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    Chasman Chasman Presentation Transcript

    • 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
    • Disclosure
      Funding for this research provided by
      AstraZeneca
      Celera
    • Background and research questions
      Background
      There is large inter-individual response to statin therapy as measured by LDL-C reduction, a strong predictor of risk 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?
    • Some previous genetic analyses of LDL-C lowering with statin treatment
      Candidate gene analysis1
      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
      1JAMA. 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.
      2PLoS One. 2010 5:e9763 , N Engl J Med. 2008 ;359:789, Circ Cardio Genet. 2009 2:173.
    • Known pharmacologic pathways for statin therapy
      temporal sequence of statin pharmacology
      CYP’s
      ABCB1
      ABCG2
      SLCO1B1
      HMGCR
      LDLR
      APOE
      ABCG5/8
    • Genome-wide association study (GWAS)
      Focus on single nucleotide polymorphisms (SNPs), the most prevalent form of genetic variation in people
      SNPs typically have two alleles, the major allele (≥50% in the population) and the minor allele (<50%)
      In a single experiment, examine all common SNPs at once. For 1% allele frequency, approx. 1 million SNPs.
      Require very stringent significance, e.g. p < 5 x 10-8
      Test for association of the minor allele with LDL-C response among individuals taking statin
    • 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 population1
      Genotyping on the Illumina Omni 1M Quad platform by Illumina
      8,782 of the 12,649 JUPITER participants with consent and 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%
      1N Engl J Med. 2008 359:2195.
    • Clinical characteristics of study sample(all European ancestry)
    • 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 ΔLDL-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
    • Genome-wide association of baseline LDL-C
       ~820K SNPs 
    • Genome-wide association ofLDL-C lowering with rosuvastatin
      < Absolute LDL-C reduction
      Fractional LDL-C reduction >
    • Genome-wide association of LDL-C lowering with placebo
      < Absolute LDL-C reduction
      Fractional LDL-C reduction >
    • Magnitude of effects: best SNP at each locus
      LDL-C lowering
      # high LD
      Baseline LDL-C
    • Distribution of effect by genotype
    • 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
    • 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.
    • 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
    • Sub-genome-wide significant loci(5x10-8<P<5x10-6)
    • IDOL (inducible degrader of LDL receptor)
      • IDOL (originally named MYLIP)
      Sterol responsive ubiquitin-mediated pathway for post-transcriptional regulation (degradation?) of the LDL receptor1
      Regulated by LXR
      Recently associated with baseline LDL-C2
      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
      1Science 2009 325:100-104
      2PLoS Genetics 2009 5:e1000730. Nature 2010 466:707-13.
    • Candidate associations
      1,2locus-wide best SNP for absolute (1) or fractional (2) LDL-C reduction
      No associations at GRIK4, CLMN, APOB, CYP3A5, CYP2C9
    • 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 (pint=0.002)
    • Influence of common genetic variation on rosuvastatin therapy in JUPITER
      temporal sequence of statin pharmacology
      CYP’s
      HMGCR
      APOB
    • Predicting LDL-C reductionGenetic score: sum of inherited “risk alleles”
      absolute LDL-C response
      fractional (%) LDL-C response
    • Effects of genetic score
      Estimates per unit of score, i.e. per inherited allele
    • 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
    • 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
    • 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