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Blood Pressure Genetics Just Don’t Add Up

2015; Lippincott Williams & Wilkins; Volume: 8; Issue: 4 Linguagem: Inglês

10.1161/circgenetics.115.001188

1942-325X

Stephen Harrap, Brian J. Morris,

Renin-Angiotensin System Studies

HomeCirculation: Cardiovascular GeneticsVol. 8, No. 4Blood Pressure Genetics Just Don't Add Up Free AccessEditorialPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBlood Pressure Genetics Just Don't Add Up Stephen B. Harrap, MBBS, PhD and Brian J. Morris, PhD, DSc Stephen B. HarrapStephen B. Harrap Department of Physiology, The University of Melbourne, Victoria, Australia (S.B.H.) and School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, Australia (B.J.M.). and Brian J. MorrisBrian J. Morris Department of Physiology, The University of Melbourne, Victoria, Australia (S.B.H.) and School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, Australia (B.J.M.). Originally published1 Aug 2015https://doi.org/10.1161/CIRCGENETICS.115.001188Circulation: Cardiovascular Genetics. 2015;8:541–543For a primary cardiovascular risk factor,1 that is clearly heritable,2 the genetics of blood pressure have proven frustratingly difficult. In human genetics, blood pressure came last in the early searches for genes for common conditions3 and sounded a warning that still resonates.4 Bigger and bigger studies have found increasing numbers of loci with smaller and smaller effects. It is unclear whether this bad case of diminishing returns is the result of a phenotype that is a moving target, or blood pressure homeostasis that is physiologically (and therefore genetically) complex, or simple overestimation of the genetic contribution. Nevertheless, the search continues.Article see p 610The search in animals spans some 50 years, and genetically hypertensive strains such as the spontaneously hypertensive rat and Dahl rats are still very much in the race. The Dahl salt-sensitive (SS) rat is special in that it epitomizes an epigenetic paradigm. These animals respond to many external stimuli, usually high-salt diet, with the development of hypertension.5 Presumably, such exposures reset blood pressure through changes in gene expression and physiology. Understanding the genetic predisposition to such effects is of real importance.It might seem quaint in the modern era of genomics and precise genetic modification such as CRISPR, but genetic segregation analysis (that began with Mendel and peas) forms the foundation for identifying the genomic regions (loci) linked with blood pressure.This process usually begins with a first generation (F1) cross of 2 inbred strains with contrasting blood pressures. The F1 is in theory a genetically homogeneous population and heterozygous at all alleles (points of DNA sequence difference between the 2 strains). The average blood pressure of F1 animals will reflect the outcome of the battle between alleles for high and low blood pressure. En passant, the alleles for low and high blood pressure do not necessarily come from low- and high-pressure parents, respectively.6,7 Generally, the mean F1 blood pressure is less than the midpoint between the 2 parental strains and that indicates a degree of dominance of alleles for low blood pressure.8 However, the degree of dominance depends on the nature (presumably genetic background) of the low-pressure strain. Partial dominance for low blood pressure alleles has been reported when the Dahl SS is crossed with the Dahl SR (salt-resistant) rat.9 However, in the article by Crespo et al10 in the present issue of Circulation Cardiovascular Genetics, the F1 cross of Dahl SS with Lewis had low blood pressure, suggesting complete dominance.The implication is that in an F1 cross with Dahl SS, Lewis alleles are more effective at resisting the hypertensive effects of a high-salt diet than are Dahl SR alleles. But these are not necessarily the same alleles. Indeed, the Lewis is more distant genetically from Dahl SS than is Dahl SR,11 with potential for its own unique loci for low blood pressure.Expanding on this idea, Crespo et al10 postulate that somewhere in the Lewis genome there exists a locus that acts as a master hypertension suppressor. One premise for this concept offered by Crespo et al10 is that the Lewis rat shows rigid resistance to blood pressure change. However, there are both genetic12,13 and renovascular14 studies that indicate that the Lewis rat is not immune to hypertensive stimuli.To support their case, Crespo et al10 use blood pressure studies of congenic animals. In these experiments, selective breeding is used to transfer a chromosomal segment from one strain to another—a technique used for 30 years in the Dahl rats.6Most often part of a chromosome from a normotensive strain is transferred to (and effectively substitutes) the same position in the Dahl SS rat. If the blood pressure in the resultant congenic animal