Based on human/mouse comparative sequence analysis we have identified a fourth member of the chromosome 11 apolipoprotein (apoAI, apoCIII, apoAIV) gene cluster which we have named apolipoprotein AV (apoAV). Our recent studies in humans and mice indicate that apoAV is an important determinant of plasma triglyceride levels. In mice, the overexpression of a human apoAV transgene resulted in decreased plasma triglyceride concentrations, while inactivation of the mouse apoAV gene led to increased triglyceride levels. Complementing these mouse findings, three independent human studies consistently showed that two minor apoAV haplotypes are strongly associated with increased triglycerides. These initial investigations indicate that the newly discovered apolipoprotein gene, apoAV, is an important modulator of plasma triglyceride levels in mammals. Accordingly, this grant focuses on deciphering several fundamental properties of apoAV that include: 1) determining the mechanism by which apoAV affects plasma triglycerides and its atherogenic consequences using apoAV transgenic and knockout mice, 2) investigating the factors and DNA sequences involved in the regulation of apoAV expression and 3) using a combination of human haplotype studies and defined manipulations of the mouse genome to identify apoAV single nucleotide polymorphisms (SNPs) that directly participate in determining triglyceride levels in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071954-04
Application #
6995366
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Srinivas, Pothur R
Project Start
2002-12-01
Project End
2006-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$596,628
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey et al. (2007) In vivo characterization of human APOA5 haplotypes. Genomics 90:674-9
Cheng, Jan-Fang; Pennacchio, Len A (2003) Comparative and functional analysis of cardiovascular-related genes. Pharmacogenomics 4:571-82