Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels

An elevated plasma apolipoprotein B (apoB) level is a strong predictor of a therosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma a poB levels In the general population, Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mi ce of the C57BL/6 (B6) and 129/Sv (129) strains, respectively, In the prese nt article, we present the identification of two novel quantitative trait l oci (QTL) as major regulators of plasma human apoB levels in the Fz and Ng (backcrossed) offspring (n = 572) derived from crosses between the B6 and 1 29 mouse strains. These loci were designated ApoB regulator genes (Abrg), b ecause the gene products are Likely to be involved in the regulation of pla sma apoB levels either directly or indirectly, The first locus, designated Abrg1, was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker ( similar to 45.9 cM). Abrg1 contributed approximately 35% of the genetic var iance. The second locus, designated Abrg2, was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker (similar to 35 cM), Abrg2 con tributed approximately 26% of the genetic variance. Epistasis between Abrg1 and Abrg2 was defected and accounted for approximately 12% of the genetic variance. The combination of these two QTL has major effects (> 70%) on the regulation of plasma human apoB levels in the tested population. In summar y, we have identified two novel loci that have a major role in the regulati on of plasma apoB levels and are likely to regulate tire secretory pathway of apoB, The human orthologs for the Abrg loci are strong candidates for hu man disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia. - Ko, C., T-L. Lee, P. W. Lau, J. Li, B. T. Davis, E. Voyaziakis, D. B. Allison, S. C. Chua,Jr:, and L-S. Huang. Tw o novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels.