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Quantitative Analysis and Characterization of Atherosclerotic Lesions in the Murine Aortic Sinus
Published on: December 7, 2013
A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the
Hayes M Dansky1, Pei Shu, M Donavan
1Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York 10021, USA.
Abstract:
Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.
Insights
Researchers identified new genetic factors influencing atherosclerosis beyond cholesterol. These findings in Apoe-deficient mice reveal novel susceptibility loci, offering new therapeutic targets for cardiovascular disease.
Area of Science:
- Cardiovascular Research
- Genetics
- Immunology
Background:
- Atherosclerosis treatments primarily target cholesterol, but efficacy varies among patients.
- This suggests other genetic factors contribute to atherosclerosis predisposition.
- Apolipoprotein E (Apoe) deficiency is a key model for studying atherosclerosis.
Purpose of the Study:
- To identify genetic loci regulating atherosclerosis susceptibility independent of cholesterol levels.
- To investigate mechanisms of atherosclerosis beyond lipoprotein regulation.
- To discover novel genetic targets for atherosclerosis intervention.
Main Methods:
- Quantitative trait locus (QTL) analysis was performed on two inbred strains of Apoe-deficient mice.
- Crosses between C57BL/6 and FVB/N Apoe-deficient mice were utilized.
- Statistical analysis identified significant and suggestive genetic loci influencing lesion size.
Main Results:
- A significant locus on chromosome 10 explained 19% of the variance in lesion area, independent of cholesterol.
- Two suggestive loci on chromosomes 14 and 19 each accounted for 7-8% of lesion variance.
- Five loci affecting lesion size, but not lipoprotein levels, were identified and partially confirmed in a separate cross.
Conclusions:
- Previously unreported atherosclerosis susceptibility loci have been identified.
- These loci are distinct from those linked to lipoprotein levels.
- The findings provide new insights into the genetic basis of atherosclerosis and potential therapeutic avenues.
