Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice.

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Animals, Cholesterol-HDL, Crosses-Genetic, Dietary-Fats, Epistasis-Genetic, Lipoproteins-HDL, Mice-Inbred-C57BL, Mice-Inbred-DBA, Species-Specificity

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Physiol Genomics 2010 Nov; 42A(4):228-34.


Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J x DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain.