Abstract 68: The WWOX Gene Modulates HDL Metabolism and Lipoprotein Gene Expression

Low plasma HDL cholesterol (HDL-C) constitutes a major risk factor for coronary artery disease. We previously identified a region-wide association between low HDL-C and the WW domain-containing oxidoreductase ( WWOX) gene in dyslipidemic families and low HDL-C cases and controls (rs2548861, P=6.9x10 -7 ). Here, through a combination of in vivo functional studies, gene microarray and next generation resequencing, we investigated the role of WWOXin lipoprotein and HDL metabolism. Using total Wwox-/- and Wwoxliver-specific ( hep -/- ) mice, we found decreased apoA-I and ABCA1protein levels in hepatic tissues. Analyses of lipoprotein profiles in Wwox-/- littermates also showed marked reductions in serum HDL-C and apoA-I levels, with no effect in Wwoxhep -/- mice. A sex-specific difference was however observed in female Wwoxhep -/- mice, showing a significant increase in plasma triglycerides levels. We further obtained evidence of a gender-specific effect by gene microarray analyses in Wwoxhep -/- hepatocytes, where it was identified that WWOXdisruption alters primarily lipid metabolic pathways in females. We observed a significant reduction (P