Perfil genómico de riesgo en la práctica clínica
Palabras clave:
BIOLOGÍA MOLECULAR, GENOMA HUMANO, GENÉTICA MEDICAResumen
En los últimos diez años se ha visto un aumento exponencial tanto de los conocimientos en genética médica como en la capacidad de analizar el genoma humano. En los próximos años es probable que estas tendencias continúen, haciendo necesaria la incorporación de estas herramientas en la práctica médica diaria. En estos momentos asistimos a los primeros intentos serios de aplicación de la genómica humana a la atención de la salud. El conocimiento de las bases genéticas, y las interacciones a nivel molecular que llevan a las enfermedades humanas, tiene potencialidades enormes para mejorar el diagnóstico, el pronóstico, el tratamiento y la prevención de las mismas, e implica el desafío de cómo interpretar esta información y cómo educar a los médicos para utilizarla.
En este trabajo analizamos los últimos desarrollos, los beneficios y las limitaciones del análisis genómico en la clínica, las herramientas utilizadas para ello, esbozamos algunas tendencias y su extrapolación al futuro inmediato y, finalmente, analizamos la situación en nuestro medio.
Citas
(2) Khoury MJ, Gwinn M, Yoon PW, Dowling N, Moore CA, Bradley L. The continuum of translation research in genomic medicine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention? Genet Med 2007; 9: 665-74.
(3) Yoon PW, Chen B, Faucett A, Clyne M, Gwinn M, Lubin IM, et al. Public health impact of genetic tests at the end of the 20th century. Genet Med 2001; 3: 405-10.
(4) Khoury MJ. Genetics and genomics in practice: the continuum from genetic disease to genetic information in health and disease. Genet Med 2003; 5(4): 261-8.
(5) Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359(6396): 641-4.
(6) Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973; 288(14): 704-6.
(7) Human Genome Project Information. Medicine and the New Genetics. Disponible en:www.ornl.gov/sci/techresources/Human_Genome/medicine/medicine.shtml. [Consulta: marzo 2009].
(8) Collins F. Shattuck lecture-medical and societal consequences of the Human Genome Project. N Engl J Med 1999; 341(1): 28-37.
(9) Munroe JB. A coalition to drive personalized medicine forward. Personalized Med 2004; 1(1): 9-13.
(10) Guttmacher A, Collins F. Genomic Medicine - a primer. N Engl J Med 2002; 347(19): 1512-20.
(11) Lander ES. The new genomics: global views of biology. Science 1996; 274: 536-9.
(12) Schadt EE. Embracing complexity of common human diseases through technology integration. Nat Rev Genet 2007; 8: S24.
(13) Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007; 8: 657-62.
(14) Manolio TA, Brooks LA, Collins FS. HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118: 1590-605.
(15) Pearson TA, Manolio TA. How to interpret a genome-wide association study. JAMA 2008; 299(11): 1335-44.
(16) Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, et al. The diploid genome sequence of an individual human. PLoS Biology 2007; 5(10): e254.
(17) Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 2008; 452: 872-77.
(18) Wang J, Wang W, Li R, Li Y, Tian G, Goodman L, et al. The diploid genome sequence of an Asian individual. Nature 2008; 456(7218): 60-5.
(19) Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 2008; 456(7218): 53-9.
(20) Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456: 66-72.
(21) Ng PC, Zhao Q, Levy S, Strausberg RL, Venter JC. Individual genomes instead of race for personalized medicine. Clin Pharmacol Ther 2008; 84(3): 306-9.
(22) Check E. Celebrity genomes alarm researchers. Nature 2007; 447: 358-9.
(23) Illumina/ Solexa Ld. The illumina genoma analyzer. Disponible en: http://www.solexa.com/. [Consulta: marzo 2009].
(24) Bennett ST, Barnes C, Cox A, Davies L, Brown C. Toward the 1,000 dollars human genome. Pharmacogenomics 2005; 6(4): 373-82.
(25) Mardis ER. Anticipating the $1,000 genome. Genome Biol 2006, 7: 112.
