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Objectives Identify SNPs associated with mild statin-induced side effects. Background Statin-induced side effects can interfere with therapy. SNPs in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with CK elevation. Methods The STRENGTH study was a pharmacogenetics study of statin efficacy and safety. Subjects (n=509) were randomized to atorvastatin 10mg, simvastatin 20mg, or pravastatin 10mg followed by 80mg, 80mg, and 40mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK>3× baseline during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested seven reduced function alleles for association with the CAE. Results The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and nine CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p<0.01). SLCO1B1*5 was associated with CAE (percent with ≥ 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p=0.03) and those with CAE with no significant CK elevation (p≤ 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be highest in those carriers assigned to simvastatin. Conclusions SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome wide association study of statin myopathy with CK > 3 times normal to milder, statin-induced, muscle side effects.

Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case-control WGA study in schizophrenia, examining B500 000 markers, which revealed a strong effect (P = 3.7 Â 10 À7 ) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case-control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.

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clinicaltrials.gov Identifier: NCT00683592.