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Genetics of Hypertension Yen-Pei Christy Chang, Ph.D. GenEpi, PREV 789, April 28, 2013 Cardiac Output Peripheral Resistance Arterial Blood Pressure Blood Pressure Regulation Regulated through: Salt and Water Balance in Kidney Autonomic Nervous System Hormonal Responses GLOMERULUS The kidney filters per day: 150-200 liters of blood 500-600 grams of sodium Urinary excretion is: 1-2 liters of fluid 5 grams of sodium 70-80 % 20-25% 5-10% 1% 0.5-1% Renal Salt Reabsorption Intravascular Volume Volume Delivery to Heart Cardiac Output Systemic Vascular Resistance Essential Hypertension Vascular compliance Systolic (SBP) Diastolic (DBP) 24-h BP Profile Typical College Student Time of day 22:00 02:00 06:00 10:00 14:00 Blood pressure (mm Hg) 180 160 140 120 100 80 AwakeningSleepAwake Awake SBP DBP Hypertension in the Elderly BP levels vary with age SBP rises continuously DBP rises until 6th decade then tends to fall These changes are largely due to aortic stiffening 160 140 120 100 80 60 1524 2534 3544 4554 5564 6574 7584 8599 Age Group (y) SBP DBP Hypertension affects 1/4 adults living in industrialized countries and is associated with increased risk of stroke, renal failure, heart failure and coronary heart disease. Systolic BP Diastolic BP Normal 140 mm Hg 90 mm Hg Normal BP versus Hypertension 30% to 60% of the blood pressure variability in the general population is determined by genetic factors. Robert Platt George Pickering Pseudohypoaldosteronism, type I ENaC, a, b, g Pseudohypoaldosteronism, type IIA 1q31-42 Pseudohypoaldosteronism, type IIB PRKWNK4 Pseudohypoaldosteronism, type IIC PRKWNK1 Hypertension-Brachydactyly 12p11-12 Liddles syndrome ENaC b and g subunits Gitelmans syndrome SLC12A3 Bartters syndrome NKCC2, ROMK, CLCNKB Adrenal hyperplasia CYP11B, CYP17A1 Glucorticoid-remediable aldosteronism CYP11B1, CYB11B2 Apparent mineralocorticoid excess HSD11B2 Monogenic Forms of Human Hypertension / Hypotension Molecular Mechanism of Human Hypertension R.P. Lifton, A.G. Gharavi, and D.S. Geller, Cell 104(4); 545-556 Rare monogenic Mendelian forms of hyper / hypotension are caused by mutations in genes that regulate renal sodium handling Renal Salt Reabsorption Cardiac Output Systemic Vascular Resistance Monogenic Forms of Hypertension Susceptibility Genes for EH = Monogenic HTN Genes? Effect of Westernization on BP Diet Activities Growth and development Lifestyle Environmental exposures Diet: Salt Paleolithic Modern 500-700 mg 3,000-7,000 mg Urinary sodium (g) % HTN 0 3 6 Threshold ? 30 20 10 0 Defenses Hypotheses About Effect of Westernization on BP “Fight or Flight” Heightened Defense Reaction Heart rate Blood pressure distribution of blood flow Renal sodium retention Paleolithic Modern Hypertension With such a complex system controlling blood pressure, effects of mutation in one gene may not result in phenotypic difference Multiple mutations or gene variants may be necessary to affect homeostasis Correct environmental conditions may be necessary to affect homeostasis Genomewide linkage analyses of hypertension-related traits in human Over 35 publications Vary in study design and power Samples: US Whites, US Blacks, Chinese, Finnish, Mexican American, Nigerians Phenotypes: SBP, DBP, PP, hypertension status, age of onset, longitudinal BP change No region consistently demonstrated significant linkage Evidence of linkage found in some regions in multiple studies: 1q, 2p, 3p, 6q, 7q, 12q, 15q, 17q, 18q, 19p Evolutionary Conservation of Genomes Many genes have been conserved with respect to function and sequence across evolution Genome organization also tends to be conserved across relatively close species, i.e. large segments of chromosomes have remained intact in mammalian species Mapped, orthologous genes allow for the identification of conserved segments and the generation of comparative maps What makes a good genetic model? 1. Characteristics of the clinical picture No model can match the complete clinical picture, as no single patient reflects the entire clinical spectrum. 2. Inbred (homozygous through-out the genome) Reduced heterogeneity: genetics and etiology 3. Physiologically and pathologically well characterized. 