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Dr. Chasman on Pharmacogenetics of Statin Therapies

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Pharmacogenetics of Statin Therapies

Pharmacogenetics of Statin Therapies

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  • 1. Pharmacogenetics of Statin Therapies Daniel I. Chasman, Ph.D. Division of Preventive Medicine Brigham and Women’s Hospital Johanna and Ralph DeStefano Personalized Health Care Conference OSU Medical Center Columbus, OH Oct 6, 2011
  • 2. Disclosure Funding for this research provided by AstraZeneca Celera
  • 3. Background and research questions
    • Background
      • There is large inter-individual response to statin therapy as measured by LDL-C reduction. Some of this variation may be correlated with genetic variation.
    • Research questions
      • What genes, in the entire genome, carry common genetic variation associated with LDL-C lowering on statin therapy?
      • What are the magnitudes of these effects?
      • Are there interactions involving these gene variants?
      • To what extent do the genetic effects explain variation in inter-individual statin response?
  • 4. Some previous genetic analyses of LDL-C lowering with statin treatment
    • Candidate gene analysis 1
      • HMGCR – target of statin therapy
      • APOE – major apolipoprotein of VLDL, IDL, chylomicrons
      • LDLR – LDL receptor
      • ABCG5/8 – sterol transporters
      • CYP7A1 – cytochrome P450 family metabolizing enzyme
      • ABCG2 – transporter in liver, kidney
    • Genome-wide association studies (GWAS) 2
      • CLMN association in GWAS of PRINCE, CAP, and TNT (pravastatin, simvastatin, atorvastatin)
      • GRIK4 association in GWAS of TNT (atorvastatin)
      • SLCO1B1 association myopathy GWAS of SEARCH (simvastatin)
    References 1 JAMA. 2004 291:2821, ATVB 2010 30:1485, Circ. 2008 117:1537; Athero. 2004 175:287; Am J Cardi. 2004 93:104. Athero. 2001 158:183. Circulation Cardiovascular genetics 2010 doi: 10.1161. 2 PLoS One. 2010 5:e9763 , N Engl J Med. 2008 ;359:789, Circ Cardio Genet. 2009 2:173.
  • 5. Known pharmacologic pathways for statin therapy CYP’s LDLR APOE ABCG5/8 HMGCR temporal sequence of statin pharmacology ABCB1 ABCG2 SLCO1B1 degradation hepatocyte inhibition of cholesterol synthesis hepatocyte effects on cholesterol transport hepatocyte vascular system peripheral tissues uptake intestine hepatocyte excretion hepatocyte renal cells
  • 6. Genome-wide association study (GWAS)
    • Focus on s ingle n ucleotide p olymorphisms (SNPs), the most prevalent form of genetic variation in people
    • SNPs typically have two alleles, the major allele signified here as “A” and the minor allele signified as “a”
    • In a single experiment, examine all common SNPs at once. For 1% allele frequency, approx. 1 million SNPs
    • Test for association of the minor allele with LDL-C response among individuals taking statin
  • 7. Population with genome-wide data from JUPITER
    • JUPITER trial enrolled 17,802 participants with LDL-C < 130mg/dL and C-reactive protein (CRP) ≥ 2mg/L for primary prevention with random allocation to rosuvastatin (20 mg/day). Treatment highly effective in this population 1
    • Genotyping on the Illumina Omni 1M Quad platform by Illumina
    • 8,782 of the 12,649 JUPITER participants with genotype had verified European ancestry
    • Compliance limits sample to 6,934
    • SNPs excluded when failing Hardy-Weinberg equilibrium test at P < 10 -6 , with the exception of rs7412 at APOE (E2 v. E3)
    • 820,411 SNPs pass QC with minor allele frequency > 1%
    1 N Engl J Med. 2008 359:2195.
  • 8. Clinical characteristics of study sample (all European ancestry) characteristic placebo statin p* 3414 3520 age (yrs) 66.0 (60.0-71.0) 66.0 (60.0-71.0) 0.52 sex (N (%) female) 1086 (31.8) 1112 (31.6) 0.86 BMI (kg/m^2) 28.7 (25.6-32.1) 28.7 (25.8-32.1) 0.76 hypertension (N (%)) 1886 (55.2) 1985 (56.4) 0.35 smoking_cigs (N (%)) 443 (13.0) 460 (13.1) 0.94 LDL-C (mg/dL) 110.0 ( 97.0-120.0) 110.0 ( 96.0-120.0) 0.16 HDL-C (mg/dL) 50.0 (41.0-61.0) 49.0 (41.0-60.0) 0.40 triglycerides (mg/dL) 115.5 (84.0-163.0) 117.0 (85.0-167.0) 0.10 Δ LDL-C (mg/dL) 3.0 (-15.0-7.0) -54.0 (41.0-66.0) Δ HDL-C (mg/dL) 1.0 (-5.0-3.0) 3.0 (-8.0-1.0) Δ triglycerides (mg/dL) 0 (-24-25) -18.5 (-3.0-50.0)
  • 9. Defining LDL-C response to statin therapy
    • Absolute LDL-C response:
      • LDL-C at 12 months – LDL-C baseline
    • Fractional LDL-C response:
    • LDL-C at 12 months – LDL-C baseline = absolute Δ LDL-C
    • LDL-C baseline LDL-C baseline
    • Statistical power: JUPITER sample with genome-wide genetic information is the largest to date with a single statin administered at a single dose
    Δ LDL-C (mg/dL) Δ fr. LDL-C (%) MAF p=0.05 5x10 -8 p=0.05 5x10 -8 0.05 3.8 8.5 3.7 8.3 0.1 2.8 6.2 2.7 6.0 0.2 2.1 4.7 2.0 4.5 0.5 1.7 3.7 1.6 3.6
  • 10. Genome-wide association of baseline LDL-C  ~820K SNPs 
  • 11. Genome-wide association of LDL-C lowering with rosuvastatin < Absolute LDL-C reduction Fractional LDL-C reduction >
  • 12. Genome-wide association of LDL-C lowering with placebo < Absolute LDL-C reduction Fractional LDL-C reduction >
  • 13. Magnitude of effects: best SNP at each locus LDL-C lowering Baseline LDL-C # high LD     absolute LDL-C reduction (mg/dL) fractional LDL-C reduction (%) chr. pos. gene SNP MAF effect (se) p SNP MAF effect (se) p* 1p32.3 PCSK9 rs17111584 0.05 4.3 (1.4) 5.8E-04 rs11591147 0.03 -4.5 (1.7) 3.1E-04 4q22.1 ABCG2 rs2199936 # 0.11 -5.2 (0.9) 2.1E-12 rs1481012 # 0.11 -5.1 (0.9) 1.7E-15 6q26 LPA rs10455872 0.05 6.2 (1.3) 3.5E-09 rs10455872 0.05 6.8 (1.2) 5.0E-15 19q13.32 APOE rs71352238 0.10 4.2 (1.0) 2.9E-04 rs7412 0.15 -5.1 (0.8) 5.8E-19     baseline LDL-C (mg/dL) chr. pos. gene SNP MAF effect (se) p 1p32.3 PCSK9 rs11591147 0.03 -5.0 (0.8) 4.7E-11 4q22.1 ABCG2 N.S. 6q26 LPA N.S. 19q13.32 APOE rs7412 0.15 -6.1 (0.4) 1.6E-53
  • 14. Distribution of effect by genotype
  • 15. Total genetic effect: proportion of variance explained at genome-wide loci “ ● ” indicates locus with genome-wide association (p<5x10 -8 ) For comparison, age, BMI, sex, smoking status, region explain: 3.5% of absolute LDL-C response 3.7% of fractional LDL-C response
  • 16. Genes from genome-wide analysis
    • PCSK9 (chr. 1)
      • Serine protease with functions in LDLR protein degradation
    • ABCG2 (chr. 4)
      • Widely-expressed (hepatic, renal, elsewhere) transporter studied for multi-drug resistance phenotype in chemotherapy (as BCRP ). Variation also associated with plasma urate levels. Effects observed in candidate analysis of LDL-C lowering with rosuvastatin*.
