Update on Genetics in Hypertension

Christian Delles

BHF Glasgow Cardiovascular Research CentreInstitute of Cardiovascular and Medical SciencesUniversity of Glasgow

Cardiovascular Continuum

Twin studies, pedigree studiesBP variability attributable to all genetic factors: 25% to 65%

Heritability (h2)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 ContinuumDistribution of Blood Pressure in the Population

Analysis of the Third National Health and Nutrition Examination Survey, 1988-1994

Cardiovascular ContinuumThe Platt vs Pickering Debate

George Pickering Robert Platt

National Portrait Gallery, London

Cardiovascular ContinuumThe Platt vs Pickering Debate

Delles C. Genetics of Hypertension. Future Medicine 2013

Pickering Platt

Monogenic Traits

Deutsche Bundespost

Thomas SR 2009

Monogenic Forms of Hypertension

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 ContinuumDistribution of Blood Pressure in the Population

Analysis of the Third National Health and Nutrition Examination Survey, 1988-1994

Cardiovascular ContinuumDefinition of Hypertension

ESH/ESC Guidelines. J Hypertens 2013

Cardiovascular ContinuumQualitative vs Quantitative Trait

139/80mmHg

141/80mmHg

100/60mmHg

200/120mmHg

Quantitative trait

139/80mmHg

141/80mmHg

140/90 mmHg

Qualitative trait

Normotensive Hypertensive

Study Designs

Delles C. Genetics of Hypertension. Future Medicine 2013

Cardiovascular ContinuumBlood 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 ContinuumAmbulatory 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 ContinuumPAMELA Study

Padmanabhan S et al. J Hypertens 2010

Monogenic Traits

Candidate gene studies

Cardiovascular ContinuumRenin-Angiotensin-Aldosterone System

Rad A 2006

Cardiovascular ContinuumCYP11B2 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

Illumina Affymetrix

Wellcome Trust Case-Control Consortium

WTCCC. Nature 2007

WTCCC. Nature 2007

Cases and Controls in WTCCC

Collection 58C UKBS BD CAD CD HT RA T1D T2D No Samples 1480 1458 1868 1926 1748 1952 1860 1963 1924 % Male / %Female

50/50 48/52 37/63 79/21 39/61 40/60 25/75 51/49 58/42

Eastern 11 12 3 10 25 16 20 17 26 E&WRidings 9 6 1 26 0 1 10 10 0 London 8 5 7 2 22 18 2 4 10 Midlands 9 12 24 6 1 4 16 6 1 Northern 8 10 9 10 20 3 3 8 15 North Midlands

7 3 6 15 1 13 8 7 5

Northwestern 11 11 3 8 1 3 19 11 3 Southeastern 7 11 5 4 1 8 2 3 2 Southern 8 8 6 4 14 5 12 8 18 Southwestern 8 9 6 6 1 3 1 9 19 Scotland 10 9 10 5 14 24 3 10 0 Wales 5 5 21 5 0 1 1 7 1

WTCCC. Nature 2007

Crohn’s Disease

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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