressure versus that of long-term treatment. Where, high blood pressure is the only risk factor to which an individual is exposed, the results of clinical trials over many years have defined levels of pressure above which the benefits of treatment outweigh the side effects and complications of treatment. The absolute level of pressure that defines this treatment threshold has been falling over the years, partly as the result of safer drugs. Today, most guidelines specify blood pressure greater than 140/90 mmHg as meriting treatment. This blood pressure is associated with an approximate doubling in cardiovascular risk.

5However, where blood pressure is combined with other risk factors such as old age, high cholesterol, obesity, diabetes or a previous cardiovascular event, the balance of risk changes.

6Compared with the lowest blood pressures in the population, an average level of blood pressure (say 120/80 mmHg) might be associated with only a 50% increase in cardiovascular risk. However, when this blood pressure is combined with another risk factor (such as diabetes), the resulting risk of cardiovascular disease might exceed 200% – the same risk as for a blood pressure of 140/90 mmHg. The question then becomes, should an average blood pressure be treated in someone in whom the total cardiovascular risk exceeds twice normal?

7This question has been addressed by a number of studies, which have examined whether blood pressure reduction by pharmacological means, no matter what the starting blood pressure, is of benefit in people with underlying increases in cardiovascular risk.

  • 5 PROGRESS Collaborative Group, “Randomised trial of a perindopril-based blood pressure lowering regi (...)

8Cerebrovascular diseases, such as stroke or transient ischemic attack, are known to be closely associated with blood pressure. The PROGRESS Study tested the effects of routine blood pressure reduction in individuals who had previously experienced a cerebrovascular event5. In those people receiving treatment the risk of subsequent stroke was reduced by 29% and the risk of heart attack was reduced by 38%. When considering those people with average and low blood pressure, the benefits of treatment for prevention of cardiovascular complications outweighed any risks of treatment.

  • 6 Patel A., MacMahon S., Chalmers J., Neal B., Billot L., Woodward M., Marre M., Cooper M., Glasziou (...)

9The ADVANCE Study addressed a similar blood pressure reduction strategy in people with type 2 diabetes mellitus 6 Routine blood pressure lowering resulted in a significant reduction in the likelihood of death, particularly cardiovascular death and an improvement in diabetic complications affecting the kidneys – irrespective of whether subjects had high, average or low blood pressure at the start of the trial.

10These clinical trials and others such as LIPID and HOPE are changing the way in which we consider and treat cardiovascular risk factors. Old definitions such as hypertension and normotension are becoming less relevant in situations where total cardiovascular risk is elevated and routine blood pressure treatment can be demonstrated to be effective and safe.

2. Resetting genetic predisposition to hypertension

11Conditions such as high blood pressure generally become obvious in middle age. But what explains the transition from normal blood pressures to high blood pressure? One might expect to find clues to the processes around early adulthood, when genes that predispose to high blood pressure might be activated by some developmental-stage specific signal. Although we know little about the precise molecular basis for genetic predisposition, it is possible to study the physiological changes that might be activated in predisposed young adults.

  • 7 Harrap S.B., Cumming A.D., Davies D.L., Foy C.J.W., Fraser R., Lever A.F., Watt G.C.M., “Glomerular (...)
  • 8 Watt G.C.M., Harrap S.B., Foy C.J.W., Holton D.W., Edwards H.E., Davidson H.R., Connor J.M., Lever (...)

12One might expect to find the physiological characteristics of the predisposition to high blood pressure in young adult offspring from families in which both parents have documented high blood pressure. Our studies in such subjects have revealed abnormalities in the function of the kidneys, taking the form of a significant increase in the rate at which the kidneys filter blood – the glomerular filtration rate (GFR)7. Such an increase might in itself damage the kidneys long-term, but it might also be indicative of an underlying abnormality of blood vessel (in this case glomerular) control. Indeed, the pattern of blood flow and filtration would be consistent with increased actions of the hormone angiotensin II 8, which is a key component of the renin-angiotensin system (RAS) and a major cardiovascular control system. We have also found evidence to support activation of the RAS in young adults from families in which both parents have high blood pressure. These changes seem to be transient, because in high blood pressure in later life, the GFR and activation of the RAS falls.

