the genetics revolution€¦ · il23r as, ibd, ps il12b as, ibd, ps, ms il12rb2 as, ibd stat3 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,
Princess Alexandra Hospital,Brisbane, Australia.
Lessons learnt:• Current practice in rheumatology was of uncertainbenefit• Much more research was required to make progress.
• At risk
• Presymptomatic Disease
FUTURE?
• Symptomatic Early Disease
• Established Disease CURRENT
Sequencing – the next revolution
1977 1993 1998 2004 2009100bp 1000bp 96000bp 30Gb 600Gb
• Whole exome scan currently costs <1 MRIscan
•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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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
D1113GC1117GC1117Y(2)G11127SN1131YR1137P(2)C1153Y
E1200G3623delGC1223Y(2)
3839-1G>TN1282SC1320SA3963Gdel Ex 31(2)
N1382S
C1497SC1513R
C1610G4857delA
5137ins4C1721Y5241ins5B
5672del117bN1893KG1910VC1928R C1977Y
R1997X
6163+2del16bR2057XR2057QY2062XC2099W6314del66C2111YY2113X
D2127EN2144SC2151W
C2258RQ2262XI2269TR2282W(2)E2447K
6513delT
7456del366C2489RC2511RC2522SR2680C(2)
C2686F8052-2A>G8051+5G>A
G4459+1A
R122C(2)C129Y
W217GR240C
1604delTR545C(3)N548IR565X
E616GR627C (2)
D723AY746C2293+2T>CC750G
C816SC832Y
R861XC862RC890R
C926R
G1013R(4)K1023NV984IC996R
3208+5G>TC1032YC1039YK1043RI1048T1048del IC1053RC1055G1058insC3174insTGC3192delA3445insCdel Ex 25
I1071SD1072GE1073DE1073K(3)C1074RS10779C1086W
D1113GC1117GC1117Y(2)G11127SN1131YR1137P(2)C1153Y
D1155N3464del17C1166YR1170H (2)C1171WN1173KI1175TC1182SC1182W
C1242YN1246SC1249SE1260X 3965-2A>G
del Ex 32 (2)A1337PN1341S4011delT4020delC
D1404YP1424AC1429S
C1589FE1605X
G4943-1CC1663RV1667I
C1818YE1823XR1832CP1837S
D1930N5788+5G>A(3)5898delA
D2127EN2144SC2151W
6739+1G>CC2221SC2232Y
C2307S6997+1G>A
7205-2A>G(2)
D2607GE2610KG8051+1AH2623PN2624SG2627R
R2680C(2)C2686F8052-2A>G8051+5G>A
R2726W8236delGAW2756XR2776X8525del5
755del8b2399delC C2017R
L2309VI2023T
I2585TC2577R
C423G
C2535X
COOHNH2
N- and C-termini
hybridEGF-like proline-rich TBcbEGF-like
WES in Marfans Disease and OsteogenesisImperfecta
• We identified 13/13 mutations in OI and 11/11 mutationsin MFS
– Non-synonymous SNPs and small indels (up to 10bp)
• Costs were ~%50 lower than current commercialsequencing
• Enables– antenatal diagnosis
– Diagnostic certainty
– Identification of phenocopies e.g MODY.
• We identified 13/13 mutations in OI and 11/11 mutationsin MFS
– Non-synonymous SNPs and small indels (up to 10bp)
• Costs were ~%50 lower than current commercialsequencing
• Enables– antenatal diagnosis
– Diagnostic certainty
– Identification of phenocopies e.g MODY.
Sequencing Based Microbial Profiling
• Allows species level sensitive and specificprofiling of viral, bacterial and fungalpathogens even culture free
• Potential clinical and research applicationsextensive
• Cost is low– 16S rRNA sequence lab cost in research is
currently $65.
• Allows species level sensitive and specificprofiling of viral, bacterial and fungalpathogens even culture free
• Potential clinical and research applicationsextensive
• Cost is low– 16S rRNA sequence lab cost in research is
currently $65.
Community profiling using 16SrRNA
Mary-Ellen Costello, submited, ISME Journal 2013
Lena Peltonen-Palotie (RIP)
• Head of Wellcome TrustSanger centre
• Died of metastaticmalignancy withunknown primary
• The first cancer genomesequenced– Guided her
chemotherapy regimen
• Head of Wellcome TrustSanger centre
• Died of metastaticmalignancy withunknown primary
• The first cancer genomesequenced– Guided her
chemotherapy regimen
Cancer Sequencing
• Already extensively used in blood cancers inclinical setting
• Increasing relevance in other cancers, and willbecome standard of care for seriousmalignancies
• Establishing this in clinical practice will take alot of work!
• Already extensively used in blood cancers inclinical setting
• Increasing relevance in other cancers, and willbecome standard of care for seriousmalignancies
• Establishing this in clinical practice will take alot of work!
The Genomics Revolution
• Technological advances in genomics haverevolutionised research and are ready fortranslation into clinical practice.
• Many areas of clinical practice will be affected,not just heritable disease investigation.
• Implementation of genomics into clinicalpractice requires further research and plannedroll out to maximise the potential benefit.
• Technological advances in genomics haverevolutionised research and are ready fortranslation into clinical practice.
• Many areas of clinical practice will be affected,not just heritable disease investigation.
• Implementation of genomics into clinicalpractice requires further research and plannedroll out to maximise the potential benefit.