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Genetics of Familial Hypercholesterolemia
Marina Cuchel, MD, PhD University of Pennsylvania
NLA 2013 Clinical Lipid Update 21 September 2013 – Baltimore
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Presenter Disclosure Information
Financial disclosure: Research support, speaker bureau and travel support from Aegerion Pharmaceuticals
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Introduction
• What is Familial hypercholesterolemia (FH)?
• What are the underlying genetic defects that cause FH?
• How does the molecular basis of FH affect lipid lowering treatment?
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Familial Hypercholesterolemia (FH)
• Inherited disorder • Severe hypercholesterolemia with lifelong
accumulation of plasma LDL-C • Premature CVD
Soutar AK and Naoumova RP (2007) Mechanisms of Disease: genetic causes of familial hypercholesterolemia Nat Clin Pract Cardiovasc Med 4: 214–225 doi:10.1038/ncpcardio0836
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Familial Hypercholesterolemia (FH)
• inherited disorder • severe hypercholesterolemia with lifelong
accumulation of plasma LDL-C • premature CVD
Soutar AK and Naoumova RP (2007) Mechanisms of Disease: genetic causes of familial hypercholesterolemia Nat Clin Pract Cardiovasc Med 4: 214–225 doi:10.1038/ncpcardio0836
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Screening for familial hypercholesterolaemia. Bender, Robert; Bell, Damon; Hooper, Amanda; Edwards, Glenn; van Bockxmeer, Frank; Watts, Gerald; Burnett, John Pathology. 44(2):122-128, February 2012. DOI: 10.1097/PAT.0b013e32834efa07
(B) Achilles tendon xanthoma
Clinical Manifestations of FH
(D) Xanthelasmata
(C) Corneal arcus (A) Extensor tendon xanthomata
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FH: very high cholesterol exposure from birth, CHD earlier in life
Cumulative exposure (cholesterol yrs) by age: FH vs. unaffected individuals
Horton et al. J Lipid Res. 2009;50:S172-S177.
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FH - Clinical Diagnosis
• Well defined set of criteria to make the diagnosis of FH.
– MEDPED (Make Early Diagnosis to Prevent Early Deaths)
– Simon Broome Registry
– Dutch Lipid Clinic Network
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• All take into consideration a combination of the following:
– Untreated LDL-C levels (>190 mg/dl; >155 mg/dl if <16yo)
– Family history (LDL-C↑; premature CHD+)
– Clinical history (premature CHD+)
– Physical examination (presence of xanthomas; corneal arcus)
– DNA analysis
FH - Clinical Diagnosis
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Overlap of Clinical and Mutation Diagnosis of Heterozygous Familial Hypercholesterolemia
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
© The Author 2013. Published by Oxford University Press on behalf of the European Society of
Cardiology.
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Molecular Bases of FH Why Is It Important to Know Them?
• Understanding of the genetic causes of FH has been instrumental in the development of lipid-lowering drugs
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Molecular Bases of FH Why Is It Important to Know Them?
• Understanding of the genetic causes of FH has been instrumental in the development of lipid-lowering drugs
• Knowledge of the genetic mutation(s) responsible for FH may improve adherence to therapeutic plan
• Knowledge of the genetic mutation(s) facilitate the identification of other family members affected by FH
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Estimated % Diagnosed FH in Different Countries, as a Fraction of Those Predicted Based on a Frequency of 1/500 in the General Population
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
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HoFH is Caused by Mutations in Genes Affecting LDL Receptor Functionality
LDLR
apoB
TG
B100
VLDL
LDL
TG
IDL TG
X LDLR
apoB
TG
B100
VLDL
LDL
TG
IDL TG
X X
• The impaired LDLR functionality leads to a decreased clearance of LDL particles from plasma
HeFH LDL-C >190 mg/dl
HoFH LDL-C > 500 mg/dl
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Molecular Causes of FH
LDLR (chr 19p13):
Primary familial
hypercholesterolemia
OMIM: 143890
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FH Is Most Frequently Caused by LDLR Mutations
• Mutation in LDLR are found in ~95% of the confirmed cases of HoFH
• More than 1,000 LDLR mutations have been reported
• Based on the mutations patients can be divided in receptor negative (<2% activity) or receptor defective
• The type of mutations affect the LDL-C levels and the response to treatment
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Molecular Causes of FH
LDLR (chr 19p13):
Primary familial
hypercholesterolemia
OMIM: 143890
APOB (chr 2p24):
Familial defective Apo B
OMIM:144010
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PCSK9 (chr 1p32):
Proprotein convertase
subtilisin/kexin type 9
OMIM: 603776
Molecular Causes of FH
LDLR (chr 19p13):
Primary familial
hypercholesterolemia
OMIM: 143890
APOB (chr 2p24):
Familial defective Apo B
OMIM:144010
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PCSK9 (chr 1p32):
Proprotein convertase
subtilisin/kexin type 9
OMIM: 603776
Molecular Causes of FH
LDLR (chr 19p13):
Primary familial
hypercholesterolemia
OMIM: 143890
APOB (chr 2p24):
Familial defective Apo B
OMIM:144010
LDLRAP1 (chr 1p36):
Autosomal recessive
hypercholesterolemia
OMIM: 603813 ~95% due to mutations in LDLR gene ~5% due to other mutations in APOB, PCSK9 and LDLRAP1 (ARH) genes
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What Is the Frequency of Mutations Affecting LDLR Functionality?
• Based on early estimates FH frequency is thought to be 1:500 for HeFH and 1, 000,000 for HoFH
• Higher frequency is found in some populations (founder effect)
• Systematic genetic characterization of patients and relatives via cascade screening and exome sequencing suggests frequency >1:500 (~1:200)
• Recent advancements have demonstrated the genetic heterogeneity of subjects with clinical diagnosis of HoFH
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Heterozygous and Homozygous FH
• Heterozygous FH – one mutation in one allele
• True homozygous FH – same mutation in both alleles of same gene
• Compound heterozygous FH – different mutations in the two alleles of the same gene
• Double heterozygous FH – different mutations in two alleles of different genes
X
X X
X
X
Mother Father Offspring
X
X
X
LDLR APOB PCSK9 LDLRAP1
X
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Broad Spectrum of LDL-C levels in FH
Harada-Shida et al. J Ateroscler Thromb, 2012; 19:1043-1060
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LDL-C Levels Correlate With Residual LDLR Activity
Bertolini S et al. Arterioscler Thromb Vasc Biol 1999;19:408-418
N=32 HoFH
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LDLR negative (n=18) LDLR defective (n=16) p
Median (range)
Age (yr) at visit 1 11.5 (3.3 - 29) 28.1 (3.3 - 44.6) 0.008
Age at 1st xanthomas 2.0 (0.25 - 4) 7.0 (1 - 15) <0.001
Age (yr) at FH dx 3.0 (0.5 - 7) 8.0 (2 - 17) <0.001
TC (mg/dl) at dx 895 (602-1260) 686 (519-900) 0.002
Age (yr) at start of Rx 5.0 (1.2 - 10) 16.0 (2 - 31) 0.001
Age (yr) at CAD 12.5 (6 - 16) 22.0 (16 - 37) 0.004
Lipid profile at visit 1 Mean (SD)
TC (mg/dl) 618 (238) 453 (162) 0.025
LDL-C (mg/dl) 535 (214) 393(159) 0.040
Apo B (mg/dl) 388 (142) 293 (92) 0.032
Penn HoFH Cohort: LDLR Negative Subjects Have a More Severe Phenotype
Kolansky DM, Am J Cardiol 2008; 102:14-38-43
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LDL-R mutation LDL-C (mmol/L)
Mean ± SE Range
Receptor defective
G571E 5.68 ± 0.41 4.19–7.33
P664L 6.40 ± 0.35 4.91–10.60
V502M 6.19 ± 0.28 4.20–8.52
313+1g>a 6.89 ± 0.40 4.59–9.09
D200G 6.74 ± 0.16 4.00–11.41
Receptor negative
ΔEx2–12 7.36 ± 0.29 4.78–10.90
Fs453 7.48 ± 0.17 3.91–12.29
G528D 7.76 ± 0.20 4.73–11.98
Fs572 8.24 ± 0.34 4.64–12.16
D558Y 8.19 ± 0.28 4.90–11.74
E207K 8.65 ± 0.42 5.09–10.66
ΔEx13,14 8.62 ± 0.45 7.00–10.04
Total 7.35 ± 0.09 3.91–12.29
[151-475 mg/dl] Adapted from Table 2 in: Bertolini S et al. Atherosclerosis 2004;174: 57-65
LDL-C Levels Correlate With Residual LDLR Activity
N=570 HeFH
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Common Genetic Variants Contribute to the Lipid Phenotype in FH
• Common genetic variants of genes affecting LDL metabolism affect LDL-C levels in FH patients with a known mutation
• Bertolini et al. 2004 (ApoE, apoB, MTP)
• Talmud et al. Lancet 2013 (12 variants score)
• Common genetic variants of genes affecting LDL metabolism affect LDL-C levels in FH patients without a known mutation
• Talmud et al. Lancet 2013 (12 variants score)
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LDL-C Burden in Individuals With/Without FH as a Function of the Age of Initiation of Statin Therapy
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
© The Author 2013. Published by Oxford University Press on behalf of the European Society of
Cardiology.
