Human Evidence That the Apolipoprotein A-II Gene Is Implicated in Visceral Fat Accumulation and Metabolism of Triglyceride-Rich Lipoproteins

Background—Apolipoprotein (apo) A-II is a major structural protein of plasma HDLs, but little is known regarding its functions. Methods and Results—To investigate the physiological role of apoA-II in humans, we screened the promoter region of the apoA-II gene for a functional polymorphism and used this polymorphism as a tool in association studies. A common, functional polymorphism in the promoter region of the apoA-II gene, a T to C substitution at position 2265, was found. Electrophoretic mobility shift assays demonstrated that the 2265T/C polymorphism influences the binding of nuclear proteins, whereas transient transfection studies in human hepatoma cells showed a reduced basal rate of transcription of the 2265C allele compared with the 2265T allele. The 2265C allele was associated with decreased plasma apoA-II concentration and decreased waist circumference in healthy 50-year-old men. In addition, oral fat tolerance tests provided evidence that the 2265C allele enhances postprandial metabolism of large VLDLs. Conclusions—ApoA-II appears to promote visceral fat accumulation and impair metabolism of large VLDLs. (Circulation. 2001;104:1223-1228.)