is lower than the Dahl SS rat, the assumption is that this region of the Dahl SS chromosome carries a locus that contributes to hypertension in response to exposure to a high-salt diet. Loci of this nature have been identified on most of the autosomal chromosomes of the Dahl SS rat, with at least 30 independent blood pressure loci suggested.However, things don't add up. The sum of the parts (the fall in blood pressure for each locus substituted) is almost an order of magnitude greater than the whole (being the difference between the Dahl SS and control strain blood pressures).15 The most widely accepted explanation for this disparity is epistasis, whereby independent loci interact (at a molecular or physiological level). Evidence for epistasis in rodent blood pressure has been around for some time.8The idea is that the Dahl SS rats possess a unique complement of interdependent loci that work as a team. Each locus is necessary for the full expression of the phenotype. Remove one, and the whole team suffers. In other words, the effects of individual loci are not additive. Also, the fall in blood pressure on removing a locus is no indication of the effect of the locus in isolation.Crespo et al10 tested for such effects by creating several congenic animals, in which loci from the Dahl SS were placed on to the background of the Lewis rat. In isolation, single loci had little effect on blood pressure. By combining Dahl SS loci in other congenic animals, it became apparent that as the team rebuilt the blood pressure started to rise, but not in an additive fashion. This would all be consistent with the epistatic model in which each Dahl SS locus is necessary but not sufficient. One presumes that a continued amalgamation of loci in new congenic animals would see blood pressure edge ever closer to the Dahl SS levels. Unfortunately, Crespo et al10 abandoned that approach. Their logic was that after having added 2 loci on chromosomes 7 and 17 to the 5 loci on chromosome 10 without any extra effect on blood pressure, the addition of other loci from different chromosomes would be pointless. However, we shall never know. For example, would adding the chromosome 8 locus to the combination have caused a major increment in blood pressure? This is essentially unfinished business that merits thorough testing of all possible permutations and combinations if epistasis is to be understood properly.Instead, Crespo et al10 ascribed the low blood pressures in the congenic animals to the actions of a hypertension suppressor somewhere on the Lewis genome. They took another breeding approach and crossed the Dahl SS and Lewis rats to create an F1 population and backcrossed these animals on to the Dahl SS rats at each subsequent generation. Basically, this concentrates the amount of Dahl SS genome (beginning with 50% in the F1) with each backcross. The logic was that with each such generation, the retention of the Lewis hypertension suppressor would be less likely. Viewed from another perspective though, the chances of the team of high blood pressure loci reforming would increase.Between the second and third backcross generation, the theoretical average proportion of Lewis genome decreased from 12.5% to 6.3% (and the fraction of Dahl genome increased from 87.5% to 93.8%) and the average blood pressure increased from 106 mm Hg to 133 mm Hg. This was interpreted as a signal of the loss of the Lewis hypertension suppressor locus, despite the fact that the third backcross blood pressure fell well short of the blood pressure of intact Dahl SS rats (of ≈195 mm Hg).It is important to recognize that the backcross animals are not genetically homogeneous, whereas the F1 and the congenic animals are. The segregation of alleles occurs across the genome and each backcross animal is unique. This is evident from the genome linkage data in the 6 second- and 7 third-generation backcross rats. Crespo et al10 focused their attention on chromosome 18 where the loss of the Lewis allele (and the gain of the Dahl allele) appeared to be associated with higher blood pressures. Indeed, the focus tended to overlook the fact that this locus could not be interpreted without taking into account all the other segregating loci in these animals. Proper linkage analyses in backcross animals require much greater number of animals and denser maps to account for genome segregation. They cannot be viewed through the prism of congenic reasoning.Notwithstanding, given the evidence, the interpretation preferring the loss of a putative hypertension suppressor over the reestablishment of homozygosity at a locus or loci for high blood pressure seems premature. This same laboratory has reported 3 epistatic loci for high blood pressure on chromosome 18, 1 of which (C18QTL3) shares markers with the assumed hypertension suppressor.16The concept of a distinct and powerful molecular agent to oppose any force raising blood