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Sali M.K. Farhan , Robert A. Hegele. Genetics 101 for Cardiologists: Rare Genetic Variants and Monogenic Cardiovascular Disease. Canadian Journal of Cardiology Volume 29, Issue 1 2013 18 - 22
Molecular Bases of FH and Drug Target Development
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LDLR Synthesis is Tightly Regulated by an Intracellular Cholesterol Pool
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If cholesterol pool depletion
LDLR and Cholesterol Synthesis Are Enhanced by Depletion of Intracellular Cholesterol
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HMG-CoA
Mevalonate
Cholesterol
HMG-CoA reductase Statins
LDLR
Statins Up-Regulate the LDLR
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Statins Up-Regulate the LDLR
• Statins are the first line of treatment for all forms of hypercholesterolemia, including HoFH
• Statins are very effective in lowering LDL-C in polygenic hypercholesterolemia and HeFH
• Statins efficacy in HoFH varies from minimal to ~30% reduction in LDL-C
→ LDLR defective patients respond better than LDLR negative patients
• Co-administration of with other lipid lowering treatments is frequently necessary
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Most Lipid Lowering Drugs Affect LDL Catabolism By Up-Regulating the LDLR
statins ezetimibe bile acid sequestrants PCSK9 -inhibitors
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Mullard A. Nature Reviews Drug Discovery . 2012.11, 817-819
PCSK9 Inhibition Prevents the Degradation of The LDLR
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Mullard A. Nature Reviews Drug Discovery . 2012.11, 817-819
PCSK9 Inhibition Prevents the Degradation of The LDLR
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Raal F et al. J Am Heart Assoc 2013;2:e000028
PCSK9 Levels Are Elevated in FH
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Raal F et al. Circulation 2012;126:2408-2417
PCSK9 Inhibition Lower LDL-C in HeFH Results From a Phase 2 Study
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apoB
TG
B100
VLDL
LDL
TG
IDL
TG
Novel Lipid Lowering Drugs Affect LDL Production by Inhibiting VLDL Secretion
MTP
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apoB
TG
B100
VLDL
LDL
TG
IDL
TG
Novel Lipid Lowering Drugs Affect LDL Production by Inhibiting VLDL Secretion
Mipomersen
MTP
Lomitapide
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Rall FJ, Lancet 2010. 375: 998 - 1006
Mipomersen Lowers LDL-C in FH
LDL-C
ApoB
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-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%
0 10 20 30 40 50 60 70 80
LDL-C % change
apoB % change
TC % change
41
Ch
ang
e fr
om
Bas
elin
e
Study Week
Lomitapide Lowers LDL-C in HoFH
Efficacy Phase Safety Phase
Data are mean, 95%CI (n=23) Cuchel et al, HoFH Phase 3 lomitapide study
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Summary
• FH is an inherited disorder characterized by lifelong severe hypercholesterolemia and premature CVD
• FH is underdiagnosed
• FH is caused by mutations on LDLR, APOB , PCSK9 and LDLAP1
• Mutations associated with LDLR negative status results in a more severe phenotype
• Common genetic variants contribute to the LDL-C levels
• Current and novel drugs have been developed based on the understanding of the molecular bases of FH