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Genetic loci determining bone density in mice with diet-induced atherosclerosis

¹ Departments of Pathology and Laboratory Medicine
² Orthopedic Surgery
³ Radiology
⁴ Medicine
⁵ Microbiology, Immunology and Molecular Genetics
⁶ Biomathematics, University of California, Los Angeles, California 90095
⁷ Department of Bioinformatics, Rosetta Inpharmatics, Kirkland, Washington 98034

This study investigates the phenotypic and genetic relationships among bone-density-related traits and those of adipose tissue and plasma lipids in mice with diet-induced atherosclerosis. Sixteen-month-old female F2 progeny of a C57BL/6J and DBA/2J intercross, which had received an atherogenic diet for 4 mo, were examined for multiple measures of femoral bone mass, density, and biomechanical properties using both computerized tomographic and radiographic methods. In addition, body weight and length, adipose tissue mass, plasma lipids and insulin, and aortic fatty lesions were assessed. Bone mass was inversely correlated with extent of atherosclerosis and with a prooxidant lipid profile and directly correlated with body weight, length, and, most strongly, adipose tissue mass. Quantitative trait locus (QTL) analysis, using composite interval mapping (CIM) and multi-trait analysis, identified six loci with multi-trait CIM LOD scores > 5. Three of these coincided with loci linked with adipose tissue and plasma high-density lipoprotein. Application of statistical tests for distinguishing close linkage vs. pleiotropy supported the presence of a potential pleiotropic effect of two of the loci on these traits. This study shows that bone mass in older female mice with atherosclerosis has multiple genetic determinants and provides phenotypic and genetic evidence linking the regulation of bone density with adipose tissue and plasma lipids.

adipose tissue; plasma lipids; quantitative trait locus analysis; leptin; biomechanics; genetic pleiotropy

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