Update on Genetics in Hypertension Christian Delles BHF Glasgow Cardiovascular Research Centre Institute of Cardiovascular and Medical Sciences University.

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Presentation transcript:

Update on Genetics in Hypertension Christian Delles BHF Glasgow Cardiovascular Research Centre Institute of Cardiovascular and Medical Sciences University of Glasgow

Cardiovascular Continuum Twin studies, pedigree studies BP variability attributable to all genetic factors: 25% to 65% Heritability ( h 2 ) Fraction of variation in disease susceptibility due to genetic factors: Systolic BP 15-40%, diastolic BP 15-30% Sibling recurrent risk ( s) Degree of elevated risk of disease for a sibling of an affected individual compared with a member of the general population: Hypertension around 1.2–1.5 Heritability Padmanabhan S et al. J Hypertens 2008

Cardiovascular Continuum Distribution of Blood Pressure in the Population Analysis of the Third National Health and Nutrition Examination Survey,

Cardiovascular Continuum The Platt vs Pickering Debate George PickeringRobert Platt National Portrait Gallery, London

Cardiovascular Continuum The Platt vs Pickering Debate Delles C. Genetics of Hypertension. Future Medicine 2013 PickeringPlatt

Monogenic Traits Deutsche Bundespost

Thomas SR 2009 Monogenic Forms of Hypertension

Padmanabhan S et al. Trends Genet 2012 … cont.

Monogenic Forms of Hypertension Padmanabhan S et al. Trends Genet 2012 … cont.

Padmanabhan S et al. J Hypertens 2008 The Platt vs Pickering Debate

Monogenic Traits Definition of the phenotype

Cardiovascular Continuum Distribution of Blood Pressure in the Population Analysis of the Third National Health and Nutrition Examination Survey,

Cardiovascular Continuum Definition of Hypertension ESH/ESC Guidelines. J Hypertens 2013

Cardiovascular Continuum Qualitative vs Quantitative Trait 139/80 mmHg 141/80 mmHg 100/60 mmHg 200/120 mmHg Quantitative trait 139/80 mmHg 141/80 mmHg 140/90 mmHg Qualitative trait NormotensiveHypertensive

Study Designs Delles C. Genetics of Hypertension. Future Medicine 2013

Cardiovascular Continuum Blood Pressure The measurement [of blood pressure] is likely the clinical procedure of greatest importance that is performed in the sloppiest manner. Norman Kaplan. Am J Hypertens 1998

Cardiovascular Continuum Ambulatory Blood Pressure Monitoring Precise assessment of blood pressure Better determinant of hypertension-related organ damage Detection of white coat hypertension Detection of masked hypertension

Cardiovascular Continuum PAMELA Study Padmanabhan S et al. J Hypertens 2010

Monogenic Traits Candidate gene studies

Cardiovascular Continuum Renin-Angiotensin-Aldosterone System Rad A 2006

Cardiovascular Continuum CYP11B2 and Hypertension Sookoian S et al. J Hypertens 2007

Monogenic Traits Genome wide association studies

Genomics Genomics is the study of an organism's entire genome. "Unbiased" (hypothesis-free) approach

Genome-wide Arrays IlluminaAffymetrix

Wellcome Trust Case-Control Consortium WTCCC. Nature 2007

Cases and Controls in WTCCC

WTCCC. Nature 2007 Crohn’s Disease -log P -value

WTCCC. Nature 2007

Global BPGen Newton-Cheh C et al. Nat Genet 2009

Global BPgen Study: 34,433 Subjects Newton-Cheh C et al. Nat Genet 2009

Global BPgen Study: 34,433 Subjects Newton-Cheh C et al. Nat Genet 2009

Relationship of SNPs to Blood Pressure Traits Newton-Cheh C et al. Nat Genet 2009

International Consortium for BP GWAS International Consortium for Blood Pressure Genome-Wide Association Studies. Nature 2011

200,000 Individuals: 16 Novel Loci International Consortium for Blood Pressure Genome-Wide Association Studies. Nature 2011

Monogenic Traits GWAS into the extremes of blood pressure