Bile Acid Malabsorption in Cystic Fibrosis; Membrane Vesicles, a Tool for Revealing the Role of the Ileal Brush Border Membrane

ABSTRACT. Increased fecal bile acid loss in cystic fibrosis (CF) may result from ileal dysfunction. A method to quantitate in vitro Na+‐dependent taurocholate uptake into brush border membrane vesicles prepared from frozen ileum and ileal biopsy specimen is described. This transport across the ileal brush border membrane can be measured selectively, in contrast to in vivo measurements which represent a complex overall process. Preliminary results obtained with ileal specimen of 2 CF patients, suggest that in vitro bile acid uptake is low but not abnormal. Copyrigh

Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Diabetes mellitus: pathophysiological changes and therap

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageMutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.Dutch Heart Foundation (2006B190) and Unilever, UK. Additional funding was provided by Pfizer and MSD The Netherlands. SEH acknowledges BHF support (RG 2008/008) and also funding from the Department of Health’s NIHR Biomedical Research Centre funding scheme. ER is supported by grant FIS PS09/01292 from ISCIII, Spain