Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans

Craig H Warden, Aaron Daluiski, Xiangdong Bu, Deborah A. Purcell-Huynh, Cynthia De Meester, Bie Huoy Shieh, Donald L. Puppione, Richard M. Gray, Gerald M. Reaven, Y. D Ida Chen, Jerome I. Rotter, Aldons J. Lusis

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Although it has been hypothesized that the synteny between mouse and human genes provides an approach to the localization of genes that determine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipoprotein A-II (apoAII) and free fatty acid (FFA) levels. ApoAII is the second most abundant protein of high density lipoprotein particles, but its function remains largely unknown. We now show that, in a backcross between strains Mus spretus and C57BL/6J, apoAII levels correlate with plasma FFA concentrations on both chow (P < 0.0001) and high-fat (P < 0.0003) diets and that apoAII levels are linked to the apoAII gene (P < 0.0002). To test whether variations of the apoAII gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease. The segregation of the apoAII gene was followed by using an informative simple sequence repeat in the second intron of the gene and two nearby genetic markers. Robust sib-pair linkage analysis was performed on members of these families using the SAGE linkage programs. The results suggest linkage between the human apoAII gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with plasma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linkage with a gene controlling FFA levels (P = 0.003). Evidence for nonrandom segregation was seen with markers as far as 6-12 centimorgans from the apoAII structural locus. These data provide evidence, in two species, that the apoAII gene is linked to a gene that controls plasma apoAII levels and that apoAII influences, by an unknown mechanism, plasma FFA levels. The results illustrate the utility of animal studies for analysis of complex traits.

Original languageEnglish (US)
Pages (from-to)10886-10890
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number22
StatePublished - Nov 15 1993

Keywords

  • Animal models
  • Atherosclerosis
  • Complex genetic traits
  • Sib pair

ASJC Scopus subject areas

  • General
  • Genetics

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    Warden, C. H., Daluiski, A., Bu, X., Purcell-Huynh, D. A., De Meester, C., Shieh, B. H., Puppione, D. L., Gray, R. M., Reaven, G. M., Chen, Y. D. I., Rotter, J. I., & Lusis, A. J. (1993). Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 90(22), 10886-10890.