Natural genetic variation affecting calcium homeostasis
Abstract
Calcium (Ca) is essential for multiple functions within the body including skeletal health. The level of Ca in the serum is tightly regulated. During periods of habitual low Ca intake, the body senses a decrease in serum Ca and increases renal conversion of 25 hydroxyvitamin D (25(OH)D) to 1,25 dihydroxyvitamin D (1,25(OH)2D). 1,25(OH)2D acts through the vitamin D receptor (VDR) to increase intestinal Ca absorption, renal Ca reabsorption and skeletal Ca resorption. Efficient intestinal Ca absorption, especially during periods of low Ca intake, is critical for protecting bone mass. Ca absorption and its primary regulator, 1,25(OH)2D, are affected by both genetic and environmental factors. However, the genetic architecture of these phenotypes has not been carefully studied in a controlled environment. Using genetically characterized mouse models in a controlled environment the studies in this dissertation characterize the natural genetic variation affecting intestinal Ca absorption, 25(OH)D, and 1,25(OH)2D under normal and low dietary Ca conditions. This dietary intervention allowed for the study of gene-by-diet interactions (i.e. variability in the adaptation of these parameters to habitual low Ca intake). The relationship of Ca absorption to known regulators and cellular mediators is examined, elucidating significant effects of genetics on these relationships and identifying gaps in our current knowledge of intestinal Ca absorption. In addition, specific genetic loci affecting intestinal Ca absorption, 1,25(OH)2D, 25(OH)D, and diet-induced adaptation are identified in the mouse genome. These quantitative trait loci (QTLs) represent novel variation affecting Ca absorption and vitamin D metabolites. Identification of the causal variation underlying these QTLs will expand our knowledge of Ca homeostatic pathways. These studies serve as a foundation for identification of individual variation in Ca homeostasis and personalized dietary recommendations.
Degree
Ph.D.
Advisors
Fleet, Purdue University.
Subject Area
Genetics|Nutrition|Physiology
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