| First Author | Paigen B | Year | 1986 |
| Journal | Mouse News Lett | Volume | 76 |
| Pages | 73 | Mgi Jnum | J:32776 |
| Mgi Id | MGI:80266 | Citation | Paigen B, et al. (1986) Genetics of artherosclerosis susceptibility among inbred strains of mice. Mouse News Lett 76:73 |
| abstractText | Full text of MNL contribution: GENETICS OF ARTHEROSCLEROSIS SUSCEPTIBILITY AMONG INBRED STRAINS OF MICE. Paigen B., Mitchell D., Holmes P., LeBoef R.C. Children's Hospital Medical Center, Oakland, CA, USA Inbred strains of mice vary in the number of aortic lesions formed in response to a high fat diet containing by weight 15% fat, 1.25% cholesterol and 0.5% cholic acid. A genetic analysis using recombinant inbred (RI) lines between the atherosclerosis- susceptible strain C57BL/6 and resistant strains C3H or BALB/c showed that one gene determining atherosclerosis susceptibility, called ath-1, maps on chromosome 1 near the genes, Alp-2 and Hdl-1, determining apolipoprotein A-II structure and HDL structure. This map position was confirmed by classic crosses between C57BL/6 and C3H and between C57BL/6 and BALB/c. F1 progeny are intermediate in phenotype. Analysis of the RI lines between C57BL/6 and atherosclerosis-resistant strain A revealed a second gene, ath-2. Evaluation of all available RI lines narrowed the map position of ath-2 to about 2% of the genome. A cross is now in progress to determine the exact location. Both ath-1 and ath-2 affect HDL levels in mice on a high fat diet. Atherosclerosis resistant mice have higher levels of HDL, consistent with epidemiological observations showing that persons with higher HDL levels have a reduced risk of heart disease. A number of investigators have mapped genes involved in heart disease in both humans and mouse. The emerging picture shows that genes involved in lipoprotein structure and metabolism cluster and that these clusters are on homologous regions of murine and human chromosomes. On murine chromosome 1 and human chromosome 1 are the genes determining structure of apolipoprotein A-II. Also found in the mouse cluster is Hdl-1, a gene determining the structure of HDL: no analogue is yet known in humans. We suggest that two human traits may be possible analogs of ath-1. The first is a human DNA polymorphism, mapping near apo A-II in humans, which is associated with variation in HDL quantity. The second is hyperalphalipoproteinemia, a trait characterized by elevated levels of HDL and resistance to heart disease. Mapping has not been done for this trait, but the phenotype is analogous to murine strains carrying the resistant phenotype for ath-1. We have also found that male sex or testosterone-treatment of females results in higher HDL levels in some strains. Among strains and sexes, the HDL level is highly correlated with the formation of atherosclerotic lesions. Thus whether the HDL level is altered genetically or by hormones, the resulting HDL level is critical in determining lesion formation. The mouse model may prove useful in determining how HDL levels are regulated and why high HDL levels are protective for heart disease. |
