Hypertension, Genes, and Environment
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 7 Linguagem: Inglês
10.1161/circulationaha.117.032196
ISSN1524-4539
Autores Tópico(s)Health, Environment, Cognitive Aging
ResumoHomeCirculationVol. 137, No. 7Hypertension, Genes, and Environment Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHypertension, Genes, and EnvironmentChallenges for Prevention and Risk Prediction Richard Cooper, MD Richard CooperRichard Cooper Department of Public Health Sciences, Loyola University Medical School, Maywood, IL. Originally published13 Feb 2018https://doi.org/10.1161/CIRCULATIONAHA.117.032196Circulation. 2018;137:662–664Article, see p 653Despite substantial progress in treatment and control, hypertension still accounts for 10% of the population attributable risk for all-cause mortality in most societies.1 In addition to better pharmacological control, a preventive population approach is needed because the lifetime incidence of hypertension is 90%, and the years spent with a high normal blood pressure (BP) also have vascular consequences. Unfortunately, the challenge of primary prevention has not even been seriously addressed, at least in the United States.2 Therefore, much research on BP is an attempt to move forward from the traditional, and some might say antiquated, approach of repeated measurements of a patient's BP, estimation of average risk based on data from published studies, followed by life-long therapy with daily medications. Enthusiasts of the precision medicine paradigm argue that prediction of risk based on genetic susceptibility, coupled with individualized choices of therapy, will add great efficiency to the management of high BP.To address that question, in this issue of Circulation, Pazoki and colleagues3 compared the relative impact of lifestyle factors on BP versus a suite of 314 risk alleles in a cohort of 277 000 persons in the UK Biobank. The main finding was a systolic BP difference of 3.5 mm Hg in the high- versus low-risk tertiles of risk, which was equivalent for both lifestyle factors and genetic risk. As expected, clinical events tracked the BP gradient. The broad overlap of BPs across the risk strata will mean that perhaps half of patients could be misclassified and therefore both measures have little predictive value. The conclusion emphasized by the authors is the lack of interaction between the risk domains, that is, lifestyle factors made a similar contribution irrespective of the patient's genetic profile, offering the same benefit from prevention across genetic risk strata. The authors also note that this finding replicates almost precisely a prior study with coronary disease.4Two secondary issues deserve further attention: the inherent weakness of the methods available to quantify lifestyle and the clinical meaning of the risk estimates used to summarize the data. As the authors clearly state, our ability to categorize the risk of high BP in surveys is extremely crude; most information is obtained from body mass index, which usually accounts for 5% to 10% of the variance.5 This unhappy fact of life reflects the underlying pathogenesis of the condition: it is the result of cumulative lifetime exposure to modest excesses of the causative agents, which are primarily nutritional in origin. A single measurement of a trait with large day-to-day variability—as is the case with sodium and potassium intake and some other nutrients—has virtually no discriminatory power.6 Thus, the actual measured risk gradient associated with lifestyle factors bears no quantitative relationship to their lifetime effect: the estimate will be strongly biased toward a lower value no matter how the categories of risk are parameterized. A second unhappy corollary follows: to lower BP by altering lifestyle requires large changes, usually beyond that which patients can sustain. Perhaps we do patients a disservice by badgering them to reduce exposure to these lifestyle factors through individual choice because meaningful change will only be achieved by modifying food production, food preparation, and the entire social framework related to physical activity.7 However, as the authors argue, genetic risk is theoretically more precise because the metric is fixed and there is little measurement error. Therefore, it is tempting to assume that more information is available from molecular characterization of risk, as enshrined in the precision medicine paradigm. This view, in my opinion, reflects a lack of understanding of the pathogenesis of hypertension as well as coronary disease.Interpretation of risk estimates from genetic epidemiology is not usually framed in a manner that has clinical utility.8 Relative risk estimates for cardiovascular conditions, for single variants and even genomic risk scores, are invariably in the range of 1.1 to 2.0, as is the case in this analysis.3 Effects of that magnitude are totally out of range in terms of clinical utility; for both screening and diagnostic tests, odds ratios must generally be ≥20 before they have relevance.8 When genetic risk scores are assigned P values of 10−320, as they are here, this is not evidence of a strong association but rather a relationship that is unlikely to have occurred by chance. There is a growing desire to give molecular research translational relevance, but before we can begin to make judgments about utility, the language of risk description must be changed. A measured, head-to-head comparison of the value of DNA-based evidence on the same metrics for prediction as current tools, from CT scans to clinical laboratory tests, is needed.Molecular genetics has changed and maybe even disrupted large domains of clinical research, on both etiologic and therapeutic questions. This rapid shift in the center of gravity away from traditional disciplines such as physiology, nutrition, and use of model organisms for drug development to studies using the vast array of genotyping and sequencing technologies now available has resulted in undeclared warfare among many traditionalists and champions of genomic or precision medicine.9,10 Depending on your perspective, genomics, in its broadest sense, is either grossly oversold or offers the potential for breakthroughs on every conceivable challenge facing biomedicine. At the outset, when everything was unknown, dismissing the field as hype and claiming that all of biomedicine was going to be revolutionized were both premature in equal measure. However, for many traits, we now have traveled some way down the gene discovery road, and judgments are due. For most common cardiovascular diseases, we have stable estimates of the impact of heritable factors, as summarized by the current paper and the study by Khera et al4 on coronary disease. Risk prediction from DNA-based methods is not going to be helpful for cardiovascular diseases unless we are surprised and whole-genome sequencing brings a second wave of disruption. The vague predictions about biological insights and novel therapies are based on hope and desire, not evidence. Measuring BP, lipids, and so on will remain clinical mainstays, and the probabilistic nature of these disorders will not be rendered anything near deterministic. Larger studies will enlarge the storehouse of risk variants and potentially illuminate more of the pathophysiologic processes. Indeed, a new study with 1 million participants will soon move the genetics of hypertension incrementally forward in exactly that fashion.11 However, in my view, it is probably time for clinical research and the practice of cardiology to return to its roots and promote healthful living environments, improved nutrition, and careful patient management.7,10 After all, those traditional approaches have lowered coronary mortality rates by >80% in the last half century and hold the clear promise of more reductions to come from lower BP treatment goals, widespread use of statins, and assurance of access for the underserved.12,13 The main message of the report by Pazoki et al3 for me is that we need a synthesis of what genomics has taught us with the much more mature disciplines of epidemiology, randomized trials, and outcomes research. It remains to be seen, of course, whether the nascent signs of breakthroughs in other fields, particularly cancer and immune function disorders, predict substantial health benefits for patients with those disorders.14Every living organism on this planet is unique. Physicians have always dreamed of being able to offer patients a precise diagnosis, prognosis, and treatment plan centered on that patient as a unique physical and psychic being, not on averages drawn from studies of other people. When hearing that goal articulated, I am reminded of an exchange that took place in a clinical teaching conference some years ago. Summarizing the benefit of a particular treatment, the speaker used a familiar heuristic: "You need to treat 100 patients for 5 years to prevent 10 new events." A beleaguered young physician raised his hand and said, "If you could just tell me who those 10 people are you would save me a lot of trouble." It is better to accept our imperfect knowledge of unalterably probabilistic reality and continue to drive the risk of cardiovascular disease out of more lives than to chase the unrealistic hopes of taming nature's infinite variety.