(26) Wolinsky H. The thousand-dollar genome. Genetic brinkmanship or personalized medicine? EMBO Rep 2007: 8(10): 900-3.
(27) Hood L, Heath JR, Phelps ME, Lin B. Systems biology and new technologies enable predictive and preventative medicine. Science 2004; 306(5696): 640-3.
(28) Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT, et al. Concept, design and implementation of a cardiovascular gene-centric 50 K SNP array for large-scale genomic association studies. PLoS One 2008; 3(10): e3583.
(29) Church GM. The personal genome project. Mol Syst Biol 2005; 1: 0030.
(30) Goetz T. How the personal genome project could unlock the mysteries of life. (26/07/2008). Wired Magazine 2008. Disponible en: http://www.wired.com/medtech/stemcells/magazine/16-08/ff_church. [Consulta: marzo 2009].
(31) Locke, S. Meet my genome: 10 people release their DNA on the Web. (21/10/2008). Disponible en: http://www.sciam.com/blog/60-second-science/post.cfm?id=meet-my-genome-10-people-release-th-2008-10-21. [Consulta: marzo 2009].
(32) Pinker S. My genome, my self. New York Times (11/01/2009). Disponible en: http://www.nytimes.com/2009/01/11/magazine/11Genome-t.html?pagewanted=1&_r=1&ref= magazine. [Consulta: marzo 2009].
(33) Rockhill B, Kawachi I, Colditz GA. Individual risk prediction and population-wide disease prevention. Epidemiol Rev 2000; 22: 176-80.
(34) Paolo Vineis, Paul Schulte, Anthony J McMichae. Misconceptions about the use of genetic tests in populations. Lancet 2001; 357: 709-12.
(35) Hunter DJ, Khoury MJ, Drazen JM. Letting the genome out of the bottle - will we get our wish? N Engl J Med 358; 2: 105-7.
(36) Pollack A. Gene testing questioned by regulators. New York Times (26/06/2008). Disponible en: http://www.nytimes.com/2008/06/26/business/26gene.html?ref=health. [Consulta: marzo 2009].
(37) Wadman M. Gene-testing firms face legal battle. Nature 2008; 453 (7199): 1148-9.
(38) LRRK2 (18/09/2008). Disponible en: http://too.blogspot.com/. [Consulta: marzo 2009].
(39) Lewontin R. La diversidad humana. Barcelona: Prensa Científica, 1984.
(40) Helen M, Colhoun, Paul M McKeigue, George Davey Smith. Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865-72.
(41) Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet 2001; 17: 502-10.
(42) Thomas PD, Kejariwal A. Coding single-nucleotide polymorphisms associated with complex vs mendelian disease: evolutionary evidence for differences in molecular effects. PNAS 2004; 101(43): 15398-403.
(43) Tishkoff SA, Williams SM. Genetic analysis of African populations: human evolution and complex disease. Nat Rev Gen 2002; 3: 611-21.
(44) Mulder HJ, van Geel PP, Schalij MJ, van Gilst WH, Zwinderman AH, Bruschke AV. DD ACE gene polymorphism is associated with increased coronary artery endothelial dysfunction: the PREFACE trial. Heart 2003; 89: 557-8.
(45) Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM, Witteman JCM. Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness a meta-analysis. Stroke 2003; 34: 1634-9.
(46) Prak ET, Kazazian HH Jr. Mobile elements and the human genome. Nat Rev Genet 2000; 1: 134-44.
(47) Stoll M, Esperón P, Raggio V. Diagnóstico molecular del polimorfismo I/D del gene de la Enzima Convertidora de Angiotensina (ECA) como factor de riesgo cardiovascular. Rev Urug Patol Clín 2003; 37: 23-31.
(48) Freeman JL, Perry GH, Feuk L, Redon R, McCarroll SA, Altshuler DM, et al. Copy number variation: new insights in genome diversity. Genome Res 2006; 16: 949-61.
(49) Sebat J. Major changes in our DNA lead to major changes in our thinking. Nat Genet 2007; 39: S3-5.
(50) Iles MM. What can genome-wide association studies tell us about the genetics of common disease? PLoS Genet 2008; 4(2): e33.
