HTA_génétique_sanaa0401

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Genetics of human hypertension

Jean-Louis GEORGES, MD

Versailles Hospital and INSERM U525, Paris, France

Cardiovascular Epidemiologic and Molecular Genetics

General Secretary ofFrench Yemeni Medical Association


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Italian-French-Yemeni Medical

Friendship

Pr Mancioli

Taiz, Gumhuri Hospital, 60s

Dr Viallard


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Italian Doctors in Taiz

1950-70

Dr Bucci : surgeon

Dr Repetto : surgeon

Dr Paparoni : surgeon

Dr Horn : neurologist

Dr Merighi : biologist

Dra Ianello : biologist

Dr Resucci : radiologist

Dr Mancioli : internist and

cardiologist

Dr Parinello : cardiologist

Dr Severino, Sunicci,


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advances and pitfails


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- Despite a comprehensive knowledge of physiologic systems involved in BP

regulation, and the well-established role of environmental factors (diet,

lifestyle), the pathogenesis of essential hypertension remains largelyunknown

- The difficulty in defining the primary causes of hypertension from physiological

or epidemiological studies alone has motivated the application of genetic

approaches to hypertension

- The influence of genetic factors is attested by the results of family studies, twin

studies, adoption studies as well as the existence of rare Mendelian forms of

hypertension or hypotension

-Identification of genes involved in blood pressure regulation would help tounderstand primary physiologic mechanisms and to identify potential targets for

therapeutic intervention



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Lack of specificity of the phenotype : quantitative BP ? hypertension (threshold ?

pre-treatment BP levels ?

Multifactorial etiology

Relatively low heritability (h2 = 15-40% for BP)

No major gene with drastic effect (e.g. loss of function) except for rare Mendelianforms

Several genes with modest quantitative effect within the range of normal

variations

Most of the susceptibility genes to common diseases do not have a primary

etiological role in the predisposition to disease, but rather act as responsemodifiers to exogenous factors (stress, diet, lifestyle, obesity, drug intake )

Difficulties encountered in the genetic dissection of hypertension


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Linkage studies: - parametric methods (lod-score) for Mendelian forms

- non parametric methods (sib-pairs) for common forms

Association studies: - candidate genes (based on pathophysiological

knowledge)

- whole-genome (dense maps of anonymous markers)

Animal models: - inbred and congenic strains

- genetically engineered animals

Different approaches for the genetic investigation of hypertension


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Renin-angiotensin-aldosterone system AGT, ACE, renin, AGTR1,

CYP11B2, 11HSD2

Epithelial sodium channel SCNN1A, SCNN1B, SCNN1G

Cathecholaminergic/adrenergic function ADRA1B, ADRA2A, ADRB1,

ADRB2, GNB3

Kallikrein-kinin system KLK1, BDKRB2

Endothelin system ET1, ETA, ETB

Extracellular matrix Collagen, Elastin

Miscellaneous -adducin, TGF-, eNOS, SAHprostacyclin synthase, IGF-1, ANP

glucocorticoid receptor

Candidate genes for human hypertension


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Evidence for a role of the AGT gene in hypertension Pathophysiology (key role of the RAS in vascular volume homeostasis)

Linkage ofAGTgene with hypertension in sib-pairs

Association of theAGT/T235M polymorphism with hypertension

Intermediate phenotype (plasma AGT levels)

Engineered animal models (0 to 4 copies of theAGTgene) demonstrating a causal link

between increasedAGTexpression and elevated BP

Functionality of a promoter polymorphism (A-6G) which affectsAGTbasal transcription

rates (decrease of 20%-50%)

However Lack of consistent reproducibility among studies

Weak genetic effect (OR 1.2), clinical significance ? Ethnic differences in allele frequency, linkage disequilibrium pattern and effect of

polymorphisms of theAGTgene

Other polymorphisms of theAGTgene which might be functional (nucleotide 67 ?)

Angiotensinogen gene and hypertension


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Endothelin-1 (ET-1) gene and blood pressure

ET-1 is a powerful vasoconstrictor and peptide produced byendothelial and SMC cells

ET-1 is found in a variety of tissues where it acts as a modulator of

vasomotor tone, cell proliferation, and hormone production

There is accumulating evidence from experimental and clinicaldata that ET-1 plays an important role in the pathophysiology of

the vascular system and in particular in the hypertensive process

Long-term treatment by an endothelin-receptor antagonist in

hypertensive patients results in blood pressure reduction


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Effect of ET1/K198N polymorphismon blood pressure levels in the ECTIM study

1 0 0

1 1 0

1 2 0

1 3 0

1 4 0

6 0

7 0

8 0

9 0

1 0 0

SBP (mm Hg) DBP (mm Hg)

Genotype KK KN NN KK KN NN


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Regression slopes of systolic blood pressure levels on BMIaccording to the ET1/K198N genotype

1 0 0

1 2 0

1 4 0

1 6 0

1 8 0

1 5 2 0 2 5 3 0 3 5 4 0 4 5

B M I (k g /2)

SBP(mmH

g)

Lys/Lys

Asn+

Interaction genotype*BMI: p < 0.001


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110

120

130

140

150

26

BMI (kg/m2)

SBP(m

mHg)

Lys/Lys

Asn+

p = 0.15 p = 0.009

Effect of ET1/K198N polymorphismon systolic blood pressure according to level of BMI


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The ET1 gene in human hypertension The interaction with BMI has been further confirmed in two independent studies

In vitroexperiments have shown that the ET1/K198N polymorphism was relate

to change in vascular reactivity

Plasma ET-1 concentrations is raised in obesity-associated hypertension

Weight loss due to diet has been shown to be accompanied by a marked

decrease of ET-1 levels in both obese and non-obese subjects

Obesity might be a factor that enhances the expression of the ET1 gene,

possibly through an up-regulation by insulin, which is known to stimulate ET-1

production

BMI is a crucial factor to account for studying the role of the ET1 gene


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Animal models for genetic dissection of hypertension Bred strains of animals with divergent BP (identification of unknown genes

Inbred strains: detection of chromosomal regions containing QTLs controllingBP by linkage analysis of markers covering the whole genome (20- to 35-cM

intervals)

Congenic strains: fine mapping of QTLs (


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Where we are

Considerable progress has been accomplished in the identification of mutations causing

rare Mendelian forms of hypertension

Results in the area of essential hypertension are more disappointing. No gene with a

substantial effect has been so far identified

What are the improvements to be expected in the near future

More homogeneous definition of subsets of hypertension (low-renin)

Intermediate biochemical or physiological phenotypes (circulating levels of proteins,renal blood flow, glomerular filtration rate, sodium-lithium countertransport, intracellular

sodium content, urinary sodium excretion, renovascular response to AngII infusion)

Analysis of groups of genes operating in a given network (systems)

High-throughput technology (transcriptomics, proteomics, metabonomics)

Genome resources (gene sequences, dense maps of markers)

Comparative genomics

Statistical analysis (haplotypes, genetic systems)

Better accounting for environmental factors

Conclusion and perspectives

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