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  1. 1. Pharmacogenetics of Statin Therapies <br />Daniel I. Chasman, Ph.D.<br />Division of Preventive Medicine<br />Brigham and Women’s Hospital<br />Johanna and Ralph DeStefano Personalized Health Care Conference OSU Medical Center<br />Columbus, OH<br />Oct 6, 2011<br />
  2. 2. Disclosure<br />Funding for this research provided by<br />AstraZeneca<br />Celera<br />
  3. 3. Background and research questions<br />Background<br />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.<br />Research questions<br />What genes, in the entire genome, carry common genetic variation associated with LDL-C lowering on statin therapy?<br />What are the magnitudes of these effects?<br />Are there interactions involving these gene variants?<br />To what extent do the genetic effects explain variation in inter-individual statin response?<br />
  4. 4. Some previous genetic analyses of LDL-C lowering with statin treatment<br />Candidate gene analysis1<br />HMGCR – target of statin therapy<br />APOE – major apolipoprotein of VLDL, IDL, chylomicrons<br />LDLR – LDL receptor<br />ABCG5/8 – sterol transporters<br />CYP7A1 – cytochrome P450 family metabolizing enzyme<br />ABCG2 – transporter in liver, kidney<br />Genome-wide association studies (GWAS)2<br />CLMN association in GWAS of PRINCE, CAP, and TNT (pravastatin, simvastatin, atorvastatin)<br />GRIK4 association in GWAS of TNT (atorvastatin)<br />SLCO1B1 association myopathy GWAS of SEARCH (simvastatin)<br />References<br />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. <br />2PLoS One. 2010 5:e9763 , N Engl J Med. 2008 ;359:789, Circ Cardio Genet. 2009 2:173. <br />
  5. 5. Known pharmacologic pathways for statin therapy<br />temporal sequence of statin pharmacology<br />CYP’s<br />ABCB1<br />ABCG2<br />SLCO1B1<br />HMGCR<br />LDLR<br />APOE<br />ABCG5/8<br />
  6. 6. Genome-wide association study (GWAS)<br />Focus on single nucleotide polymorphisms (SNPs), the most prevalent form of genetic variation in people<br />SNPs typically have two alleles, the major allele (≥50% in the population) and the minor allele (<50%)<br />In a single experiment, examine all common SNPs at once. For 1% allele frequency, approx. 1 million SNPs.<br />Require very stringent significance, e.g. p < 5 x 10-8<br />Test for association of the minor allele with LDL-C response among individuals taking statin<br />
  7. 7. Population with genome-wide data from JUPITER<br />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<br />Genotyping on the Illumina Omni 1M Quad platform by Illumina<br />8,782 of the 12,649 JUPITER participants with consent and genotype had verified European ancestry<br />Compliance limits sample to 6,934<br />SNPs excluded when failing Hardy-Weinberg equilibrium test at P < 10-6, with the exception of rs7412 at APOE (E2 v. E3)<br />820,411 SNPs pass QC with minor allele frequency > 1%<br />1N Engl J Med. 2008 359:2195. <br />
  8. 8. Clinical characteristics of study sample(all European ancestry)<br />
  9. 9. Defining LDL-C response to statin therapy<br />Absolute LDL-C response:<br />LDL-C at 12 months – LDL-C baseline<br />Fractional (%) LDL-C response:<br />LDL-C at 12 months – LDL-C baseline = absolute ΔLDL-C<br /> LDL-C baseline LDL-C baseline<br />Statistical power: JUPITER sample with genome-wide genetic information is the largest to date with a single statin administered at a single dose<br />
  10. 10. Genome-wide association of baseline LDL-C<br /> ~820K SNPs <br />
  11. 11. Genome-wide association ofLDL-C lowering with rosuvastatin<br />< Absolute LDL-C reduction<br />Fractional LDL-C reduction ><br />
  12. 12. Genome-wide association of LDL-C lowering with placebo<br />< Absolute LDL-C reduction<br />Fractional LDL-C reduction ><br />
  13. 13. Magnitude of effects: best SNP at each locus<br />LDL-C lowering<br /># high LD<br />Baseline LDL-C<br />
  14. 14. Distribution of effect by genotype<br />