(51) Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI. Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet 2008; 82: 100-12.
(52) Wang L, Fan C, Topol SE, Topol EJ, Wang Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 2003; 302: 1578-81.
(53) Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, Mc Pherson R, Hobbs HH. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305, 869-72.
(54) Cho JH, Abraham C. Inflammatory bowel disease genetics: Nod2. Ann Rev Med 2007; 58: 401-16.
(55) Romeo S, Pennacchio LA, Fu Y, Boerwinkle E, Tybjaerg-Hansen A, et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 2007; 39: 513-6.
(56) Freeman JL, Perry G, Feuk L, Redon R, McCarroll SA, Altshuler DM, et al. Copy number variation: new insights in genome diversity. Genome Res 2006; 16: 949-61.
(57) Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al. Global variation in copy number in the human genome. Nature 2006; 444: 444-54.
(58) McCarroll SA, Altshuler DM. Copy-number variation and association studies of human disease. Nat Genet 2007; 39: S37-S42.
(59) Lupski JR. Genomic rearrangements and sporadic disease. Nat Genet 2007; 39: S43-S47.
(60) González E, Kulkarni H, Bolívar H, Mangano A, Sánchez R, Catano G, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307: 1434-40.
(61) Aitman TJ, Dong R, Vyse TJ, Norsworthy PJ, Johnson MD, Smith J, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006; 439: 851-5.
(62) Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007; 80: 1037-54.
(63) Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L, et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007; 39: 721-3.
(64) Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009; 41: 334-41. Disponible en: http://www.nature. com/ng/journal/v41/n3/abs/ng.327.html. [Consulta: marzo 2009].
(65) Estivill X, Armengol L. Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies. PLoS Genet 2007; 3(10): e190.
(66) 1000 Genomes. A deep catalog of human genetic variation. Disponible en: http://www.1000genomes.org/page.php?page= home. [Consulta: marzo 2009].
(67) Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 2004; 20: 350-8.
(68) Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 2006; 174(3): 341-8.
(69) Mattick JS. RNA regulation: a new genetics? Nat Rev Genet 2005; 5: 316-23.
(70) Mattick JS. Challenging the dogma: the hidden layers of non-protein-coding RNAs in complex organisms. Bioessays 2003; 25: 930-9.
(71) Van Rooij E, Olson E. MicroRNAs: powerfull new regulators of heart disease and provocative therapeutic targets. J Clin Invest 2007; 117: 2369-76.
(72) Morgan HD, Sutherland H, Martin D, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nature 1999; 23: 314-8.
(73) Hatchwell E, Greally JM. The potencial role of epigenomic dysregulation in complex human disease. Trends Genet 2007; 23(11): 588-95.
(74) Ordovas JM, Mooser V. Nutrigenomics and nutrigenetics. Curr Op Lipidol 2004, 15: 101-8.
(75) Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome. Diabetes 2005; 54: 1899-906.
(76) Tang WY, Ho SM. Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 2007; 8(2): 173-82.
(77) Strohman RC. Linear genetics, non-linear epigenetics: complementary approaches to understanding complex diseases. Integr Physiol Behav Sci 1995; 30(4): 273-82.
(78) Oligny LL. Cancer and epigenesis: a developmental perspective. Adv Pediatr 2003, 50: 59-80.
(79) Cho KS, Elizondo LI, Boerkoel CF. Advances in chromatin remodeling and human disease. Curr Opin Genet Dev 2004; 14(3): 308-15.
(80) Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet 2002; 10: 682-8.
(81) Peedicayil J. Epialleles and common disease. Med Hypotheses 2005; 64: 215.
(82) Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 2006; 174(3): 341-8.
(83) Yang Q, Khoury MJ, Botto L, Friedman JM, Flanders WD. Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes. Am J Hum Genet 2003; 72: 636-49.
(84) Khoury MJ, Yang Q, Gwinn M, Little J, Flanders D. An epidemiologic assessment of genomic profiling for measuring susceptibility to common diseases and targeting interventions. Genet Med 2004; 6(1): 38-47.
