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.

Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis

“…Under normal conditions, blood 1,25(OH) 2 D levels are controlled by multiple mechanisms including genetic factors [27], blood IGF-1 levels [28, 29], blood FGF-23 levels [27], and blood 25(OH)D levels [29]. It has been shown that blood IGF-1 levels positively [28, 29] and blood FGF-23 levels negatively [27] correlate with blood 1,25(OH) 2 D levels. However, blood 25(OH)D levels do not correlate with blood 1,25(OH) 2 D levels [27, 30].…”

“…It has been shown that blood IGF-1 levels positively [28, 29] and blood FGF-23 levels negatively [27] correlate with blood 1,25(OH) 2 D levels. However, blood 25(OH)D levels do not correlate with blood 1,25(OH) 2 D levels [27, 30]. Blood 1,25(OH) 2 D levels change only when blood 25(OH)D levels change dramatically [30].…”

A platform for experimental precision medicine: The extended BXD mouse family

“…The BXD Family Is the Largest and the Most Deeply Phenotyped Mammalian Genetic Reference Panel Data sets for the BXD encompass multiple levels-from single molecules to complex behavioral repertoires and to traits measured with environmental perturbations, including exposure to alcohol and drugs of abuse (Dickson et al, 2019;Mulligan et al, 2018;Thé berge et al, 2019;Zhou et al, 2018), infectious agents (Boon et al, 2014;Chella Krishnan et al, 2016;Russo et al, 2015), dietary modifications (Fleet et al, 2016;Jha et al, 2018bJha et al, , 2018aJones and Jellen, 2017;Reyes Fernandez et al, 2016;Rodrigues et al, 2017), stress (Diessler et al, 2018;Jung et al, 2017), and even as a function of age (Sandoval-Sierra et al, 2020;Williams et al, 2020). This phenome is linked to over 500 publications, including state-of-the-art proteome, metabolome (Williams et al, 2018(Williams et al, , 2020, epigenome (Baker et al, 2019;Sandoval-Sierra et al, 2019), and metagenome (Perez-Munoz et al, 2019) data sets available on GeneNetwork.org.…”

“…This phenome extends back to Taylor's (1973) analysis of cadmium toxicity, through to recent studies of metabolism (Roy et al, 2020;Wang et al, 2013Wang et al, , 2016bWilliams et al, 2016Williams et al, , 2020Wu et al, 2014), addiction (Dickson et al, 2016(Dickson et al, , 2019Mulligan et al, 2013), behavior (Carhuatanta et al, 2014;Graybeal et al, 2014;Mulligan and Williams, 2015;Philip et al, 2010), infectious disease (Hayes et al, 2014;McKnite et al, 2012;Wang et al, 2020), epigenetics (Baker et al, 2019; Sandoval-Sierra et al, 2020), and even indirect genetic effects (Ashbrook et al, 2015a(Ashbrook et al, , 2017Baud et al, 2017). BXDs have been used to test developmental and evolutionary hypotheses (Hager et al, 2012;Oren et al, 2015;Seecharan et al, 2003), to study GXE and consequences of treatments as a function of age, diet, and sex (Fleet et al, 2016;Philip et al, 2010;Roy et al, 2020;Sandoval-Sierra et al, 2020;Williams et al, 2016Williams et al, , 2020, gene pleiotropy (Wang et al, 2016a), and to test behavioral predictions based on differences in brain architecture (Yang et al, 2008).…”

Is the vitamin D status of patients with COVID-19 associated with reduced mortality?

“…Therefore, a possible hypothesis that could explain our findings would be that tissue damage in the kidneys and to a lesser extent in the lung caused by SARS-CoV2 may lead to an active decrease of 1,25(OH)D, responsible for the majority of biological actions of Vitamin D, but not in the form usually determined in plasma, Calcifediol. Previous studies showed that blood 25(OH)D levels may not correlate with blood 1,25(OH)2D levels in some clinical conditions [63][64][65].…”