cardiovascular continuum sampling from extremes padmanabhan s et al. plos genet 2011
TRANSCRIPT
Cardiovascular ContinuumSampling from Extremes
Padmanabhan S et al. PLoS Genet 2011
Cardiovascular ContinuumSampling from Extremes
Padmanabhan S et al. PLoS Genet 2011
Cardiovascular ContinuumUMOD Gene
Padmanabhan S et al. PLoS Genet 2011
Cardiovascular ContinuumUMOD: a Novel Hypertension Candidate Gene
Padmanabhan S et al. PLoS Genet 2011
Monogenic TraitsUMOD Gene
Köttgen A et al. Nat Genet 2009
Monogenic Traits
Padmanabhan S et al. Hypertension 2014
Uromodulin and Blood Pressure
Monogenic TraitsBlood Pressure in Umod+/+ (WT) and Umod−/− (KO)
Graham LA et al. Hypertension 2014
Monogenic Traits
Graham LA et al. Hypertension 2014
Umod+/+ Umod-/-
Salt Sensitivity in Umod+/+ (WT) and Umod−/− (KO)
Monogenic Traits
Graham LA et al. Hypertension 2014
Pressure Natriuresis Curves
Monogenic Traits
What have we learned from GWAS?
Monogenic Traits
New Targets?
What Have we Learned from GWAS?
NHGRI GWA Catalogwww.genome.gov/GWAStudieswww.ebi.ac.uk/fgpt/gwas/
Published Genome-Wide Associations through 12/2012Published GWA at p≤5X10-8 for 17 trait categories
Monogenic TraitsUromodulin?
Padmanabhan S et al. Hypertension 2014
Monogenic Traits
Risk Prediction/Stratification?
What Have we Learned from GWAS?
Monogenic TraitsRisk Prediction?
Padmanabhan S et al. Trends Genet 2012
Monogenic Traits
No direct genetic linksbetween CKD and Hypertension
(Exception: UMOD)
What Have we Learned from GWAS?
Monogenic Traits
Current and future strategies
Thomas SR 2009
Monogenic Forms of Hypertension
Cardiovascular ContinuumDetection of Rare/Private Mutations
Lifton RP et al. Nat Genet 2008
Cardiovascular ContinuumDetection of rare/private mutations
Lifton RP et al. Nat Genet 2008
Rare (private) mutations could
explain the "missing heritability",
i.e. heritability that is not explained
by common genetic variants.
"Missing Heritability"
Systems Biology and "Omics"
DNA
mRNA
Protein
Metabolitessmall molecules
Proteomics
Metabolomics
Genomics
TranscriptomicsmiRNAs
Monogenic Traits
DNA Methylation Histone Modification
Non-coding RNAs, microRNAs
Epigenetics
Friso S et al. Translat Res 2014
Cardiovascular ContinuumCardiovascular Continuum
Dzau V et al. Circulation 2006
Risk factors
Oxidative andmechanical stress
Inflammation
Early tissue dysfunction
Atherothrombosis andprogressive CV disease
Tissue injury(MI, stroke, renal
insufficiency,peripheral arterial
insufficiency)
Pathologicalremodeling
Target organ damage
End-organ failure(CHF, ESRD)
Death
Altered gene expression
Altered protein expression
Genome
BHF Glasgow Cardiovascular Research Centre
Log Rank (Mantel-Cox) P=0.021
CAD Score: Survival Analysis in ASCOT
< Mean> Mean
Brown C et al. SCF 2013
Collagen alpha-1(II) chain
10 100 1000 10000 100000
0
50
100
150
200
250
ID:35339
eGF
R (
MD
RD
) m
l/min
/1,7
3m²
Collagen alpha-1(III) chain
1 10 100 1000 10000 100000 1000000
0
20
40
60
80
100
120
140
160
180
ID:156878
eGF
R (
MD
RD
) m
l/min
/1,7
3m²
Roscioni SS et al. Diabetologia 2013
Normo Micro Micro Macro
Prediction of Diabetic Nephropathy
Roscioni SS et al. Diabetologia 2013
Normo Normo Normo Micro Micro Micro Micro Macro
Prediction of Diabetic Nephropathy
WTCCC
Why did WTCCC find "hits" for many diseases, but not for hypertension?
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
If 5% of controls would meet the definition of cases, then loss of power of the GWAS is approximately the same as that due to
the reduction of sample size by 10%.
"Caseness" of Controls
WTCCC. Nature 2007
Challenges
• Possible caseness of controls• Accurate definition of the phenotype• Precise assessment of the phenotype• Multiple pathways, multiple genes
What can be done?
Cardiovascular ContinuumIncreasing the Sample Size
OR=1.5
CHARGE Consortium
Levy D et al. Nat Genet 2009
CHARGE Consortium: 29,136 Subjects
Levy D et al. Nat Genet 2009