Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL- XXXX without Modification of Metabolic or Inflammatory Markers.

@entity32 @entity8359 @entity28 @entity72326 @entity72325 @entity9478 @entity9477 @entity731 @entity413 @entity165
OBJECTIVE: Phosphoinositide 3-kinase y (PI3Ky) is a G-protein-coupled receptor-activated lipid kinase mainly expressed in leukocytes and cells of the cardiovascular system. PI3Ky plays an important signaling role in inflammatory processes. Since subclinical @entity32 is a hallmark of @entity731 , @entity28 -related insulin resistance, and pancreatic b-cell failure, we asked whether common genetic variation in the PI3Ky gene ( @entity8359 ) contributes to body fat content/distribution, serum adipokine/cytokine concentrations, alterations in plasma lipid profiles, insulin sensitivity, insulin release, and @entity413 homeostasis. STUDY DESIGN: Using a tagging single nucleotide polymorphism (SNP) approach, we analyzed genotype-phenotype associations in 2,068 German subjects genotyped for 10 @entity8359 SNPs and characterized by oral @entity413 tolerance tests. In subgroups, data from hyperinsulinaemic-euglycaemic clamps, magnetic resonance spectroscopy of the liver, whole-body magnetic resonance imaging, and intravenous @entity413 tolerance tests were available, and peripheral blood mononuclear cells (PBMCs) were used for gene expression analysis. RESULTS: After appropriate adjustment, none of the @entity8359 tagging SNPs was significantly associated with body fat content/distribution, adipokine/cytokine concentrations, insulin sensitivity, insulin secretion, or blood @entity413 concentrations (p>0.0127, all; Bonferroni-corrected a-level: 0.0051). However, six non-linked SNPs displayed at least nominal associations with plasma HDL- @entity165 concentrations, two of them ( @entity72325 and @entity72326 ) reaching the level of study-wide significance (p = 0.0003 and p = 0.0004, respectively). More precisely, @entity72325 and @entity72326 influenced @entity9477 -, but not @entity9478 -, @entity165 . With respect to the SNPs' in vivo functionality, @entity72325 was significantly associated with @entity8359 mRNA expression in PBMCs. CONCLUSIONS: We could demonstrate that common genetic variation in the @entity8359 locus, possibly via altered @entity8359 gene expression, determines plasma HDL- @entity165 concentrations. Since @entity9477 -, but not @entity9478 -, @entity165 is influenced by @entity8359 variants, PI3Ky may play a role in HDL clearance rather than in HDL biogenesis. Even though the molecular pathways connecting PI3Ky and HDL metabolism remain to be further elucidated, this finding could add a novel aspect to the pathophysiological role of PI3Ky in atherogenesis.