  • 9 Harrap S.B., Doyle A.E., “Renal hemodynamics and total body sodium in immature spontaneously hypert (...)
  • 10 Harrap S.B., Doyle A.E., “Genetic co-segregation of blood pressure and renal hemodynamics in the sp (...)

13We have observed similar activation of the RAS in young animals without hypertension from a widely used rat model of high blood pressure – the Spontaneously Hypertensive Rat (SHR). However, RAS activation in SHR is associated with a different pattern of renal function, being characterised by a reduction in GFR 9. Breeding experiments showed that these abnormalities appear to be linked to the genes that determine blood pressure 10. Just as in humans, these abnormalities disappear as high blood pressure develops in later adulthood.

14These apparently transient expressions of genetic programming for high blood pressure raise the possibility that if one could block these effects at a critical time it might be possible to reset the inherent predisposition.

  • 11 Harrap S.B., Nicolaci J., Doyle A.E., “Persistent effects on blood pressure and renal hemodynamics (...)
  • 12 Harrap S.B., Wang B.-Z., MacLellan D.G., “Transplantation studies of the role of the kidney in long (...)
  • 13 Harrap S.B., Van der Merwe W.M., Griffin S.A., Macpherson F., Lever A.F., “Brief ACE inhibitor trea (...)
  • 14 Harrap S.B., Mirakian C., Datodi S.R., Lever A.F., “Blood pressure and lifespan following brief ACE (...)

15In young SHR, it is possible to normalise the abnormalities in renal function and lower blood pressure by treatment with agents that interfere with the RAS. More importantly, a brief period of treatment is followed by a sustained reduction in blood pressure in adulthood 11 and depends on the kidneys 12. In fact, it is possible to define that 4-weeks treatment from 6 to 10 weeks of age in SHR can reduce blood pressure long-term 13 and extend life 14.

16This remarkable ability to reduce blood pressure long after treatment has stopped offers interesting potential for redefining treatment paradigms. Could we treat young people in their adolescence and early adulthood and avoid long-term drug use in later life?

  • 15 Julius S., Nesbitt S.D., Egan B.M., Weber M.A., Michelson E.L., Kaciroti N., Black H.R., Grimm R.H. (...)
  • 16 Sasamura H., Nakaya H., Julius S., Takebayashi T., Sato Y., Uno H., Takeuchi M., Ishiguro K., Murak (...)

17This possibility is the focus of the TROPHY Study 15 and the forth coming STAR-CAST Study 16. The TROPHY selected subjects simply on the basis of blood pressure and there was no account taken of family history of high blood pressure or measures of renal function or activity of the RAS. Two years after stopping 2-years of treatment with an angiotensin receptor blocking drug, the blood pressure was slightly lower than control subjects and still rising towards control levels.

18The results of the TROPHY Trial are far from conclusive and it has created a deal of controversy on methodological grounds. However, it could also be criticised for not following subjects long enough after treatment to determine whether a real “persistent” effect exists.

19However, perhaps the most important issue for studies such as TROPHY is the ability to select those who might actually harbour a genetic predisposition that is actually dependent on the RAS and sensitive to its blockade. Among inbred strains of rats, very few other than SHR show prevention after short-term treatment. In man the hypothesis needs to be tested on those who share the genetic mechanisms of the SHR. Eventually this might be direct genetic testing, but at least family history and RAS/renal phenotypes could help those most likely to achieve a benefit.

20The possibility of resetting genetic predisposition to hypertension is tantalising indeed. The potential to reduce blood pressure-related morbidity and mortality while at the same reducing drug side-effects and costs is certainly a goal worthy of further effort.

3. Baldness genetics – more than skin deep

21The condition male pattern baldness is common, estimated to be present in 50% of white males by 50 years of age. It is characterized by the loss of hair from the scalp in a defined pattern and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Understanding male pattern baldness might also reveal some fundamental secrets of biology.

22Hair follicles on the scalp seem to be pre-programmed to undergo a transformation from the normal long growing phases and short resting phases to cycles of long rest and short growth periods. This process is coupled with progressive miniaturization of the follicle.

  • 17 Taylor P.J., “Big head ? Bald head ! Skull expansion : alternative model for the primary mechanism (...)

