All samples in our analysis were derived from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study. The study population, experimental design, and genotyping procedures have been described in detail previously [6 (link)]. Briefly, this study contains individuals from two statin trials: the Cholesterol and Pharmacogenetics (CAP) study [8 (link)], and the Pravastatin Inflammation/CRP Evaluation (PRINCE) study [9 (link)]. The PRINCE study consists of two cohorts, one containing individuals with history of CVD (secondary prevention cohort) and the other containing individuals with no history of CVD (primary prevention cohort). Participant characteristics are summarized in Table 1 .
Genotyping was conducted in two stages. The first stage individuals were genotyped on the Illumina HumanHap300 bead chip and the second stage individuals were genotyped on the Illumina HumanQuad610 bead chip and a custom-made iSelect chip. The HumanHap300 and the HumanQuad610 chips (henceforth referred to as the 300K chip and the 610K chip) were designed to tag common variation among individuals of European ancestry while 12,959 SNPs in the iSelect chip were selected to increase coverage of candidate SNPs for cardiovascular disease regardless of minor allele frequency (MAF). Our analyses reported here utilized a total of 1,868 Caucasian individuals for whom complete LDL subfraction phenotype data were available (see below).
To maximize genomic coverage and combine the multiple groups genotyped on different SNP chips, we performed genotype imputation [10 (link)] [11 (link)], using an imputation protocol that has been previously described [12 (link)]. Briefly, genotype imputation was performed using IMPUTE2 [10 (link)] with an integrated reference panel that included 120 CEU haplotypes from the 1000 Genomes Pilot Project (“1000G”) [13 (link)] and 1910 worldwide haplotypes from the HapMap Phase 3 Project (“HM3”) [14 (link)]. This procedure generated genotypes (either genotyped or imputed) for 7,836,525 SNPs.
Genotyping was conducted in two stages. The first stage individuals were genotyped on the Illumina HumanHap300 bead chip and the second stage individuals were genotyped on the Illumina HumanQuad610 bead chip and a custom-made iSelect chip. The HumanHap300 and the HumanQuad610 chips (henceforth referred to as the 300K chip and the 610K chip) were designed to tag common variation among individuals of European ancestry while 12,959 SNPs in the iSelect chip were selected to increase coverage of candidate SNPs for cardiovascular disease regardless of minor allele frequency (MAF). Our analyses reported here utilized a total of 1,868 Caucasian individuals for whom complete LDL subfraction phenotype data were available (see below).
To maximize genomic coverage and combine the multiple groups genotyped on different SNP chips, we performed genotype imputation [10 (link)] [11 (link)], using an imputation protocol that has been previously described [12 (link)]. Briefly, genotype imputation was performed using IMPUTE2 [10 (link)] with an integrated reference panel that included 120 CEU haplotypes from the 1000 Genomes Pilot Project (“1000G”) [13 (link)] and 1910 worldwide haplotypes from the HapMap Phase 3 Project (“HM3”) [14 (link)]. This procedure generated genotypes (either genotyped or imputed) for 7,836,525 SNPs.
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