(85) Yang QH, Khoury MJ, Friedman JM, Little J, Flanders WD. How many genes underlie the occurrence of common complex diseases in the population? Int J Epidemiol 2005; 34, 1129-37.
(86) Humphries SE, Talmud PJ, Hawe E, Bolla M, Day INM, Miller GJ. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 2001; 358, 115-9.
(87) Talmud PJ, Bujac SR, Hall S, Miller GJ, Humphries SE. Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers. Atherosclerosis 2000; 149(1): 75-81.
(88) Talmud PJ, Stephens JW, Hawe E, Demissie S, Cupples LA, Hurel SJ, et al. The significant increase in cardiovascular disease risk in APOE epsilon 4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4. Ann Hum Genet 2005; 69, 613-22.
(89) Williams SM, Ritchiea MD, Phillips JA, Dawsone E, Princed M, Dzhurad E. Multilocus analysis of hypertension: a hierarchical approach. Hum Hered 2004; 57: 28-38.
(90) Williams SM, Addy JH, Phillips JA 3rd, Dai M, Kpodonu J, Afful J, et al. Combinations of variations in multiple genes are associated with hypertension. Hypertension 2000; 36; 2-6.
(91) Flex A, Gaetani E, Papaleo P, Straface G, Proia AS, Pecorini G. Proinflammatory genetic profiles in subjects with history of ischemic stroke. Stroke 2004; 35: 2270-5.
(92) Pezzini A, Grassi M, Del Zotto E, Archetti S, Spezi R, Vergani V, et al. Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults. Stroke 2005; 36: 533-9.
(93) Grassi M, Assanelli D, Mozzini C, Albertini F, Salvadori G, Archetti S, et al. Modeling premature occurrence of acute coronary syndrome with atherogenic and thrombogenic risk factors and gene markers in extended families. J Thromb Haemost 2005; 3(10): 2238-44.
(94) Stoll M, Esperón P, Raggio V, Lorenzo M, Artucio MC, Kuster F. Combination of genetic polymorphisms and smoker status in high risk families. World Congress of Cardiology, 16 (Buenos Aires, 18-21 may 2008).
(95) Drenos F, Whittaker JC, Humphries SE. The use of meta-analysis risk estimates for candidate genes in combination to predict coronary heart disease risk. Ann Hum Genet 2007; 71 (Pt 5): 611-9.
(96) Yamada Y. Identification of genetic factors and development of genetic risk diagnosis systems for cardiovascular diseases and stroke. Circ J 2006; 70: 1240-8.
(97) Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, Zegginie E, et al. Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med 2006; 3(10): e374.
(98) Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa Bo, Tuomi T, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 2008; 359: 2220-32.
(99) Meigs JB, Shrader P, Sullivan LM, McAteer JB, Fox CS, Dupuis J, et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008; 359: 2208-19.
(100) Bouchard L, Tremblay A, Bouchard C, Pérusse L. Contribution of several candidate gene polymorphisms in the determination of adiposity changes: results from the Québec Family Study. Int J Obes (Lond) 2007; 31(6): 891-9.
(101) Ribalta J, Halkes C, Salazar J, Masana L, Cabezas MC. Additive effects of the PPARG, APOE, and FABP-2 genes in increasing daylong triglycerides of normolipidemic women to concentrations comparable to those in men. Clin Chem 2005; 51(5): 864-71.
(102) Demchuk E, Yucesoy B, Johnson V, Andrew M, Weston A, Germolec DR, et al. A statistical model for assessing genetic susceptibility as a risk factor in multifactorial diseases: lessons from occupational asthma. Environ Health Perspect 2007; 115: 231-4.
(103) Pharoah P, Antoniou A, Easton DF, Ponder B. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 2008; 358: 2796-803.
(104) Croce CM. Oncogenes and cancer. N Engl J Med 2008; 358: 502-11.
(105) Austin M, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a huge association review. Am J Epidemiol 2004; 160(5): 421-9.
(106) Stoll M, Esperón P, Raggio V. Progresos en la identificación de pacientes con Hipercolesterolemia Familiar (HF). Avances hacia un registro nacional de HF. Bol Com Hon Salud Cardiov 2005; VII (1): 42-3.
