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 atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a hu- man apoB transgenic (HuBTg) mouse model, we have pre- viously shown that hepatic apoB-100 secretion is a major de- terminant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F 2 and N 2 (backcrossed) offspring (n � 572) derived from crosses between the B6 and 129 mouse strains. These loci were des- ignated ApoB regulator genes ( Abrg ), because the gene prod- ucts are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, des- ignated 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 ( � 45.9 cM). Abrg1 contributed approximately 35% of the genetic vari- ance. 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 ( � 35 cM). Abrg2 contributed approximately 26% of the genetic variance. Epistasis be- tween Abrg1 and Abrg2 was detected and accounted for ap- proximately 12% of the genetic variance. The combination of these two QTL has major effects ( � 70%) on the regula- tion of plasma human apoB levels in the tested popula- tion. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candi- dates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipopro-