Upload
hoangbao
View
229
Download
5
Embed Size (px)
Citation preview
Human Genetics Impact on Clinical Practice in Lipidology
National Lipid AssociationNew Orleans
May 19th, 2016
Muredach Reilly MB MSColumbia University
Human Genetics Impact on Clinical Practice in Lipidology
Muredach Reilly MB MS
DISCLOSURE INFORMATION: None applicable.
UNLABELED/UNAPPROVED USE:ISIS-APOCIIIRx
• Review genetic and clinical concepts
• Summarize genomic discoveries in lipids and CHD
• Highlight causal lipid pathways in CHD
• Discuss novel genome-based therapeutics
Educational Objectives
• New discoveries: new targets & biology
• Causality and directionality
• Therapeutic translation
• Precision medicine
Genetics - Impact in Clinic
Traditional Risk Factors for CHD…
– Age– Male gender– Smoking– Hypertension– Diabetes mellitus – High LDL cholesterol / apoB lipoproteins– Low HDL cholesterol
explain only about 60-70% of early heart attacks
Coronary Disease is Influenced by Genetics
If your mother or father had early-onset cardiovascular disease, your risk of early heart disease is:
Men 3.2 times average
Lloyd-Jones, JAMA 2004
Women 2.9 times average
Genomic Discovery Strategies
50%
5%
0.5%
0.05%
Allele Frequency
Effect Size Strong Moderate Weak
Common variants
Rare variants/Mendelian
Low‐frequency variants
An Exomic View of the Genome(Exome-seq Identifies Low Frequency and Rare Variants
in Protein Coding Genes)
Genome
Exome
1-2% genome encodes protein coding genes (~20K) but ~80% of genome is functional
DNA Variants
Cardiovascular risk factorsLipids and other
Cardiovascular risk factorsCoronary disease and
atherosclerosis
New biologyNew therapeutic targets
??
DNA Variants
Cardiovascular risk factorsLipids and other
Cardiovascular risk factorsCoronary disease and
atherosclerosis
New biologyNew therapeutic targets
??
Mendelian Causes of Extreme High LDL-C Levels Helped Confirm the “LDL Hypothesis”
Freq
uency (%
)
LDL cholesterol 760 mg/dL (normal < 130 mg/dL)
Inherited Syndromes of Extremes of LDL-C: PCSK9 Mutations
Freq
uency (%
)
LDL‐C
Gain of function mutations in PCSK9
Loss of function mutations in PCSK9
Gene Locus GWAS SNP Disorder and lipid phenotypeABCA1 9q31.1 rs1883025 Tangier disease: low HDLABCG5 2p21 rs4299376 Sitosterolemia: high LDLABCG8 2p21 rs4299376 Sitosterolemia: high LDLAPOA1 11q23‐q24 rs964184 ApoA‐I deficiency: low HDLAPOA5 11q23 rs964184 ApoA‐V deficiency: high VLDL and chylomicronsAPOB 2p24 rs515135 Familial hypobetalipoproteinemia: low LDL
Familial defective ApoB‐100: high LDLAPOC2 19q13 rs4420638 Familial ApoC‐II deficiency: high chylomicronsAPOE 19q13 rs4420638 Familial dysbetalipoproteinemia: high VLDL remnants
and chylomicronsCETP 16q13 rs173539 Cholesteryl ester transfer protein deficiency: high HDLLCAT 16q22 rs2271293 Lecithin‐cholesterol acyltransferase deficiency (fish‐
eye disease): low HDLLDLR 19p13 rs6511720 Familial hypercholesterolemia: high LDL
LDLRAP1 1p36‐p35 rs12027135 Autosomal recessive hypercholesterolemia: high LDL
LIPC 15q22 rs10468017 Familial hepatic lipase deficiency: high VLDL remnants
LPL 8p21 rs12678919 Lipoprotein lipase deficiency: high chylomicronsMTTP 4q24 N/A Abetalipoproteinemia: low LDLPCSK9 1p32 rs11206510 Autosomal‐dominant hypercholesterolemia: high LDL
PCSK9 deficiency: low LDLSAR1B 5q31.1 N/A Chylomicron retention disease: low chylomicrons
Mendelian Lipid Disorders
LDL-C HDL-C TriglyceridesABCG5/8 HFE SORT1 ABCA1 HNF4A PDE3A ACSS2 GALNT2
ABO HMGCR ST3GAL4 ABCA8 IRS1 PGS1 AFF1 GCKR
ANGPTL3 HNF1A TIMD4 ADM KLF14 PLTP ANGPTL3 IRS1
APOA HPR TOP1 ANGPTL4 LACTB PPP1R3B ANKRD55 JMJD1C
APOB IDOL TRIB1 APOA LCAT SBNO1 APOA LIPC
APOE IRF2BP2 APOB LILRA/B SCARB1 APOB LPL
BRAP LDLR APOE LIPC SLC39A8 APOE LRP1
BTNL2 LDLRAP1 ARL15 LIPG STARD3 BTNL2 MLXIPL
CBLN3 LPA C6orf106 LPA TRIB1 CAPN3 MSL2L1
CETP MAFB CETP LPL TRPS1 CETP NAT2
CILP2 MOSC1 CITED2 LRP1 TTC39B CILP2 PINX1
CYP7A1 NPC1L1 CMIP LRP4 UBASH3B COBLL1 PLA2G6
DNAH11 OSBPL7 COBLL1 MACF1 UBE2L3 CTF1 PLTP
FADS PCSK9 DOCK6 MC4R ZNF648 CYP26A1 TIMD4
FRK PLEC1 FADS MLXIPL ZNF664 FADS TRIB1
GPAM PPP1R3B GALNT2 MMAB FRMD5 TYW1B
ZNF664Total Cholesterol
ERGIC3 EVI5 FUT2 RAB3GAP1 RAF1 SPTY2D1
Teslovich, et al Nature 2010
GWAS in > 100,000 Individuals: 95 Lipid Loci
The Role of PCSK9 in the Regulation of LDL Receptor Expression
TGRL Metabolism: Key Apolipoproteins
Fazio and Linton. Regulation and clearance of apoB‐continaing lipoproteina in Ballantyne. Clinical Lipidology, 2nd Ed.
LPL activityTG
LPL activityTG
VLDL
DNA Variants
Cardiovascular risk factorsLipids and other
Cardiovascular risk factorsCoronary disease and
atherosclerosis
New biologyNew therapeutic targets
??
?
Replicated GWAS Loci for MI/CHD:Ongoing Functional Genomics
CARDIoGRAM. Nature Genet. 2011
• ~50 CHD loci at genome-wide significance
• 12 loci for lipid traits and 5 for blood pressure
• ADAMTS7, COL4A1, TCF21, PDGF implicate VSMC, matrix
• CXCL12, IL6R, IL5 implicate inflammation and immunity
• FLT1/VEGFR1, EDNRA, GUCY1A implicate endothelium
• 13 CHD loci with consistent mouse knock out model finding
• Exomes: known loci, TGRL loci (ANGPTL4), novel loci (SEVP1)
• Mega GWAS, large exome & whole genome seq on-going
Summary: GWAS, MetaboChip and Exome-seq Loci in CHD
CARDIoGRAMplusC4D Nature Genet 2013 and Nature Genet 2015; MIGen ExSeq Nature 2015
• New discoveries: new targets & biology
• Causality and directionality in CHD
• Therapeutic translation
• Precision medicine
Impact on Clinic
Exomes (dark blue)
Why Sequence Exons?
Identify Rare Functional Variants & Establish Causal Direction
Exome-seq Identifies Mutations in Protein Coding Genes
PCSK9 Mutations: Causality and DirectionalityFreq
uency (%
)
LDL‐C
Gain of function mutations in PCSK9
Loss of function mutations in PCSK9
‐15% ‐5% 5% 15%
Causality – GWAS of LDL-C (Common Variants)
Voight. Lancet 2012;380:572. Ference. JACC 2012;60:2631.
Change in LDL-C Change in MI Riskrs3798220 (LPA)rs562338 (APOB)rs6544713 (ABCG8)rs10402271 (APOE)rs7953249 (HNF1A)rs3846663 (HMGCR)rs1501908 (TIMD4)rs11591147 (PCSK9)rs4420638 (APOE)rs599839 (SORT1)rs2228671 (LDLR)rs4299376 (ABCG8)rs4420638 (HMGCR)
‐30% ‐15% 0% 15% 30%
Increased HDL‐C Increased coronary disease
SCARB1 P376L
Zanoni, Khetarpal, Larach, et al. Science 2016
SR-BI-/- mice have elevated HDL-C levels but impaired RCT and increased atherosclerosis.
What about in humans?
The HDL Function Hypothesis
Promoting HDL functions (not raising HDL-C levels)
will reduce CV events?
Mendelian Randomization Studies
Exposed: Intervention
Randomization Method
Outcomes compared between groups
Confounders equal between groups
Randomized Controlled Trial
Exposed: Variant Allele
Control:Reference Allele
Random Segregation andAssortment of Alleles
Outcomes compared between groups
Confounders equal between groups
Mendelian Randomization
Control:No intervention
e.g., Lp(a) positiveCRP and HDL‐C negative
Jansen. Eur Heart J 2014;35:1917
Genetic variant(s)Associated with triglycerides, but not with other risk factors
Unbiased approachCommon variant (GWAS)Rare mutation (WES)
Candidate gene approachDocumented or suspected association or mechanism
Coronary diseaseTriglycerides
Mendelian Randomization Studies
APOC3 LOF Mutations Reduce TG levels and Protect against CAD
Clinical EffectSequencing Apolipoprotein C-III(APOC3)
TG MI
-39% -40%
IVS1-2GA IVS2+1GA
R19X A43T
1 in 150 individualsare heterozygous for
loss-of-function mutations
Humans with very low TG
First mechanism of lowering TG shown to reduce MI risk in humans
Loss-of-function mutations in APOC3 reduceplasma TG levels and risk of CHD
APOA5: Mendelian Randomization Study
Jorgensen. Eur Heart J 2013;34:1826.
