Abstract-To identify the genetic factors affecting susceptibility to atherosclerosis, we studied the inheritance of plasma total cholesterol (TC) and HDL cholesterol (HDL-C) concentrations and susceptibility to atherosclerotic lesion formation in an (SM/J[SM]ϫNZB/BlNJ[NZB]) outcross, an (SMϫNZB)F1[F1]ϫSM backcross, and the NXSM recombinant inbred (RI) strain set. After 18 or 26 weeks on the atherogenic diet, lesion sizes in female mice were 160Ϯ110 (SE) m 2 for NZB, 100Ϯ60 for F1, and 3800Ϯ920 for SM. After 0, 4, or 26 weeks on the atherogenic diet, NZB had higher TC and HDL-C levels than either SM or F1. The F1 progeny had TC and HDL-C levels slightly higher than or similar to the SM/J parent, while lesion size in the F1 progeny was more similar to the NZB parent. Among the 15 RI strains, 8 resembled NZB and F1, 3 resembled SM, and 4 were intermediate between NZB and SM for lesion size. For the (SMϫNZB)F1ϫSM backcross offspring, 26 resembled NZB and F1, 7 resembled SM, and 6 were intermediate between NZB and SM for lesion size. There was poor correlation between lesion size and plasma TC or HDL-C in the parental strains and the backcross. These data suggest that resistance to atherosclerosis is determined by at least one major dominant gene contributed by the NZB strain, which we have named Ath8. Ath8 segregates independently of genes controlling TC and HDL-C levels. (Arterioscler Thromb Vasc Biol. 1998;18:615-620.) Key Words: genetics Ⅲ quantitative trait loci analysis Ⅲ atherosclerosis Ⅲ recombinant inbred strains Ⅲ lipids A therosclerosis is an important disease affecting millions of Americans. Many factors, including genetics, behavior, and environment, contribute to the risk of developing atherosclerosis, and great progress has been made in identifying many of these risk factors. The mouse has become a particularly useful tool for identifying genetic factors contributing to many diseases, including atherosclerosis, 1-4 because of the existence of inbred, RI, and mutant strains 5 and the development of molecular techniques allowing for the creation of transgenic 6 and knockout mice. 7 Also, recent developments in mapping technologies have resulted in the development of high-resolution genetic 8 and physical maps of the mouse genome. -10Inbred mouse strains differ in plasma lipoprotein concentrations, responsiveness to high-fat, high-cholesterol diets, and susceptibility to atherosclerotic lesion development, 11,12 thus providing useful tools for identifying genetic factors responsible for these differences.13,14 Two of these inbred strains, SM and NZB, differ in plasma TC and HDL-C concentrations 11,15 and in susceptibility to atherosclerotic lesions.11 When female mice are fed either a chow or a high-fat, high-cholesterol diet, NZB have higher plasma TC and HDL-C concentrations than SM. When consuming a chow diet, neither strain develops atherosclerosis, but when fed the high-fat, high-cholesterol diet, NZB females are resistant to lesion formation, whereas SM females develop large lesions. Because high HD...

Mice from the inbred strain C57BLKS/J (BKS) exhibit increased susceptibility to both diabetes and atherosclerosis compared to C57BL/6J (B6) mice. To determine whether the differences in diabetes and atherosclerosis are related, we carried out a cross between B6db/db and BKS. We selected 99 female F 2 -db/db progeny, tested the progeny for plasma lipids, plasma glucose, and fatty-streak lesions, and used quantitative trait loci (QTL) analysis to identify the chromosomal regions associated with these phenotypes. No major QTL were found for total cholesterol, VLDLcholesterol, or triglycerides. Two suggestive QTL were found for HDL-cholesterol (LOD scores of 2.7 and 2.8), and two suggestive loci were found for plasma glucose (LOD scores of 2.3 and 2.0). Lesion size was not correlated with plasma lipid levels or glucose. Lesion size was determined by a locus at D12Mit49 with a LOD score of 2.5 and a significant likelihood ratio statistic. The gene for apolipoprotein apoB lies within the region, but apoB levels were similar in strains B6 and BKS. The QTL on Chr 12 was confirmed by constructing a congenic strain with BKS alleles in the QTL region on a B6 genetic background.We conclude that susceptibilities to diabetes and atherosclerosis are not conferred by the same genes in these strains and that a major gene on Chr 12, which we name Ath6 , determines the difference in atherosclerosis susceptibility.