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
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%
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
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.
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
Genetic 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 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)