68% 1.5 1.9
LPL: Mendelian Randomization Study
Thomsen. Clin Chem 2014;60:737
HR All‐Cause Mortality
0.86
0.730.43
0.77
• New discoveries: new targets & biology
• Causality and directionality in CHD
• Therapeutic translation
• Precision medicine
Impact in Clinic
Human genetics leading to smarter and faster development of
new medicines
Unmet Medical Needs in the Treatment of Elevated LDL-C
Unable To Get LDL < 100
Statin-Intolerant
LDL > 130
LDL > 160
Apheresis-eligibleLDL > 200
HoFH
High risk and on maximal tolerated statin
Mendelian Syndromes of LowLDL-C Provide New Targets for Therapy
Freq
uency (%
)
LDL‐C
LDLRCE
BLDL
CE
VLDL
TGB
apoB
CETG
Truncation Mutations in ApoB Cause Low LDL-C Levels
X
LDLR
apoB
TG
BVLDL
BLDL
Antisense Oligonucleotide to apoB: a Strategy for Reducing LDL-C
ASO to apoB (mipomersen)
X
LDLR
LDLR
apoB
Degradation
TGMTP
BVLDL
BLDL
Loss-of-function Mutations in MTP Cause Failure to Assemble and Secrete VLDL
X
LDLR
apoB
TGMTP
BVLDL
BLDL
MTP Inhibition: a Strategy for Reducing Hepatic VLDL Secretion and LDL-C
Small molecule inhibitor (lomitapide)
X
Inhibition of PCSK9 as a Novel Strategy for Reducing LDL-C
LDLR
CEB
LDL
CE
VLDL
TGB
Pcsk9
PCSK9X
Antibody, anti‐sense oligonucleotide (ASO), siRNA, small molecule inhibitor
PCSK9: From human genetic discovery to new medicine
May 2003 July 2015
• Alirocumab (Approved July 2015)• Evolocumab (Approved August 2015)• Indications:
– Patients with heterozygous familial hypercholesterolemia on maximally tolerated statin therapy with inadequate plasma LDL levels
– Patients with a history of CHD with inadequate plasma LDL levels
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm
APOC3-Targeted Therapeutic: ISIS-APOCIIIRx
Gaudet. NEJM 2014;371:2200
• New discoveries: new biology & targets
• Causality and directionality
• Therapeutic translation
• Precision medicine
Impact in Clinic
• Right diagnosis in patient & family• Cascade screen, diagnose and treat• Precision public health
• Right drug - patient (genetics): efficacy• Genome based drug selection• “N=1” trials
• Avoid wrong drug: patient safety• Gene-drug interactions•“N=1” trials
Precision Medicine
• Treasure trove of discoveries for lipids and CHD• Most novel CHD loci not related to traditional RF
• Genetic inference of causality and directionality
• LDL-C (but not HDL-C) loci relate to CHD • TG loci causal in CHD
• New therapeutics in trials – lipids (not direct CHD)
• Genetics for precision medicine
Summary – Take Home Message
Reilly GroupHanrui Zhang MD PhDXuan Zhang PhDChenyi Xue MSYing Wang PhDRob Bauer PhDAnd … more
Funding Support
Cardiology, Department of Medicine
Recent “Graduates”Jane FergusonNehal MehtaRachana ShahJennie LinRachel Ballantyne
RNA Biology
Columbia: Peter Sims, Raul Rabadan, PieroDalerba, Andrea Califano, Tom Maniatis
U.Penn: Arjun Raj, Ben Garcia
Sulzberger Genome Center: Olivier Cormonne
Collaboration & Team ScienceCARDIoGRAMplusC4D
NHLBI ESP-MI
U.Penn ColleaguesDan Rader, Danish Saleheen, Marina Cuchel
Edward Morrisey (iPS Core Facility)
Biostatistics & ModelingMingyao Li (UPenn) & Andrea Foulkes (MHC)
Columbia University Medical CenterR01-DK-090505; R01-HL-113147; R01-HL-111694; K24-HL107643. U01-HG006398
Acknowledgements
Columbia CollaboratorsDavid Goldstein,
Henry Ginsberg, Tony Ferrante, Alan Tall, Ira Tabas, many more ….