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgRichard Cooper, MD, Department of Public Health Sciences, Loyola University Medical School, 2160 S First Avenue, Maywood, IL 60153. E-mail [email protected]References1. WHO Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: World Health Organization;2009.Google Scholar2. Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D'Agostino RB, Levy D. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study.JAMA. 2002; 287:1003–1010.CrossrefMedlineGoogle Scholar3. Pazoki R, Dehghan A, Evangelou E, Warren H, Gao H, Caulfield MJ, Elliott P, Tsoulaki I. Genetic predisposition to high blood pressure and lifestyle factors: associations with midlife blood pressure levels and cardiovascular events.Circulation. 2018; 137:653–661. doi: 10.1161/CIRCULATIONAHA.117.030898.LinkGoogle Scholar4. Khera AK, Connor A., Emdin CA, Drake I, Natarajan P, Bick AG, Nancy R., Cook NR, Chasman DI, Baber U, Mehran R, Rader DJ, Fuster V, Boerwinkle E, Melander O, Orho-Melander M, Ridker PM, Kathiresan K. Genetic risk, adherence to a healthy lifestyle, and coronary disease.N Engl J Med. 2016; 375:2349–2358.CrossrefMedlineGoogle Scholar5. Cappuccio FP, Kerry SM, Adeyemo A, Luke A, Amoah AG, Bovet P, Connor MD, Forrester T, Gervasoni JP, Kaki GK, Plange-Rhule J, Thorogood M, Cooper RS. Body size and blood pressure: an analysis of Africans and the African diaspora.Epidemiology. 2008; 19:38–46. doi: 10.1097/EDE.0b013e31815c4d2c.CrossrefMedlineGoogle Scholar6. Liu K, Cooper R, McKeever J, McKeever P, Byington R, Soltero I, Stamler R, Gosch F, Stevens E, Stamler J. Assessment of the association between habitual salt intake and high blood pressure: methodological problems.Am J Epidemiol. 1979; 110:219–226.CrossrefMedlineGoogle Scholar7. Björck L, Rosengren A, Winkvist A, Capewell S, Adiels M, Bandosz P, Critchley J, Boman K, Guzman-Castillo M, O'Flaherty M, Johansson I. Changes in dietary fat intake and projections for coronary heart disease mortality in Sweden: a simulation study.PLoS One. 2016; 11:e0160474. doi: 10.1371/journal.pone.0160474.CrossrefMedlineGoogle Scholar8. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker.Am J Epidemiol. 2004; 159:882–890.CrossrefMedlineGoogle Scholar9. Evans JP, Meslin EM, Marteau TM, Caulfield T. Genomics: deflating the genomic bubble.Science. 2011; 331:861–862. doi: 10.1126/science.1198039.CrossrefMedlineGoogle Scholar10. Cooper RS, Psaty BM. Genomics and medicine: distraction, incremental progress, or the dawn of a new age?Ann Intern Med. 2003; 138:576–580.CrossrefMedlineGoogle Scholar11. Evangelos Evangelou, Helen R. Warren, David Mosen-Ansorena, Borbala Mifsud, Raha Pazoki, He Gao, Georgios Ntritsos, Niki Dimou, Claudia P. Cabrera, Ibrahim Karaman, Fu Liang Ng, Marina Evangelou, Katarzyna Witkowska, Evan Tzanis, Jacklyn N. Hellwege, Ayush Giri, Digna R. Velez Edwards, Yan V. Sun, Kelly Cho, J. Michael Gaziano, Peter W. F. Wilson, Philip S. Tsao, Csaba P. Kovesdy, Tonu Esko, Reedik Magi, Lili Milani, Peter Almgren, Thibaud Boutin, Stephanie Debette, Jun Ding, Franco Giulianini, Elizabeth G. Holliday, Anne U. Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sebastien Theriault, Niek Verweij, Sara M. Willems, Jing-Hua Zhao, Philippe Amouyel, John Connell, Renee de Mutsert, Alex S. F. Doney, Martin Farrall, Cristina Menni, Andrew D. Morris, Raymond Noordam, Guillaume Pare, Neil R. Poulter, Denis C. Shields, Alice Stanton, Simon Thom, Goncalo Abecasis, Najaf Amin, Dan E. Arking, Kristin L. Ayers, Caterina M. Barbieri, Chiara Batini, Joshua C. Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I. Boomsma, Erwin Bottinger, Peter S. Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C. Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J. Cordell, Gail Davies, Martin H. de Borst, Eco de Geus, Ian Deary, Joris Deelen, Fabiola M. Del Greco, Cumhur Y. Demirkale, Marcus Dorr, Georg B. Ehret, Roberto Elosua, Stefan Enroth, A. Mesut Erzurumluoglu, Teresa Ferreira, Mattias Franberg, Oscar H. Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J. Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B. Harris, Sarah E. Harris, Catharina A. Hartman, Aki S. Havulinna, Andrew A. Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E. Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Asa Johansson, Andrew D. Johnson, Peter Joshi, Pekka Jousilahti, J. Wouter Jukema, Antti M. Jula, Mika Kahonen, Sekar Kathiresan, Bernard D. Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S. Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J. Launer, Benjamin Lehne, Terho Lehtimaki, Daniel Levy, David C. M. Liewald, Li Lin, Lars Lind, Cecilia M. Lindgren, Yongmei Liu, Ruth J. F. Loos, Lorna M. Lopez, Lingchan Lu, Leo-Pekka Lyytikainen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P. Morris, Alanna C. Morrison, Mike A. Nalls, Priyanka Nandakumar, Christopher P. Nelson, Christopher Newton-Cheh, Teemu Niiranen, Ilja M. Nolte, Teresa Nutile, Albertine J. Oldehinkel, Ben A. Oostra, Paul F. O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Arno Palotie, Alison Pattie, Brenda W. J. H. Penninx, Markus Perola, Peter J. Munson, Annette Peters, Ozren Polasek, Peter P. Pramstaller, Nguyen Quang Tri, Olli T. Raitakari, Meixia Ren, Rainer Rettig, Kenneth Rice, Paul M. Ridker, Janina S. Reid, Harriette Riese, Samuli Ripatti, Antonietta Robino, Lynda M. Rose, Jerome I. Rotter, Igor Rudan, Daniella Ruggiero, Yasaman Saba, Cinzia F. Sala, Veikko Salomaa, Nilesh J. Samani, Antti-Pekka Sarin, Rheinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V. Smith, Harold Schneider, Siim Sober, Rossella Sorice, John M. Starr, David J. Stott, David P. Strachan, Rona J. Strawbridge, Johan Sundstrom, Morris A. Swertz, Kent D. Taylor, Alexander Teumer, Martin D. Tobin, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, Andre G. Uitterlinden, Ahmad Vaez, Peter J. van der Most, Cornelia M. van Duijn, Anne-Claire Vergnaud, Germaine C. Verwoert, Veronique Vitart, Uwe Volker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H. Wild, Gonneke Willemsen, James F. Wilson, Alan F. Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R. Attia, Adam S. Butterworth, Daniel I. Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna M. M. Howson, Markku Laakso, Edward G. Lakatta, Claudia Langenberg, Ollie Melander, Dennis O. Mook-Kanamori, Patricia B. Munroe, Colin N. A. Palmer, Lorenz Risch, Robert A. Scott, Rodney J. Scott, Peter Sever, Timothy D. Spector, Pim van der Harst, Nicholas J. Wareham, Eleftheria Zeggini, Morris J. Brown, Andres Metspalu, Adriana M. Hung, Christopher O'Donnell, Todd L. Edwards, Bruce M. Psaty, Ioanna Tzoulaki, Michael R. Barnes, Louise V. Wain, Paul Elliott, Mark J. Caulfield. Genetic analysis of over 1 million people identifies 535 novel loci for blood pressure.bioRxiv. 198234. doi: 10.1101/198234.Google Scholar12. Mensah GA, Wei GS, Sorlie PD, Fine LJ, Rosenberg Y, Kaufmann PG, Mussolino ME, Hsu LL, Addou E, Engelgau MM, Gordon D. Decline in cardiovascular mortality: possible causes and implications.Circ Res. 2017; 120:366–380. doi: 10.1161/CIRCRESAHA.116.309115.LinkGoogle Scholar13. Bress AP, Kramer H, Khatib R, Beddhu S, Cheung AK, Hess R, Bansal VK, Cao G, Yee J, Moran AE, Durazo-Arvizu R, Muntner P, Cooper RS. Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: projections from NHANES (National Health and Nutrition Examination Survey).Circulation. 2017; 135:1617–1628. doi: 10.1161/CIRCULATIONAHA.116.025322.LinkGoogle Scholar14. Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, Yang J. 10 years of GWAS discovery: biology, function, and translation.Am J Hum Genet. 2017; 101:5–22. doi: 10.1016/j.ajhg.2017.06.005.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Abramson J, Castello J, Keins S, Kourkoulis C, Rodriguez-Torres A, Myserlis E, Alabsi H, Warren A, Henry J, Gurol M, Viswanathan A, Greenberg S, Towfighi A, Skolarus L, Anderson C, Rosand J and Biffi A (2022) Biological and Social Determinants of Hypertension Severity Before vs After Intracerebral Hemorrhage, Neurology, 10.1212/WNL.0000000000200003, 98:13, (e1349-e1360), Online publication date: 29-Mar-2022. Fornal M, Lekki J, Królczyk J, Wizner B and Grodzicki T Association of sulfur content in erythrocytes with cardiovascular parameters and blood pressure, Clinical Hemorheology and Microcirculation, 10.3233/CH-211117, 79:2, (279-292) Wang W, Du T, Jiang X and Gao Y (2021) Correlation between 25-Hydroxyvitamin D, sFlt-1, PLGF, and Hypertension in Pregnancy, Journal of Healthcare Engineering, 10.1155/2021/9371953, 2021, (1-11), Online publication date: 1-Nov-2021. Cicalese S, da Silva J, Priviero F, Webb R, Eguchi S and Tostes R (2021) Vascular Stress Signaling in Hypertension, Circulation Research, 128:7, (969-992), Online publication date: 2-Apr-2021. Ji L, Tang N, Xu Z and Xu J (2020) Genes Regulate Blood Pressure, but "Environments" Cause Hypertension, Frontiers in Genetics, 10.3389/fgene.2020.580443, 11 February 13, 2018Vol 137, Issue 7 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.032196PMID: 29440195 Originally publishedFebruary 13, 2018 KeywordsgeneticspredictionEditorialshypertensionPDF download Advertisement SubjectsGeneticsPrimary Prevention
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