4. Amenable to biochemical, physiological, pharmacological, and genetic studies. Comparative Genomics and Gene Identification PKD Linkage Human chromosome 6 Linkage Rat chromosome 9 Human and Rat Autosomal Recessive Polycystic Kidney Disease PKD PKDH1 Gene in Human and Rat Ideal Cross SS BN Control F1 Intercross Frequency MAP (mmHg) BN SS P0 F2 F1 Distribution of MAP in Male Rats on High Salt Chromosomal Segregation P0 F1 F2 X X New Target Regions for Human Hypertension via Comparative Genomics. Genome Research Vol. 10(4), 473-482, April 2000 Monica Stoll, Anne E. Kwitek-Black, Allen W. Cowley Jr., Eugenie L. Harris, Stephen B. Harrap, Jos E. Krieger, Morton P. Printz, Abraham P. Provoost, Jean Sassard, and Howard J. Jacob Rat Models for Genetic Hypertension SHR x WKY SHR x DNY SHR x BN GH x BN SS x BN LH x LN Spontaneously Hypertensive Rat (SHR) High blood pressure Cardiovascular disease Genetically Hypertensive Rat (GH) Hypertension, cardiac hypertrophy Vascular disease, not salt-sensitive Dahl Salt-Sensitive Rat (SS) Salt-sensitive hypertension Hyperlipidemia, insulin resistance Lyon Hypertensive Rat (LH) Mild hypertension, hyperlipidemia Fawn-hooded Hypertensive Rat (FHH) Systolic hypertension Renal failure FHH x ACI Blood Pressure Phenotypes 27 blood pressure phenotypes Baseline Blood Pressure Maximal Response MAP, DBP, SBP, PP MAP, DBP, SBP, PP after salt-load Drug Challenges Delta BPs Linkage Analysis for Blood Pressure QTLs Genome scans in 7 intercrosses representing independent model for genetic hypertension 200-300 SSLP markers 10-20 cM spacing 57- 390 animals Linkage analysis using MAPMAKER/QTL computer package LOD score 2.8 suggestive LOD score 4.3 significant QTL #1 QTL #2 QTL #3 QTL cluster Drop of 1.6 LOD units = 95% confidence interval Analysis of QTL Clustering QTLs identified in Rat LOD score 4.3 13 LOD score 2.8-4.3 44 LOD score 2.5-2.8 11 68 blood pressure QTLs total 13 QTL clusters total 7 QTL clusters 2 or more crosses 6 QTL clusters within one cross 10 single QTLs Baseline BP 2 Max. response 7 MAP, DBP, SBP, PP 19 Salt MAP, DBP, SBP, PP 22 Drug challenge 7 Delta BP 11 Human chromosome 22 and its homologies to rat chromosomes 11, 20, 6, 14 and 7 VC-MAP : Bioinformatics-Tool for comparative maps Stoll et al., Genome Research 2000 Kwitek et al. Genome Research 2001 36 syntenic regions in human Coverage of human genome in cM: 800 cM (24%) 68 rat blood pressure QTLs = 13 QTL clusters and 10 single QTLs Coverage of rat genome in cM: 500 cM (31%) Comparative mapping Stoll et al., Genome Research 2000 Chr.1 Chr.2 51,52,53,54 30,31,32,33,38 34,35,36,37 45,46,47,48 13,14,15,16 17,18,19 20,21,22,23, 24,25,26 Mansfield et al. Krushkal et al. 39,40,41,42 20,21,22,23, 24,25,26 51,52,53,54 27,28,29 13,14,15,16 17,18,19 Chr.3 Chr.4 Predicted hypertension susceptibility loci in the human genome Stoll et al., Genome Res. 2000 Mouse Rat Family Blood Pressure Program (FBPP) 1995-2000:12,041 subjects genotyped GenNet GENOA HyperGEN SAPPHIRe FBPP 4 networks # subjects # families African American Maywood, IL 816 289 Non-Hispanic White Tecumseh, MI 1,010 303 8 BP-related linkage peaks with max. lod score 2 Comparative Genomics: Convergence of Genetic Evidence of BP-regulating Loci from Human, Rat, and Mouse Studies QTLs from multiple hypertensive and normotensive strains Mouse QTLs from multiple hypertensive and normotensive strains Rat Regions harboring BP-related loci identified by multiple genome-wide linkage scans Human Human 1q23-q32 homologous region harbors blood pressure QTLs in rat and mouse 1q Mouse Rat NHLBI FBPP, GenNet NHLBI Family Heart Study Finnish Twin Cohort Study Human C57BL/6J x A/J SWR/J x C3H/HeJ SHR x WKY SS x BN, GH x BN LH x LN Human: Perola, et al, 2000, Hunt et al. 2002; Rat: Stoll et al, 2000; Mouse: Sugiyama, et al, 2001, Dipetrillo, et al, 2004 Chromosome 1q linkage region Positional Hypertension Candidate Genes Based on Function and Expression I. Salt Transport: REN ATP1B1 CACNA1E CACNA1S II. Signal Transduction: ADORA1 ET(B)R-LP-2 SAC III. Vascular System: ANGPTL1 SELE SELL SELP IV. Lipid Metabolism SOAT1 V. Expression in Kidney: NPHS2 NIBAN VI. G-Protein Coupled Receptors RE2 GPR25 GPR52 VII. Regulator of G-protein Signaling RGS1, RGS2 RGS4, RGS5 RGS8, RGS13 RGS16, RGS18 VIII. Protein Phosphatases PPP1R12B PTPN7 PTPRC Potential Hypertension Candidate Genes Based on Location, Function and Expression I. Salt Transport: REN ATP1B1 II. Signal Transduction: ADORA1 III. Vascular System: SELE, SELL SELP IV. Lipid Metabolism V. Expression in Kidney: NPHS2 VI. G-Protein Coupled Receptors VII. Regulator of G-protein Signaling RGS4, RGS5 VIII. Protein Phosphatases Chromosome 1q linkage region RGS5, ATP1B1, and SELE are independently associated with SBP and DBP Family-Based Association Test (FBAT) P-values DBP SBP Three novel essential hypertension susceptibility candidate genes in 1q linkage region RGS5 = Regulator of G Protein Signaling 5 Expressed in cardiovascular tissue Involved in the expansion of vascular tree in early embryogenesis ATP1B1 = Beta Subunit of Na-K Transporting ATPase Provide the driving force for Na re-absorption in kidney Regulation of Na / Ca exchange and excitability in heart SELE = E-Selectin, endothelial specific adhesion molecule Is a marker of endoth