(107) Humphries SE, Cooper JA, Talmud PJ, Miller GJ. Candidate gene genotypes, along with conventional risk factor assessment, improve estimation of coronary heart disease risk in healthy UK men. Clin Chem 2007; 53: 8-16.
(108) Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nature 2008; 40(5): 584-91.
(109) Stoll M, Raggio V. La historia familiar – el primer paso a la genómica médica. Tendencias 2007; (30): 117-23.
(110) Stoll M, Raggio V. La historia familiar como instrumento de prevención en la enfermedad cardiovascular. Bol Com Hon Salud Cardiov 2002; 4(1): 43-9.
(111) Humphries SE, Ridker PM, Talmud PJ. Genetic testing for cardiovascular disease susceptibility. a useful clinical management tool or possible misinformation? Arterioscler Thromb Vasc Biol 2004; 24; 628-36.
(112) Allen JK. Genetics and cardiovascular disease. Nurs Clin North Am 2000; 35(3): 653-62.
(113) Raggio V, Esperón P, Stoll M. Polimorfismos de la apolipoproteína E: convergencia de factores de riesgo genético para arteriosclerosis y el deterioro neurológico. Bol Com Hon Salud Cardiov 2006; VIII (1): 20-4.
(114) Ray M, Ruan J, Zhang W. Variations in the transcriptome of Alzheimer’s disease reveal molecular networks involved in cardiovascular diseases. Genome Biol 2008; 9: R148.
(115) Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 2004; 62: 309-17.
(116) Mancinelli L, Cronin M, Sadée W. Pharmacogenomics: the promise of personalized medicine. AAPS PharmSci 2000; 2(1) article 4.
(117) Evans WE, Relling M. Moving towards individualized medicine with pharmacogenomics. Nature 2004; 429(6990):464-8.
(118) Evans WE, Relling M. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487-91.
(119) Raggio V, Neira P, Esperón P, Lorenzo M, Stoll M. Respuesta terapéutica inadecuada a la warfarina en un paciente genéticamente susceptible. Rev Méd Urug 2005; 21: 242-6.
(120) Raggio V, Esperón P, Taub I, Rodríguez A, Lorenzo M, Cuesta A, et al. Genotipo para CYP2C9 y apolipoproteína E y respuesta individual a la warfarina. Rev Urug Cardiol 2006; 21: 106-17.
(121) Esperón P, Raggio V, Goyeneche L, Lorenzo M, Tabú I, Stoll M. Genotipo de los genes VKORC1 y CYP2C9 en la respuesta individual a la warfarina. Rev Méd Urug 2008; 24: 267-77.
(122) Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, et al. The apolipoprotein _4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction. A substudy of the Scandinavian Simvastatin Survival Study. Circulation 2000; 101: 1366-71.
(123) Müller M, Kersten S. Nutrigenomics: goals and strategies. NRG 2003; 4: 315-22.
(124) Ordovas JM, Corella D. Nutritional genomics. Annu Rev Genomics Hum Genet 2004; 5: 71-118.
(125) Siffert W. G protein beta3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy. Nephrol Dial Transplant 2000; 15: 1298-306.
(126) Ruggenenti P, Bettinaglio P, Pinares F, Remuzzi G. Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies. Clin J Am Soc Nephrol 2008; 3(5): 1511-25.
(127) Algerholm-Larsen, B. ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large estudies in whites. Arterioscler Thromb Vasc Biol 2000; 20(2): 484.
(128) Valiño J, Fraga L, Pisano A(h), Raggio V, Esperón P, Guerra A, et al. Evaluación de polimorfismos genéticos relacionados a riesgo vascular en pacientes diabéticos tipo 2. Congreso Latinoamericano de Diabetes, 12. (San Pablo, Brasil, 2004).
(129) International HapMap Project. How will the hapmap benefit human health? Disponible en:http://www.hapmap.org/healthbenefit.html (Consulta: marzo de 2009).
(130) Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration–emerging pathogenetic and therapeutic concepts. Ann Med 2006; 38(7): 450-71.
(131) Etcheverry L, Graña M, Marotta A, Naya H, Raggio V, Ruggia R. Enabling GWAS meta-analysis through data quality management, 2008. Microsoft eScience Workshop (Indianapolis, USA, 2008).
(132) Zintzaras E, Lau J. Trends in meta-analysis of genetic association studies. J Hum Genet 2008; 53: 1-9.
(133) Chen R, Morgan AA, Dudley J, Deshpande T, Li L, Kodama K, et al. FitSNPs: highly differentially expressed genes are more likely to have variants associated with disease. Genome Biol 2008, 9: R170.
(134) Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, et al. A genomewide association study of global gene expression. Nat Genet 2007; 39: 1202-7.
(135) Hunter D, Altshuler D, Rader DJ. From Darwin’s finches to canaries in the coal mine–mining the genome for new biology. N Engl J Med 2008; 358: 2760-3.
(136) Inoue K, Lupski JR. Genetics and genomics of behavioral and psychiatric disorders. Curr Opin Genet Dev 2003, 13: 303-9.
(137) Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science 2008; 322: 881-8.
(138) International HapMap Consortium. Integrating ethics and science in the International HapMap Project. Nat Rev Genet 2004; 5: 467-75.
(139) Human Genome Project Information. Ethical, legal, and social issues. Disponible en: http://www.ornl.gov/sci/techresources/ Human_Genome/elsi/elsi.shtml. [Consulta: marzo 2009].
(140) Hardy BJ, Séguin B, Goodsaid F, Jiménez-Sánchez G, Singer PA, Daar AS. The next steps for genomic medicine: challenges and opportunities for the developing world. Nature Rev Gen 2008: S23-S27.
(141) Comisión Honoraria Para la Salud Cardiovascular. Disponible en: http://www.cardiosalud.org/. [Consulta: marzo 2009].
(142) Stoll M, Raggio V. La historia familiar como instrumento de prevención en la enfermedad cardiovascular. Bol Com Hon Salud Cardiov 2002; 4(1): 43-9.
(143) Universidad de la República. Facultad de Medicina. Departamento de Genética. Disponible en: http://www. genetica.fmed.edu.uy/. [Consulta: marzo 2009].
(144) Hospital de Clínicas. Servicio de Oncología Clínica. Disponible en: www.oncologiamedica.hc.edu.uy/grup5.html. [Consulta: marzo 2009].
(145) Larre Borges García A, Scarone M, Delgado L, Núñez J, Laporte M, Fernández G, et al. Predisposición hereditaria de padecer melanoma en familias uruguayas. Resultados preliminares. Rev Méd Urug 2007; 23: 109-15.
(146) Sarroca C, Alfano N, Bendin GT, Della Valle A, Domínguez A, Quadrelli R, et al. Hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay. Dis Colon Rectum 2000; 43(3): 353-60.
(147) Grupo Colaborativo Uruguayo. Investigación de Afecciones Oncológicas Hereditarias (GCU). Disponible en: http://www.dnsffaa.gub.uy/GCU/grupocolaborativouruguayo. htm. [Consulta: marzo 2009].
(148) Collins FS, Green ED, Guttmacher AE, Guyer MS; US National Human Genome Research Institute. A vision for the future of genomics research. Nature 2003; 422: 835-47.
(149) Collins FS, Green ED, Guttmacher AE, Guyer MS; US National Human Genome Research Institute. A vision for the future of genomics research. Nature 2003; 422: 835-47.
(150) van Langen IM, Birnie E, Leschot NJ, Bonsel GJ, Wilde A. Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era? Eur Heart J 2003; 24, 560-6.
(151) National Institute of Genomic Medicine. México. Disponible en: http://www.inmegen.org.mx. [Consulta: marzo 2009].
(152) Raggio V, Roche L, Esperón P, Stoll M. Curso on-line: introducción a la medicina genómica. Primera experiencia. Rev Méd Urug 2007; 23: 116-21.
(153) Raggio V. Un blog de genética para médicos. Disponible en: http://geneticamedicina.blogspot.com. [Consulta: marzo 2009].