EVIDENCE FOR LINKAGE OF THE APOLIPOPROTEIN-A-II LOCUS TO PLASMA APOLIPOPROTEIN-A-II AND FREE FATTY-ACID LEVELS IN MICE AND HUMANS

Although it has been hypothesized that the synteny between mouse and h uman genes provides an approach to the localization of genes that dete rmine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipopr otein A-II (apoAII) and free fatty acid (FFA) levels. ApoAII is the se cond 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 wit h 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 p lasma lipid metabolism in humans, we studied 306 individuals in 25 fam ilies enriched for coronary artery disease. The segregation of the apo AII gene was followed by using an informative simple sequence repeat i n 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 t he human apoAII gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with pl asma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linka ge with a gene controlling FFA levels (P = 0.003). Evidence for nonran dom segregation was seen with markers as far as 6-12 centimorgans from the apoAII structural locus. These data provide evidence, in two spec ies, that the apoAII gene is linked to a gene that controls plasma apo AII 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.