pressure is certainly attractive. These already exist in the form of major mutations associated with low blood pressure.17 However, we have learnt that the polygenic and multifactorial world of population variation in blood pressure is all about the balance of small forces even for genes with monogenic pedigrees.18 The number and size of these forces and the way they interact with each other and with the environment are likely to be such that we might have to accept variability, idiosyncrasy and unpredictability.19 Personalized medicine will be a real challenge. As Dahl himself originally observed: "In the absence of… genetic homogeneity… data relating intake of salt to hypertension indicate group rather than individual probability of developing hypertension."20Finally, what is the future of congenic studies such as those in the Dahl rat? The simple alignment of blood pressure with stretches of substituted chromosomes provides only circumstantial evidence, in which interpretation is in the eye of the beholder. Surely, the time has come for greater detail and resolution for these loci. Studies of the associated physiological, RNA expression and epigenetic characteristics of the congenic animals should provide a better chance of identifying the precise molecular basis of blood pressure determination and its interaction with the environment. Exploring and understanding the existing Dahl SS loci should be a top priority.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Stephen B. Harrap, MBBS, PhD, Department of Physiology, The University of Melbourne, Victoria 3010, Australia. E-mail [email protected]References1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ.Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.Lancet. 2006; 367:1747–1757. doi: 10.1016/S0140-6736(06)68770-9.CrossrefMedlineGoogle Scholar2. Harrap SB, Stebbing M, Hopper JL, Hoang HN, Giles GG.Familial patterns of covariation for cardiovascular risk factors in adults: The Victorian Family Heart Study.Am J Epidemiol. 2000; 152:704–715.CrossrefMedlineGoogle Scholar3. Wellcome Trust Case Control Consortium. 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A loss of genome buffering capacity of Dahl salt-sensitive model to modulate blood pressure as a cause of hypertension.Hum Mol Genet. 2005; 14:3877–3884. doi: 10.1093/hmg/ddi412.CrossrefMedlineGoogle Scholar17. Geller DS.Clinical evaluation of Mendelian hypertensive and hypotensive disorders.Semin Nephrol. 2010; 30:387–394. doi: 10.1016/j.semnephrol.2010.06.005.CrossrefMedlineGoogle Scholar18. Tobin MD, Tomaszewski M, Braund PS, Hajat C, Raleigh SM, Palmer TM, et al.. Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population.Hypertension. 2008; 51:1658–1664. doi: 10.1161/HYPERTENSIONAHA.108.112664.LinkGoogle Scholar19. Morrison AC, Bis JC, Hwang SJ, Ehret GB, Lumley T, Rice K, et al.. Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.PLoS One. 2014; 9:e109155. doi: 10.1371/journal.pone.0109155.CrossrefMedlineGoogle Scholar20. Dahl LK, Heine M, Tassinari L.Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion.Nature. 1962; 194:480–482.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Deng A and Ménard A (2020) Biological convergence of three human and animal model quantitative trait loci for blood pressure, Journal of Hypertension, 10.1097/HJH.0000000000002267, 38:2, (322-331), Online publication date: 1-Feb-2020. Deng A and Ménard A (2020) Functional Captures of Multiple Human Quantitative Trait Loci Regulating Blood Pressure with the Use of Orthologs in Genetically Defined Rat Models, Canadian Journal of Cardiology, 10.1016/j.cjca.2020.03.012, 36:5, (756-763), Online publication date: 1-May-2020. Deng A (2020) Modularity/non-cumulativity of quantitative trait loci on blood pressure, Journal of Human Hypertension, 10.1038/s41371-020-0319-3, 34:6, (432-439), Online publication date: 1-Jun-2020. Deng A, deBlois D, Laporte S, Gelinas D, Tardif J, Thorin E, Shi Y, Raignault A and Ménard A (2018) Novel Pathogenesis of Hypertension and Diastolic Dysfunction Caused by M3R (Muscarinic Cholinergic 3 Receptor) Signaling, Hypertension, 72:3, (755-764), Online publication date: 1-Sep-2018.Cowley A (2018) Chrm3 Gene and M3 Muscarinic Receptors Contribute to Salt-Sensitive Hypertension, Hypertension, 72:3, (588-591), Online publication date: 1-Sep-2018. Deng A (2017) Molecular Genetics of Polygenic Hypertension eLS, 10.1002/9780470015902.a0021466.pub2, (1-8) Deng A, Ménard A and Borri A (2020) Conserved mammalian modularity of quantitative trait loci revealed human functional orthologs in blood pressure control, PLOS ONE, 10.1371/journal.pone.0235756, 15:7, (e0235756) August 2015Vol 8, Issue 4 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.115.001188 Originally publishedAugust 1, 2015 KeywordsEditorialssodiumgeneticsblood pressureanimal modelsPDF download Advertisement SubjectsAnimal Models of Human DiseaseGeneticsHypertension