23Unusual postulated causes have ranged from an old idea that baldness was the result of wearing hats and depriving the scalp of sunlight and air, to more recent suggestions of skull expansion 17. However, the factors that determine male pattern baldness appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. Evidence in support of androgenic influence comes from the fact that eunuch’s do not go bald. For this reason male pattern baldness is also known as androgenetic alopecia.

24The mystery, and the potential for fundamental biological discovery, is why front hair should vanish, while that at the back of the head should flourish. Presumably genetic predisposition alters expression of key genes in a regionally specific manner to cause patterned hair loss. But what genes are involved and how are they affected?

25Prime candidates for baldness are genes encoding enzymes and receptors involved in sex steroid metabolism. Key enzymes include 5a-reductase that converts testosterone (T) to the more active dihydrotestosterone (DHT) and aromatase that converts estrogen to T. Both T and DHT to exert their effect by binding to the androgen receptor (AR), a member of the steroid-thyroid hormone nuclear receptor superfamily. In balding scalp there are observed high levels of T, DHT and AR.

  • 18 Ellis J.A., Stebbing M., Harrap S.B., “Polymorphism of the androgen receptor gene is associated wit (...)

26In 2001, we were the first to identify the AR gene was significantly associated with male pattern baldness 18. This finding has now been replicated by at least 5 other independent studies. The presence of the AR gene on the X chromosome, which men inherit from their mother, is consistent with the popular belief that baldness is inherited from the maternal grandfather.

  • 19 Kuster W., Happle R., “The inheritance of common baldness : two B or not two B ?”, J. Am. Acad. Der (...)

27However, the observed patterns of inheritance are not simply consistent with an X-linked recessive condition. For example, one often sees fathers and sons who are bald. Indeed, it has postulated for some time that male pattern baldness best fits a polygenic pattern 19.

  • 20 Hillmer A.M., Brockschmidt F.F., Hanneken S., Eigelshoven S., Steffens M., Flaquer A., Herms S., Be (...)

28Consistent with the polygenic concept, more recent genome wide association analyses have identified another locus on chromosome 20 20. This locus seems to be independent of the AR gene in its association with baldness and the identity of the gene and the mechanisms of action are not yet clear. Nevertheless, the AR appears to be significantly stronger in its association with baldness and fits nicely with the known role of androgens in this condition.

29The mystery remains as to the precise DNA variant in or around the AR gene that explains its role in baldness. We know that there are no variants in the coding sequences of the gene and so it is more likely that there are variants in regulatory regions within and outside the AR gene that control the time and tissue-specific nature of its expression. The challenge in identifying the precise variant is the fact that it might be anywhere within approximately 1 million base pairs of DNA.

30The search is now underway around the AR gene to check the many hundreds of polymorphisms to see whether any might be in critical sequences that control gene expression. This is a difficult task, as current knowledge is limited and many such sequences are not recognisable.

31However, the study of male pattern baldness offers an advantage over many other common conditions in that it is possible to obtain fresh tissue for detailed analyses of gene expression patterns. We are pursuing a complementary and promising approach that involves looking at the AR gene from balding and non-balding scalp of volunteers. This might reveal differences in the expression of the AR gene related to chemical modification of the DNA, such as methylation. Differences in methylation patterns across the AR gene might provide insights into the so-called epigenetic mechanisms that control gene expression and in this case might predispose to male pattern baldness.

32Androgenetic alopecia is a condition that might not be life threatening in itself, but might offer insights into basic molecular mechanisms that underpin many of the more serious diseases of middle age.

4. Population genetics of cardiovascular risk

  • 21 . Lawes C.M.M., “Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001”, (...)

33In the medical world, the focus of preventing death and disability is on the doctor and the patient. In the case of cardiovascular disease, which is the most common cause of death worldwide 21, this involves identifying, labelling and treating patients with high levels of risk factors such as blood pressure (hypertension), blood lipids (hypercholesterolemia), weight (obesity) and insulin resistance (type 2 diabetes).

34In the world of public health, the approach is different. Instead of patients, there are populations and instead of treatment, there is health promotion. We are all at risk of cardiovascular disease and, therefore, we all stand to benefit if risk factor levels are reduced across the population by safe and cost-effective measures that often involve diet and lifestyle.

