The Genetics Revolution Genomics and the Future of Medicine Future of Medicine Matt Brown Director | Professor of Immunogenetics, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia. [email protected]
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The Genetics Revolution€¦ · IL23R AS, IBD, PS IL12B AS, IBD, PS, MS IL12RB2 AS, IBD STAT3 IBD, PS, MS Di Cesare et al, Jour Invest Dermatology 2009) JAK2 IBD CARD9 AS, IBD ...
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The Genetics RevolutionGenomics and theFuture of Medicine
The Genetics RevolutionGenomics and theFuture of Medicine
Matt BrownDirector | Professor of Immunogenetics,
University of Queensland Diamantina Institute,Translational Research Institute,
•Whole genome sequence will cost• <$1000 within ~3 years• <1 MRI scan within 5 years.
UQ Centre for Clinical Genomics
Genetics and Medicine• Genes determine risk of disease
– Therapies targeting pathways identified by geneswill reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
• Genes determine risk of disease– Therapies targeting pathways identified by genes
will reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
Published GWA Reports, 2005 – 6/2012To
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Calendar QuarterThrough 6/30/12 postings
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2005 2006 2007 2008 2009 2010 2011 2012
IL-23 SignallingGene Diseases
IL23R AS, IBD, PS
IL12B AS, IBD, PS, MS
IL12RB2 AS, IBD
STAT3 IBD, PS, MS
Di Cesare et al, Jour Invest Dermatology 2009)
STAT3 IBD, PS, MS
JAK2 IBD
CARD9 AS, IBD
PTGER4 AS, IBD
TYK2 AS, IBD, PS, MS, RA,T1D, PBC
Osteoporosis Drug Targets and GeneticsDrug Class Drug Target Monogenic
ConditionCommon variantassociation
Bisphosphonates FarnesylPyrophosphate No No
SERMs Estrogen Receptor No Yes
Estrogen Estrogen Receptor No YesEstrogen Estrogen Receptor No Yes
DKK-1 Inhibitors DKK-1 No Yes
Cathepsin-K inhibitors Cathepsin-K Yes No
Denosumab RANKL Yes Yes
Sclerostin inhibitors Sclerostin Yes Yes
PTH analogues PTH receptor Yes Yes
Anti-sclerostinantibodies
Cathepsin Kantagonists
• Genes determine risk of disease– Therapies targeting pathways identified by genes
will reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
Genetics and Medicine• Genes determine risk of disease
– Therapies targeting pathways identified by geneswill reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
• Values of early diagnosis– Correct diagnosis for patient– Avoids harmful inappropriate treatments– Advent of anti-TNF agents means potential to retard
ankylosis.
0.5
0.6
0.7
0.8
0.9
1.0
TRUE
POSITIVE
RATE
0.0
0.1
0.2
0.3
0.4
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
TRUE
POSITIVE
RATE
FALSE POSITIVE RATE
MRI
0.5
0.6
0.7
0.8
0.9
1
TRUE
POSITIVE
RATE
B27 ALONE
0
0.1
0.2
0.3
0.4
0 0.2 0.4 0.6 0.8 1
TRUE
POSITIVE
RATE
FALSE POSITIVE RATE
B27-ERAP1-IL23R
MRI
• AUC genetic score 59%• AUC weight/age 75%
• Most diseases will not be predictable bygenetic testing– Exceptions include T1D, Alzheimer’s disease, male
coronary heart disease..
• 90% of individuals will be shown to be atabove average risk of at least one disease
• Most diseases will not be predictable bygenetic testing– Exceptions include T1D, Alzheimer’s disease, male
coronary heart disease..
• 90% of individuals will be shown to be atabove average risk of at least one disease
Science Transl Med, 2012
• Genes determine risk of disease– Therapies targeting pathways identified by genes
will reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
Genetics and Medicine
• Genes determine risk of disease– Therapies targeting pathways identified by genes
will reduce the risk of developing disease.
• Genetic tests can identify those who will getdisease.
• Genetic tests can predict those who will haveworse disease and those who will respondbest to treatments.
TNFRSF1A splice variants in AS and MS
The minor allele ofrs1800693 (MAF: 0.319)
TNFRSF1A
20
The minor allele ofrs1800693 (MAF: 0.319)
risk to AS
risk to MS
Associated with direct expression of anovel, soluble form of TNFR1 that canblock TNF akin to Etanercept
UQ Centre for Clinical Genomics
• Sequencing equipment– Four Illumina HiSeq2000 sequencers
• Each capable of sequencing 600Gigabases every 10 days
• Amounts to six 30x genomes every 10days per machine
• Per annum capacity currently >800genomes per annum.
– Two MiSeq sequencers• Run 5Gb sequence overnight
• Sequencing equipment– Four Illumina HiSeq2000 sequencers
• Each capable of sequencing 600Gigabases every 10 days
• Amounts to six 30x genomes every 10days per machine
• Per annum capacity currently >800genomes per annum.
– Two MiSeq sequencers• Run 5Gb sequence overnight
Translational Applications of Sequencing
• Providing definite genetic diagnosis of known monogenicdiseases– 1% of Australians have a clinically significant
monogenic disease– Enables appropriate follow-up/Rx of affected pts– Possibility of accurate antenatal screening.
• Diagnosis of genetic diseases of unknown aetiology• ?Improved prediction of common genetic diseases• Sequence based microbial profiling• Mutational screening for somatic diseases (e.g. cancer)
• Providing definite genetic diagnosis of known monogenicdiseases– 1% of Australians have a clinically significant
monogenic disease– Enables appropriate follow-up/Rx of affected pts– Possibility of accurate antenatal screening.
• Diagnosis of genetic diseases of unknown aetiology• ?Improved prediction of common genetic diseases• Sequence based microbial profiling• Mutational screening for somatic diseases (e.g. cancer)
248+1 G>AC111R
C166FC166SQ176X
C615RG1468TG1468+5AC476G
C587YC598W1836delAC661R
A705TC711Y
C816SC832Y
3208+5G>TC1032YC1039YK1043RI1048T1048del IC1053RC1055G1058insC3174insTGC3192delA3445insCdel Ex 25