Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Many antiretroviral drugs have large blood plasma (BP): seminal plasma (SP) ratios based on total drug concentrations. Concern exists that these drugs don’t adequately penetrate the male genital tract (MGT), resulting in a pharmacologic sanctuary with ineffective MGT concentrations despite effective blood concentrations. Efavirenz (EFV) is the most highly protein-bound antiretroviral drug, with >99% binding in blood plasma and the largest BP:SP total EFV concentration ratio, reportedly ranging from 11 to 33. To evaluate protein binding as the explanation for blood-semen differences, we developed a novel centrifugation time corrected ultrafiltration method to measure protein binding in both matrices. In 6 subjects, protein-free EFV concentrations were the same in blood and semen; median (IQR) protein-free EFV SP: BP ratio calculated for each individual was 1.21 (0.99 – 1.35). EFV protein binding was 99.82% (99.79 – 99.86) in BP and 95.26% (93.24 – 96.67) in SP. The MGT is not a pharmacological sanctuary from efavirenz.

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