title: Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice.
abstract: 1,25-Dihydroxyvitamin D (1,25[OH]2D) regulates calcium (Ca), phosphate, and bone metabolism. Serum 1,25(OH)2D levels are reduced by low vitamin D status and high fibroblast growth factor 23 (FGF23) levels and increased by low Ca intake and high PTH levels. Natural genetic variation controls serum 25-hydroxyvitamin D (25[OH]D) levels, but it is unclear how it controls serum 1,25(OH)2D or the response of serum 1,25(OH)2D levels to dietary Ca restriction (RCR). Male mice from 11 inbred lines and from 51 BXD recombinant inbred lines were fed diets with either 0.5% (basal) or 0.25% Ca from 4 to 12 weeks of age (n = 8 per line per diet). Significant variation among the lines was found in basal serum 1,25(OH)2D and in the RCR as well as basal serum 25(OH)D and FGF23 levels. 1,25(OH)2D was not correlated to 25(OH)D but was negatively correlated to FGF23 (r = -0.5). Narrow sense heritability of 1,25(OH)2D was 0.67 on the 0.5% Ca diet, 0.66 on the 0.25% Ca diet, and 0.59 for the RCR, indicating a strong genetic control of serum 1,25(OH)2D. Genetic mapping revealed many loci controlling 1,25(OH)2D (seven loci) and the RCR (three loci) as well as 25(OH)D (four loci) and FGF23 (two loci); a locus on chromosome 18 controlled both 1,25(OH)2D and FGF23. Candidate genes underlying loci include the following: Ets1 (1,25[OH]2D), Elac1 (FGF23 and 1,25[OH]2D), Tbc1d15 (RCR), Plekha8 and Lyplal1 (25[OH]D), and Trim35 (FGF23). This report is the first to reveal that serum 1,25(OH)2D levels are controlled by multiple genetic factors and that some of these genetic loci interact with the dietary environment.
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Replogle
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Perla
authors.initials: P
authors.lastname: Reyes-Fernandez
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Libo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Clinkenbeard
authors.affiliation: Departments of Nutrition Science (J.C.F., R.A.R., P.R.-F.) and Statistics (L.W., M.Z.), Purdue University, West Lafayette, Indiana 47907-2059; and Department of Medical and Molecular Genetics (E.L.C., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
mesh_terms: D000818:Animals; D002118:Calcium / Q000172:deficiency; D002136:Calcium, Dietary / Q000378:metabolism; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004032:Diet; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D059647:Gene-Environment Interaction; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci; D011995:Recombination, Genetic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D002136:Calcium, Dietary; C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; D002118:Calcium