The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid. Strains C57L, SWR, and A were notable for a high prevalence of cholelithiasis; strains C57BL/6, C3H, and SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 exhibited no cholelithiasis after consuming the diet for 18 weeks. Genetic analysis of the difference in gallstone prevalence rates between strains AKR and C57L was carried out by using the AKXL recombinant inbred strain set and (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least two genes. A major gene, named Lithl, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) was downregulated as expected in the gallstone-resistant strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggests that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. These studies indicate that genetic factors are critical in determining gallstone formation and that the genetic resources of the mouse model may permit these factors to be identified.Both atherosclerosis and cholelithiasis result from excess cholesterol; in the one case cholesterol is deposited in arterial walls, and in the other case cholesterol precipitates in the gallbladder. Both diseases are prevalent in cultures consuming a Western diet, and both can be induced in animal models by a diet high in cholesterol (1,2). In Western cultures, heart disease is the major cause of death, and gallstone disease is present in 10-40% of individuals over the age of 60 (3).Genetic factors apparently play an important role in the development of cholesterol gallstone disease. Among studies of gallstone formation in animals, Alexander and Portman (4) demonstrated that C57BL/6 mice are susceptible to cholelithiasis, but CBA mice are resistant. In both strains bile was supersaturated with cholesterol but not to the same degree (4). Fujihara et al. (5) reported that the prevalence of gallstones varied from 0% to 100% among six strains of laboratory mice.Evidence for the importance of genetic factors in human cholelithiasis is limited. Gallstone disease can be familial (6-11), and the bile from healthy sisters of female gallstone patients is more lithogenic than controls (11,12). In certain native populations of North and South America, a high percentage of adults develop cholesterol gallstones, suggesting common genetic factors (13,14).In previous studies, high fat plus high cholesterol diets produced atherosclerosis and gallstones in some strains of mice (15). In this report, we survey common inbred strains of mice for susceptibility to cholelith...

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...