  • 22 . Rose G., “Strategy of prevention : lessons from cardiovascular disease”, Br. Med. J., 282, 1981,1 (...)

35In pursuit of the genetic explanations for cardiovascular disease, much research has been based on the medical model, searching for genes that are associated with hypertension, obesity and so on. Yet those with such treatable high levels of risk factors account for only a portion of the cardiovascular deaths due to risk factors in a population 22. Modest (i.e. average) levels of risk occur in many more people and although the personal risk is not great, the impact of average risk across a population is high.

  • 23 Harrap S.B, “Private genes, public health ?”, Lancet, 349, 1997, 1338-1339.

36Therefore, the preoccupation of genetic discovery on clinical conditions such as hypertension, obesity and hypercholesterolemia might have missed the point. It is just as important to understand why someone has average rather than low blood pressure, as it is to understand why some have high rather than normal blood pressure 23.

  • 24 Harrap S.B., Stebbing M., Hopper J.L., Hoang H.N., Giles G.G., “Familial patterns of covariation fo (...)

37The Victorian Family Heart Study was established in 1990 with the aim of discovering the familial and genetic basis of cardiovascular risk in the general population 24. The study comprises approximately 800 volunteer adult families with at minimum mother, father and one natural offspring. To increase the ability to determine genetic and environmental influences, the families were enriched with those containing monozygotic and dizygotic twins.

38Simple cardiovascular risk phenotypes such as blood pressure, weight and cholesterol were measured carefully using quality controlled standardised methods. These values were the substrate of all analyses and needed to be as precise as possible.

39The first phase of analyses was to define the familial patterns of risk factors and use statistical modelling to partition the components of their variation into genetic, shared environment and individual factors. Typically, genetic factors accounted for 40% to 50% of the total variation for a risk factor, while shared familial environment accounted for about 20% to 30%.

  • 25 Ellis J.A., Stebbing M., Harrap S.B., “Association of the human Y chromosome with high blood pressu (...)
  • 26 Harrap S.B., Wong Z.Y.H., Stebbing M., Lamantia A., Bahlo M., “Blood pressure QTLs identified by ge (...)
  • 27 Wong Z.Y.H., Stebbing M., Ellis J.A., Lamantia A., Harrap S.B., “Genetic linkage of the b- and g-su (...)

40This evidence for significant genetic influence formed the basis of molecular investigation. These included studies of candidate genes such as the delineation of the involvement of the Y chromosome in blood pressure 25. An early genome-wide linkage analysis also led to the identification of chromosomal regions influencing blood pressure 26. One of these on chromosome 16 27 has subsequently been identified in several other independent studies.

  • 28 Büsst C.J., Scurrah K.J., Ellis J.A., Harrap S.B., “Selective genotyping reveals association betwee (...)

41We have recently used high-resolution association mapping and sequencing to investigate 2 genes in this region that are known to be involved in Mendelian genetic diseases of blood pressure. One of these, the gene encoding the g-subunit of the epithelial sodium channel, is associated with blood pressure in the Victorian Family Heart Study 28. There are 3 separate DNA variants in the non-coding DNA, each of which appears to contribute independently to blood pressure. We have replicated association of one of these variants with blood pressure in two independent populations and determined the overall magnitude of the variant on blood pressure across the population-wide distribution of the entire Victorian Family Heart Study (Büsst, unpublished observations). The variant is relatively common with a population frequency of about 25% and the magnitude of the blood pressure effect is estimated to be about 0.8 mmHg per copy of the variant.

42These results reflect a pattern that is emerging in relation to the genetics of quantitative risk factors. Implicated DNA variants tend to have the following characteristics: they are found in non-coding DNA, they are relatively common and they account for about 1% or less of the variance in the risk factor. This contemporary evidence supports view that cardiovascular risk factors are determined by the combination of many polygenes, each of which has only a small contribution to the level of the risk factor. It is also likely that the mechanisms by which these variants in non-coding DNA operate is via changes in gene expression rather than major distortions of protein sequence.