  15. 15. Total genetic effect: proportion of variance explained at genome-wide loci<br />“●” indicates locus with genome-wide association (p<5x10-8)<br />For comparison, age, BMI, sex, smoking status, region explain:<br />3.5% of absolute LDL-C response<br />3.7% of fractional LDL-C response<br />
  16. 16. Genes from genome-wide analysis<br />PCSK9 (chr. 1)<br />Serine protease with functions in LDLR protein degradation<br />ABCG2 (chr. 4)<br />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*.<br />LPA (chr. 6)<br />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.<br />APOE (chr. 19)<br />Major apolipoprotein component of VLDL, IDL, chylomicrons.<br />*Circ Cardiovasc Genet. 2010 Jun 1;3(3):276-85. <br />
  17. 17. Validation<br />No replication, but …<br />Genome-wide standard of significance (p<5x10-8) imposed<br />All loci previously recognized in genetics of statin response literature<br />Winner’s curse probably not a strong influence on effect estimates<br />Associations not merely due to individuals with extreme LDL-C since such individuals were excluded by the trial design<br />No effects at all in placebo<br />
  18. 18. Sub-genome-wide significant loci(5x10-8<P<5x10-6)<br />
  19. 19. IDOL (inducible degrader of LDL receptor)<br /><ul><li>IDOL (originally named MYLIP)</li></ul>Sterol responsive ubiquitin-mediated pathway for post-transcriptional regulation (degradation?) of the LDL receptor1<br />Regulated by LXR<br />Recently associated with baseline LDL-C2<br />Candidate therapeutic target for “statin-like” regulation of<br /> LDL-C levels mediated through the LDL receptor<br /><ul><li>EPB41LD</li></ul>Unknown function but shares band 4.1 homology with IDOL<br />1Science 2009 325:100-104<br />2PLoS Genetics 2009 5:e1000730. Nature 2010 466:707-13.<br />
  20. 20. Candidate associations<br />1,2locus-wide best SNP for absolute (1) or fractional (2) LDL-C reduction<br />No associations at GRIK4, CLMN, APOB, CYP3A5, CYP2C9<br />
  21. 21. Interaction analysis<br />No interaction among lead SNPs at genome-wide loci<br />No interaction between lead SNPs and other SNPs across genome<br />No interaction with sex<br />No evidence for conditional associations within top loci<br />However, evidence for PCSK9 X LDLR interaction with fractional LDL-C reduction (pint=0.002)<br />
  22. 22. Influence of common genetic variation on rosuvastatin therapy in JUPITER<br />temporal sequence of statin pharmacology<br />CYP’s<br />HMGCR<br />APOB<br />
  23. 23. Predicting LDL-C reductionGenetic score: sum of inherited “risk alleles”<br />absolute LDL-C response<br />fractional (%) LDL-C response<br />
  24. 24. Effects of genetic score<br />Estimates per unit of score, i.e. per inherited allele<br />
  25. 25. Another candidate (KIF6)<br />KIF6 gene non-synonymous variant (rs20455, MAF=34.7%). Minor allele (719Arg) has greater CV risk and greater response to atorvastatin (CARE, WOSCOP).<br />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<br />
  26. 26. Summary<br />In JUPITER, three (3) loci genome-wide significant association for LDL-C reduction with random rosuvastatin (20mg/dL) allocation: ABCG2, LPA, APOE<br />An additional locus (PCSK9) for LDL-C reduction arises from genome-wide association with baseline LDL-C.<br />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)<br />In total, 2.8% and 6.7% of the variance explained by four loci in absolute and fractional LDL-C reduction respectively<br />A sub-genome-wide association at IDOL is consistent with current understanding of LDL receptor regulation<br />Additional candidate analysis supports a role for variation in SLCO1B1 and LDLR<br />A genetic risk score reveals dependence of median LDL-C response on genetics but only explains a small proportion of the variance<br />No interaction effects with rosuvastatin observed for KIF6 variant<br />
  27. 27. Collaborators and support<br />BWH<br />Paul M Ridker, MD, MPH<br />Audrey Chu, PhD<br />Franco Guilianini, PhD<br />Jean MacFadyen, BS<br />AstraZeneca<br />Fredrik Nyberg, MD, PhD, MPH<br />Bryan Barratt, PhD<br />Support<br />AstraZeneca<br />Celera<br />