    • LPA (chr. 6)
      • Apolipoprotein(a) component of Lp(a). Plasma Lp(a) levels almost entirely determined by genetic variation at LPA . LDL-C includes contribution from cholesterol in Lp(a) particles.
    • APOE (chr. 19)
      • Major apolipoprotein component of VLDL, IDL, chylomicrons.
    *Circ Cardiovasc Genet. 2010 Jun 1;3(3):276-85.
  • 17. Validation
    • No replication, but …
    • Genome-wide standard of significance (p<5x10 -8 ) imposed
    • All loci previously recognized in genetics of statin response literature
    • Winner’s curse probably not a strong influence on effect estimates
    • Associations not merely due to individuals with extreme LDL-C since such individuals were excluded by the trial design
    • No effects at all in placebo
  • 18. Sub-genome-wide significant loci (5x10 -8 <P<5x10 -6 ) absolute LDL-C reduction (mg/dL) fractional LDL-C reduction (%) chr. SNP pos maf beta (se)* p* beta (se)* p* genes 2q21.3 rs6730157 135623558 0.35 3.4 (0.6) 3.0E-05 3.7 (0.6) 8.2E-07 RAB3GAP1 6p22.3 rs6924995 16269404 0.21 4.1 (0.7) 5.3E-07 3.8 (2.9) 1.4E-06 IDOL (MYLIP) 6q23.1 rs7769153 131298057 0.03 8.9 (1.9) 1.1E-04 10.3 (1.8) 1.7E-07 EPB41L2 9q22.1 rs1875620 90729879 0.45 2.8 (0.6) 7.2E-07 2.2 (0.6) 3.7E-04 C9orf47, S1PR3, SHC3 19p12 rs931608 22405962 0.12 4.2 (0.9) 2.7E-07 3.6 (0.9) 7.9E-07 LOC342994, ZNF98
  • 19. IDOL (inducible degrader of LDL receptor)
    • IDOL (originally named MYLIP )
      • Sterol responsive ubiquitin-mediated pathway for post-transcriptional regulation (degradation?) of the LDL receptor 1
      • Regulated by LXR
      • Recently associated with baseline LDL-C 2
      • Candidate therapeutic target for “statin-like” regulation of LDL-C levels mediated through the LDL receptor
    • EPB41LD
      • Unknown function but shares band 4.1 homology with IDOL
    1 Science 2009 325:100-104 2 PLoS Genetics 2009 5:e1000730. Nature 2010 466:707-13.
  • 20. Candidate associations No associations at GRIK4, CLMN, CYP3A5, CYP2C9 1,2 locus-wide best SNP for absolute (1) or fractional (2) LDL-C reduction           absolute LDL-C reduction (mg/dL)   fractional LDL-C reduction (%) chr gene SNP pos maf effect* (se) p*   effect* (se) p* 5 HMGCR rs17244841 74678611 0.05 1.9 (2.0) 5.00E-01 1.8 (2.0) 5.70E-01 rs17238540 74691254 0.02 1.7 (2.0) 6.20E-01 1.6 (2.0) 8.30E-01 rs12916 74692295 0.39 1.1 (0.6) 3.10E-01 1 (0.6) 3.90E-01 rs698912 1 74717529 0.20 1.2 (0.7) 9.7e-02 (9.5e-01) 0.99 (0.7) 1.3e-01 (9.8e-01) rs10474433 2 74652599 0.33 1.0 (0.6) 2.6e-01 (1e+00) 1.1 (0.6) 9.5e-02 (9.4e-01) 12 SLCO1B1 rs4149056 21222816 0.16 2.7 (0.8) 1.70E-04 2.6 (0.8) 7.70E-05 rs4363657 21259989 0.17 2.8 (0.8) 1.80E-04 2.8 (0.7) 4.00E-05 rs12317268 1,2 21243808 0.16 3.2 (0.8) 2.9e-05 (3.8e-03) 3.2 (0.8) 4.1e-06 (5.3e-04) 19 LDLR rs6511720 11063306 0.15 -1.7 (0.8) 1.50E-01 -2.6 (0.8) 4.60E-03 rs688 11088602 0.43 -0.58 (0.6) 5.50E-01 -0.4 (0.6) 9.50E-01 rs1433099 11103658 0.27 0.023 (0.7) 5.90E-01 0.28 (0.6) 6.30E-01 rs11672123 1 11055823 0.05 4.4 (1.0) 6.6e-04 (2.4e-02) 4 (1) 5.9e-03 (2.0e-01)     rs11668477 2 11056030 0.24 -1.9 (0.7) 9.2e-03 (2.9e-01)   -2.1 (0.7) 1.8e-03 (6.4e-02)
  • 21. Interaction analysis
    • No interaction among lead SNPs at genome-wide loci
    • No interaction between lead SNPs and other SNPs across genome
    • No interaction with sex
    • No evidence for conditional associations within top loci
    • However, evidence for PCSK9 X LDLR interaction with fractional LDL-C reduction (p int =0.002)
    rs11668477 ( LDLR ) rs11591147 ( PCSK9 ) non-carrier carrier (~15%) non-carrier -51.6% -52.0 carrier (~6%) -51.5 -57.0
  • 22. Influence of common genetic variation on rosuvastatin therapy in JUPITER CYP’s HMGCR APOB temporal sequence of statin pharmacology degradation hepatocyte inhibition of cholesterol synthesis hepatocyte effects on cholesterol transport hepatocyte vascular system peripheral tissues APOE PCSK9 LPA LDLR IDOL uptake intestine hepatocyte SLCO1B1 excretion hepatocyte renal cells ABCG2
  • 23. Genetic score: sum of inherited “risk alleles” absolute LDL-C response fractional LDL-C response
  • 24. Effects of genetic score Estimates per unit of score, i.e. per inherited allele   beta (95% CI) R 2 OR > median absolute Δ LDL-C -5.0 (mg/dL) (-6.06- -3.93) 2.3 1.54 (1.41-1.69) fractional Δ LDL-C -5.5 (%) (-6.57- -4.5) 3.1 1.93 (1.75-2.12)
  • 25. Another candidate ( KIF6 )
    • KIF6 gene non-synonymous variant (rs20455, MAF=34.7%). Minor allele (719Arg) has greater CV risk and greater response to atorvastatin (CARE, WOSCOP).
    • No effect observed in JUPITER. See: Ridker et al. Circ Cardiovasc Genet. 2011 Apr 14. Lack of association may be related to differences between rosuvastatin and other statins
  • 26. Summary
    • In JUPITER, three (3) loci genome-wide significant association for LDL-C reduction with random rosuvastatin (20mg/dL) allocation: ABCG2, LPA, APOE
    • An additional locus ( PCSK9 ) for LDL-C reduction arises from genome-wide association with baseline LDL-C.
    • Per allele, the lead SNPs are associated with a -5.2 mg/dL ( ABCG2 ) and a +6.2 mg/dL ( LPA ) change in absolute LDL-C; a -5.1 mg/dL change in fractional LDL-C change ( APOE )
    • In total, 2.8% and 6.7% of the variance explained by four loci in absolute and fractional LDL-C reduction respectively
    • A sub-genome-wide association at IDOL is consistent with current understanding of LDL receptor regulation
    • Additional candidate analysis supports a role for variation in SLCO1B1 and LDLR
    • A genetic risk score reveals dependence of median LDL-C response on genetics but only explains a small proportion of the variance
    • No interaction effects with rosuvastatin observed for KIF6 variant
  • 27. Collaborators and support
    • BWH
      • Paul M Ridker, MD, MPH
      • Audrey Chu, PhD
      • Franco Guilianini, PhD
      • Jean MacFadyen, BS
    • AstraZeneca
      • Fredrik Nyberg, MD, PhD, MPH
      • Bryan Barratt, PhD
    • Support
      • AstraZeneca
      • Celera

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