43The effect of individual genetic variants might be small, but there is reason to expect that their pathophysiological actions might be common. If such mechanisms can be understood, it might be possible to apply novel population-wide health promotion initiatives based on genetic causes that are widely distributed in the general community. Even small reductions in the population mean blood pressure could have a benefit equivalent to identifying and effectively treating a large proportion of hypertensive patients.

44As unexpected as it might be, molecular genetic research might repay its dividends in the form of simple, safe and effective public health measures for the benefit of us all.

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Notes

1 Lawes C.M.M., Vander Hoorn S., Rodgers A., “Global burden of blood-pressure-related disease, 2001”, Lancet, 371, 2008, 1513-18 et Ezzati M., Lopez A.D., Rodgers A., Vander Hoorn S., Murray C.J.L., “Selected major risk factors and global and regional burden of disease”, Lancet, 360, 2002, 1347-60.

2 Kearney P.M., Whelton M., Reynolds K., Muntner P., Whelton P.K., He J., “Global burden of hypertension”, Lancet, 365, 2005, 217-23.

3 Rose G., “Strategy of prevention : lessons from cardiovascular disease”, Br. Med. J., 282, 1981,1847-51.

4 Stamler J., Stamler R., Neaton J.D., “Blood-pressure, systolic and diastolic, and cardiovascular risks - united-states population-data”, Arch. Intern. Med., 153, 1993, 598-615.

5 PROGRESS Collaborative Group, “Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 patients with previous stroke or transient ischaemic attack”, Lancet, 358, 2001, 1033-1041.

6 Patel A., MacMahon S., Chalmers J., Neal B., Billot L., Woodward M., Marre M., Cooper M., Glasziou P., Grobbee D., Hamet P., Harrap S., Heller S., Liu L.S., Mancia G., Mogensen C.E., Pan C.Y., Poulter N., Rodgers A., Williams B., Bompoint S., de Galan B.E., Joshi R., Travert F., “Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes”, New England Journal of Medicine, 24, 2008, 2560-2572.

7 Harrap S.B., Cumming A.D., Davies D.L., Foy C.J.W., Fraser R., Lever A.F., Watt G.C.M., “Glomerular hyperfiltration, high renin and low-extracellular volume in high blood pressure”, Hypertension, 35, 2000, 952-957.

8 Watt G.C.M., Harrap S.B., Foy C.J.W., Holton D.W., Edwards H.E., Davidson H.R., Connor J.M., Lever A.F., Fraser R., “Abnormalities of glucocorticoid metabolism and the renin-angiotensin system : a four corners approach to the identification of genetic determinants of blood pressure”, J. Hypertension, 10, 1992, 473-482.

9 Harrap S.B., Doyle A.E., “Renal hemodynamics and total body sodium in immature spontaneously hypertensive and wistar kyoto rats”, J. Hypertension, 4(suppl 3), 1986, S249‑S252.

10 Harrap S.B., Doyle A.E., “Genetic co-segregation of blood pressure and renal hemodynamics in the spontaneously hypertensive rat”, Clin. Sci., 74, 1987, 63-69.

11 Harrap S.B., Nicolaci J., Doyle A.E., “Persistent effects on blood pressure and renal hemodynamics following chronic converting enzyme inhibition with perindopril”, Clin. Exp. Pharm. Physiol., 13, 1986, 753-765.

12 Harrap S.B., Wang B.-Z., MacLellan D.G., “Transplantation studies of the role of the kidney in long-term blood pressure reduction following brief ACE inhibitor treatment in young spontaneously hypertensive rats”, Clin. Exp. Pharmacol. Physiol., 21, 1994, 129-13.

13 Harrap S.B., Van der Merwe W.M., Griffin S.A., Macpherson F., Lever A.F., “Brief ACE inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term”, Hypertension, 16, 1990, 603-614.

14 Harrap S.B., Mirakian C., Datodi S.R., Lever A.F., “Blood pressure and lifespan following brief ACE inhibitor treatment in young spontaneously hypertensive rats”, Clin. Exp. Pharmacol. Physiol., 21, 1994, 125-128.

15 Julius S., Nesbitt S.D., Egan B.M., Weber M.A., Michelson E.L., Kaciroti N., Black H.R., Grimm R.H.Jr, Messerli F.H., Oparil S. & Schork M.A., “Trial of Preventing Hypertension (TROPHY) Study Investigators (2006). Feasibility of treating prehypertension with an angiotensin-receptor blocker.”, N. Engl. J. Med., 354, 1685-1697.

