Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6using the Ldlr knockout mouse model

Atherosclerosis is a complex disease resulting from the interaction of mult iple genes. We have used the Ldlr knockout mouse model in an interspecific genetic cross to map atherosclerosis susceptibility loci. A total of 174 (M OLF/Ei x B6.12957-Ldlr(tm1Her)) x C57BL/GJ-Ldl(tm1Her) backcross mice, homo zygous for the Ldlr null allele, were fed a Western-type diet for 3 months and then killed for quantification of aortic lesions, A genome scan was car ried out by using DNA pools and microsatellite markers spaced at approximat e to 18-centimorgan intervals. Quantitative trait locus analysis of individ ual backcross mice confirmed linkages to chromosomes 4 (Athsq1, logarithm o f odds = 6.2) and 6 (Athsq2, logarithm of odds = 6.7). Athsq1 affected lesi ons in females only whereas Athsq2 affected both sexes. Among females, the loci accounted for approximate to 50% of the total variance of lesion area. The susceptible allele at Athsq1 was derived from the MOLF/Ei genome where as the susceptible allele at Athsq2 was derived from C57BL/6J. Inheritance of susceptible alleles at both loci conferred a 2-fold difference in lesion area, suggesting an additive effect of Athsq1 and Athsq2, No associations were observed between the quantitative trait loci and levels of plasma tota l cholesterol, high density lipoprotein cholesterol, non-high density lipop rotein cholesterol, insulin, or body weight. We provide strong evidence for complex inheritance of atherosclerosis in mice with elevated plasma low de nsity lipoprotein cholesterol and show a major influence of nonlipoprotein- related factors on disease susceptibility. Athsq1 and Athsq2 represent cand idate susceptibility loci for human atherosclerosis, most likely residing o n chromosomes 1p36-32 and 12p13-12, respectively.