1、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 pe
2、r day:150-200 liters of blood500-600 grams of sodiumUrinary excretion is:1-2 liters of fluid5 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,Sy
3、stolic (SBP),Diastolic (DBP),24-h BP Profile Typical College Student,Hypertension in the Elderly,BP levels vary with age SBP rises continuously DBP rises until 6th decade then tends to fallThese changes are largely due to aortic stiffening,160 140 120 100 80 60,1524 2534 3544 4554 5564 6574 7584 859
4、9,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.,Normal BP versus Hypertension,30% to 60% of the blood pressure variability in the general population is
5、 determined by genetic factors.,Robert Platt,George Pickering,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 i
6、n 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,D
7、iet: Salt,Paleolithic Modern500-700 mg 3,000-7,000 mg,Urinary sodium (g),% HTN,0 3 6,Threshold ?,3020100,Defenses,Hypotheses About Effect of Westernization on BP,“Fight or Flight”,Heightened Defense Reaction,Heart rateBlood pressure distribution of blood flowRenal sodium retention,Paleolithic Modern
8、,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 l
9、inkage 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 changeNo region consistently demonstra
10、ted 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
11、 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 pictu
12、reNo 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 etiology3. Physiologically and pathologically well characterized.4. Amenable to biochemical, physiological, p
13、harmacological, 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,
14、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,
15、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) Hyperten
16、sion, 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,Blo
17、od Pressure Phenotypes,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 sig
18、nificant,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 wi
19、thin 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,www.rgd.mcw.edu,VC-MAP : Bioinformatics-Tool for comparative maps,Stoll et al., Genome
20、 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
21、,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
22、. 2000,Mouse,Rat,Family Blood Pressure Program (FBPP) 1995-2000:12,041 subjects genotyped,GenNet,GENOA,HyperGEN,SAPPHIRe,FBPP 4 networks,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,Hum
23、an 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;
24、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: RENATP1B1 CACNA1ECACNA1SII. Signal Transduction:ADORA1 ET(B)R-LP-2SAC III. Vascular System: ANGPTL1SELESELLSELPIV. Lipid Meta
25、bolismSOAT1,V. Expression in Kidney: NPHS2NIBANVI. G-Protein Coupled ReceptorsRE2 GPR25GPR52VII. Regulator of G-protein SignalingRGS1, RGS2RGS4, RGS5RGS8, RGS13RGS16, RGS18VIII. Protein PhosphatasesPPP1R12B PTPN7PTPRC,Potential Hypertension Candidate Genes Based on Location, Function and Expression,
26、I. Salt Transport: RENATP1B1 II. Signal Transduction: ADORA1 Vascular System: SELE, SELLSELPIV. Lipid Metabolism,V. Expression in Kidney: NPHS2VI. G-Protein Coupled ReceptorsVII. Regulator of G-protein SignalingRGS4, RGS5VIII. Protein Phosphatases,Chromosome 1q linkage region,RGS5, ATP1B1, and SELE
27、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 5Expressed in cardiovascular tissueInvolved in the expansion of vascular
28、tree in early embryogenesisATP1B1 = Beta Subunit of Na-K Transporting ATPaseProvide the driving force for Na re-absorption in kidneyRegulation of Na / Ca exchange and excitability in heart SELE = E-Selectin, endothelial specific adhesion moleculeIs a marker of endothelial function In hypertensives,
29、serum levels of SELE is elevated and endothelium-dependent vasodilation is impaired.,Population-based effect size of RGS5, ATP1B1 and SELE susceptibility alleles,Estimated Marker Effect Size with age & sex adjusted SBP (mmHg) using PBAT (P-value 0.05).,The effects of RGS5, ATP1B1 and SELE alleles ar
30、e additive,Locus A Locus BA, a B, b,# 0 AA, BB1 Aa, BBAA, Bb2 Aa, Bbaa, BBAA, bb3 aa, BbAa, bb4 aa, bb,P= 0.000006,P= 0.04,95 352 275 4152 470 673 266,# samples,0,1,2,3,4,5,6,7,8,9,1,0,Relative Phenotypic Effect,# of alleles,Few,Many,Mendelian,Rare Large effect,Complex,Common Smaller effect,Mono(oligo)genicContext-independentGenetic transmission knownDistinctive biochemistryKidney genes only?,PolygenicContext-dependentGenetic transmission complexMultiple pathwaysKidney and Vascular genes,Searching for Genes for Hypertension,Mendelian,Essential,
