Pharmacogenetics of Statin Therapies

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

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

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)

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

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

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)

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)