ABSTRACT
BACKGROUND: The beneficial effect of HMG-CoA reductase inhibitors (statins) on coronary artery disease has been linked to mechanisms beyond their lipid-lowering effect. However the existence of direct, lipid-independent effects of statin in humans is still controversial. OBJECTIVE: To investigate the early effect of atorvastatin on peripheral blood mononuclear cells (PBMC) in dyslipidemic patients using gene arrays. PATIENTS AND METHODS: Eleven male patients with primary hyperlipidemia received 20 mg atorvastatin daily for 4 weeks. Blood was collected at baseline, 12 h, 36 h, 1 and 4 weeks after the start of treatment. RESULTS: Human microarrays containing 12 650 genes were used to study the effect of atorvastatin on PBMC gene expression at all time-points. Two hundred and forty genes were significantly regulated by atorvastatin treatment, several of which are involved in hemostasis, inflammation and other processes critical to atherosclerosis. Different patterns of response over time suggested both lipid-dependent and independent effects of atorvastatin on gene expression. CONCLUSIONS: This study demonstrates for the first time that atorvastatin regulates gene expression in PBMC in man before changes in the lipid profile are detectable in serum. Using blood leukocytes as a pharmacogenomic surrogate, we have identified new in vivo targets of atorvastatin treatment.
Subject(s)
Gene Expression Regulation , Heptanoic Acids/pharmacology , Hyperlipidemias/blood , Leukocytes/drug effects , Leukocytes/metabolism , Pyrroles/pharmacology , Adult , Anticholesteremic Agents/pharmacology , Apoptosis , Atorvastatin , Cholesterol/blood , Cluster Analysis , Hemostasis , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation , Leukocytes, Mononuclear/metabolism , Lipid Metabolism , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , RNA/metabolism , Receptors, LDL/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time FactorsABSTRACT
Cleft palate most commonly occurs as a sporadic multifactorial disorder with a clear but difficult to define genetic component. As a semi-dominant disorder, X-linked cleft palate (CPX) provides a useful model to investigate a congenital defect that is little influenced by non-genetic factors. By using an Icelandic kindred, CPX has been localised between DXS1196 and DXS1217 and mapped, in a 3-Mb yeast artificial chromosome contig, at Xq21.3. Markers generated from this physical map have now been used to construct a contig of P1 and bacterial artificial chromosome clones for genomic DNA sequencing. Genomic DNA sequence analysis has revealed two novel expressed genes and two pseudogenes in the order Cen-KLHL4-LAMRL5-CAPZA1P-CPXCR1-Tel. KLHL4 and CPXCR1 are widely expressed in fetal tissues, including the tongue, mandible and palate. DNA mutation screening of CPXCR1 has revealed several sequence variants present on all affected CPX chromosomes. However, these variants have also been detected at a lower frequency on unaffected chromosomes, indicating that they are polymorphisms that are unlikely to cause the CPX phenotype.
