16- vladutiu new talk-june 1st - national lipid association · 2017-01-04 · genetic risk...
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Genetic Risk Underlying Statin‐Induced Myopathy
Georgirene D. VladutiuDepartments of Pediatrics, Neurology,and Pathology & Anatomical SciencesSchool of Medicine & Biomedical SciencesUniversity at Buffalo & Kaleida Health Laboratories, Buffalo, N.Y. USA
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Disclosure Statement
There are no conflicts of interest to disclose.Research Support: ◊ The John R. Oishei Foundation◊ NHLBI
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The Robert Guthrie Biochemical& Molecular Genetics Laboratory
Biochemical testing for metabolic disorders Primarily metabolic muscle diseases
Molecular testing for triggerable myopathies Carnitine palmitoyltransferase (CPT) II deficiency
McArdle disease (myophosphorylase deficiency)
Myoadenylate deaminase deficiency
Very long‐chain acyl‐CoA dehydrogenase deficiency
Caveolin‐3 deficiency
www.rgbmgl.org
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Increasing Referral of Statin Myopathy Cases
0
10
20
30
40
50
60
1998-2000
2001-03 2004-06
No# of biopsies
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Hypothesis
A higher proportion of individuals with statin myopathy will have underlying heritable metabolic muscle disorders than expected in the general population or in statin‐tolerant controls.
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Genetic Risk for Underlying Muscle Disease
10% of severe statin myopathy patients had disease‐causing mutations (3 disorders) 3% of statin‐tolerant controls had mutations
Carriers for CPT II deficiency and McArdledisease increased 12‐ and 20‐fold, respectively, over general population
Homozygotes for myoadenylate deaminasedeficiency increased 3.25‐fold
Vladutiu GD et al. Muscle Nerve 2006; 34:153
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Severe vs. Mild Statin Myopathy
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Definitions Severe Statin Myopathy (0.5%; ~200,000)
Incapacitating muscle pain and/or weakness; rhabdomyolysis Persistent symptoms post-therapy; progressive worsening;
CK>4XULN Can no longer tolerate lower doses of statins 11% report unsolicited “foggy thinking”; memory loss; few
transient global amnesia
Mild Statin Myopathy (10-15%; 4-6 million) Mild aches and pains Change in dose or “drug holidays” eliminates symptoms 2% report “foggy/fuzzy thinking” & memory problems
`
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Statin Myopathy Study Recruitment 2003‐12
TOTAL 875
CAUCASIAN 784
MILD MYOPATHY 362
SEVERE MYOPATHY 302
STATIN TOLERANT 120
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72% of Caucasians on statin therapy reported that CK was measured
38% reported values for CK
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Plasma Creatine Kinase
CK value known?38%
(n=216)
SevereCases65%
(n=145)
MildCases31%(n=67)
Tolerant Controls
2%(n=4)
Normal CK 40 (28%) 23 (34%) 3 (75%)
>2XULN 91 (63%) 44 (66%) 1 (25%)
> 2XULN <5XULN 23 (25%) 31 (70%) 1
> 5XULN <10XULN 22 (24%) 4 (9%) 0
> 10XULN 46 (51%) 9 (21%) 0
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Among those with known CK values, 78% had persistent symptoms post‐therapy
of varying durations
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Persistent Symptoms in Severe & Mild Cases with CK Measured
Persistent Symptoms Any Duration?78% (n=168)
Severe Cases89% (n=129)
Mild Cases58% (n=39)
Persistent Symptoms > 6 months
Normal CK 74% 60%
> 2XULN <5XULN 91% 50%
> 5XULN <10XULN 75% 0
> 10XULN 79% 75%
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Comprehensive Genotyping for Susceptibility to Metabolic Muscle Disease Microarray analysis for pathogenic mutations causing muscle diseases with overlapping symptoms 345 mutations (2 variants*) 15 genes Screened 396 statin takers; 167 non‐statin rhabdomyolysis
*SLCO1B1 & EYS gene variants
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Categories of DiseaseIncluded on Microarray
• Fatty Acid Oxidation Disorders• Glycogen Storage Diseases • Dystrophies• Myoadenylate Deaminase Def.• Malignant Hyperthermia
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Molecular Analysis of Severe Statin Myopathy 2010‐12
Disease‐Causing Mutations & Variants
Severe Statin Myopathy (%)
n=282
Non‐Statin‐Induced Rhabdo
n=167
Statin‐Tolerant Controls (%)
n=114
Total Disease Allele Frequencies
(13 genes)16.3 17.4 4.4
PYGM,CPT2,ACADACADVL,LPIN,
AMPD17.5 12.0 4.4
MalignantHyperthermia
(RYR1 & CACNA1S)
4.2 2.4 0
Vladutiu et al. Molec Genet Metab 2011; 104:167
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Frequency of Mutant Alleles in Severe Statin Myopathy
Major GenesUnderlying
Statin Myopathy
General Population
Allele Frequency
Severe Statin
Myopathy
Non‐Statin Rhabdo.
Statin‐Tolerant Controls
RYR1 1 in 2000 1 in 35 1 in 42 0
CACNA1S Unknown 1 in 70 0 0
CPT2 1 in 270 1 in 47 1 in 21 1 in 114
PYGM 1 in 170 1 in 57 1 in 21 0
ACADVL Unknown 1 in 56 1 in 167 1 in 114
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Statin Use by Test GroupsAll Races
StatinSevere Statin Myopathy (%)
n=306
Mild Statin Myopathy (%)
n=383
Statin ‐Tolerant (%)
n=117
Atorvastatin 52 54 71
Simvastatin 23 22 8.5
Rosuvastatin 13 11 5
Pravastatin 6 7 8
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CONCLUSIONS Genetic risk for heritable muscle diseases in 13 disease genes underlies >16% of severe statin myopathy cases.
Plasma CK ranges from normal to >10XULN in severe & mild cases.
Persistent symptoms post‐therapy occur in 78% of cases.
Persistent symptoms > 6 mos present in >¾ of severe cases in each CK range.
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Risk Groups Eligible for Metabolic Muscle Disease Testing
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Planned Future Research (2014)
Next Generation Targeted Sequencing of genes implicated in triggerable muscle diseases
Whole Exome Sequencing to identify new target genes and pathogenic variants causing muscle disease
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Statin MyopathyProject CollaboratorsCedars‐Sinai Medical Center, Los AngelesRobert Davidson, M.D.Dani Hackner, M.D.Prediman Shah, M.D.Michael Weisman, M.D.
Columbia University Medical Center – New YorkAlfred Slonim, M.D.
Dartmouth Hitchcock Medical Center – Lebanon, NHRobert Wortmann, M.D.
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Henry Ford Hospital – DetroitNiganand Sripathi, M.D.
Johns Hopkins University Myositis Center ‐ BaltimoreAlan Baer, M.D.Lisa Christopher‐Stine, M.D.Andrew Mammen, M.D.
McMaster Children’s Hospital/Hamilton Health Sciences FoundationSteven Baker, M.D.Mark Tarnopolsky, M.D., Ph.D.
Medical College of Wisconsin ‐MilwaukeeAlexandru Barboi, M.D.Wendy Peltier, M.D.
University at BuffaloPaul J. Isackson, Ph.D.Edward Fine, M.D.