Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment

AbstractNiemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response

Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants

This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case–control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E ? 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOE?4 and ?2/3 variants (0.09 < D?<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07–1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87)