16 Sasamura H., Nakaya H., Julius S., Takebayashi T., Sato Y., Uno H., Takeuchi M., Ishiguro K., Murakami M., Ryuzaki M., Itoh H., “The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) Study : Rationale and Study Design”, Hypertension Research, 31, 2008, 1843-184.

17 Taylor P.J., “Big head ? Bald head ! Skull expansion : alternative model for the primary mechanism of AGA”, Medical Hypotheses, 72, 2009, 23-28.

18 Ellis J.A., Stebbing M., Harrap S.B., “Polymorphism of the androgen receptor gene is associated with male pattern baldness”, J. Invest. Dermat., 116, 2001, 452-455.

19 Kuster W., Happle R., “The inheritance of common baldness : two B or not two B ?”, J. Am. Acad. Dermatol., 11, 1984, 921-926.

20 Hillmer A.M., Brockschmidt F.F., Hanneken S., Eigelshoven S., Steffens M., Flaquer A., Herms S., Becker T., Kortum A.K., Nyholt D.R. (Zhao Z.Z., Montgomery G.W., Martin N.G., Muhleisen T.W., Alblas M.A., Moebus S., Jockel K.H., Brocker-Preuss M., Erbel R., Reinartz R., Betz R.C., Cichon S., Propping P., Baur M.P., Wienker T.F., Kruse R., Nothen M.M., “Susceptibility variants for male-pattern baldness on chromosome 20p11”, Nature Genetics, 40, 2008, 1279-1281 et Richards J.B., Yuan X., Geller F., Waterworth D., Bataille V., Glass D., Song K., Waeber G., Vollenweider P., Aben K.K.H., Kiemeney L.A., Walters B., Soranzo N., Thorsteinsdottir U., Kong A., Rafnar T., Deloukas P., Sulem P., Stefansson H., Stefansson K., Spector T.D., Mooser V., “Male-pattern baldness susceptibility locus at 20p11”, Nature Genetics, 40, 2008, 1282-1284.

21 . Lawes C.M.M., “Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001”, Lancet, 371, 2008, 1513-18.

22 . Rose G., “Strategy of prevention : lessons from cardiovascular disease”, Br. Med. J., 282, 1981,1847-51.

23 Harrap S.B, “Private genes, public health ?”, Lancet, 349, 1997, 1338-1339.

24 Harrap S.B., Stebbing M., Hopper J.L., Hoang H.N., Giles G.G., “Familial patterns of covariation for cardiovascular risk factors in adults - The Victorian Family Heart Study”, Am. J. Epidemiol., 152, 2000, 704-715.

25 Ellis J.A., Stebbing M., Harrap S.B., “Association of the human Y chromosome with high blood pressure in the general population”, Hypertension, 36, 2000, 731-733.

26 Harrap S.B., Wong Z.Y.H., Stebbing M., Lamantia A., Bahlo M., “Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes”, Physiol. Genomics, 8, 2002, 99-105.

27 Wong Z.Y.H., Stebbing M., Ellis J.A., Lamantia A., Harrap S.B., “Genetic linkage of the b- and g-subunits of the epithelial sodium channel with systolic blood pressure in the general population”, Lancet, 353,1999, 1222-1225.

28 Büsst C.J., Scurrah K.J., Ellis J.A., Harrap S.B., “Selective genotyping reveals association between the epithelial sodium channel g-subunit and systolic blood pressure”, Hypertension, 50, 2007, 672-678.

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Référence papier

Cours et travaux du Collège de France. Annuaire 109e année, Collège de France, Paris, mars 2010, p. 1037-1045. ISBN 978-2-7226-0083-6

Référence électronique

Stephen B. Harrap, « Cours du Professeur B. Harrap », L’annuaire du Collège de France [En ligne], 109 | 2010, mis en ligne le 25 juin 2010, consulté le 17 septembre 2014. URL : http://annuaire-cdf.revues.org/395

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Auteur

Stephen B. Harrap

Professeur, université de Melbourne (Australie)

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Droits d’auteur

Collège de France

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