Genes in white blood cells of blacks associated with vitamin D deficiency

Created April 2013

A Genome-Wide Methylation Study of Severe Vitamin D Deficiency in African American Adolescents

The Journal of Pediatrics. Volume 162, Issue 5 , Pages 1004-1009.e1, May 2013

Haidong Zhu, MD, PhD email address , Xiaoling Wang, MD, PhD , Huidong Shi, PhD ,

Shaoyong Su, PhD , Gregory A. Harshfield, PhD , Bernard Gutin, PhD , Harold Snieder, PhD , Yanbin Dong, MD, PhD

Received 2 July 2012; received in revised form 13 September 2012; accepted 31 October 2012. published online 10 December 2012.

Objectives: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach.

Study design: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the “double hit” genes were randomly enriched.

Results:A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10−6, FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10−6, FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098).

Conclusion: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.

See also VitaminDWiki

References

  • Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000;374:334–338

  • Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281

  • Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor?. J Am Coll Cardiol. 2008;52:1949–1956

  • Woloszynska-Read A, Johnson CS, Trump DL. Vitamin D and cancer: clinical aspects. Best Pract Res Clin Endocrinol Metab. 2011;25:605–615

  • Ganji V, Zhang X, Shaikh N, Tangpricha V. Serum 25-hydroxyvitamin D concentrations are associated with prevalence of metabolic syndrome and various cardiometabolic risk factors in US children and adolescents based on assay-adjusted serum 25-hydroxyvitamin D data from NHANES 2001-2006. Am J Clin Nutr. 2011;94:225–233

  • Ginde AA, Liu MC, Camargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169:626–632

  • Dong Y, Pollock N, Stallmann-Jorgensen IS, Gutin B, Lan L, Chen TC, et al. Low 25-hydroxyvitamin D levels in adolescents: race, season, adiposity, physical activity, and fitness. Pediatrics. 2010;125:1104–1111

  • Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221:1181–1183

  • Bellia A, Garcovich C, D'Adamo M, Lombardo M, Tesauro M, Donadel G, et al. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Intern Emerg Med. 2011;

  • Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754–759

  • Mathieu C, Adorini L. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med. 2002;8:174–179

  • Nguyen TP, Scotti M, Morine MJ, Priami C. Model-based clustering reveals vitamin D dependent multi-centrality hubs in a network of vitamin-related proteins. BMC Syst Biol. 2011;5:195

  • Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 2010;465:721–727

  • Gynther P, Toropainen S, Matilainen JM, Seuter S, Carlberg C, Vaisanen S. Mechanism of 1α,25-dihydroxyvitamin D(3)-dependent repression of interleukin-12B. Biochim Biophys Acta. 2011;1813:810–818

  • Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010;19:2739–2745

  • Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376:180–188

  • Petty KH, Li K, Dong Y, Fortenberry J, Stallmann-Jorgensen I, Guo D, et al. Sex dimorphisms in inflammatory markers and adiposity in African merican youth. Int J Pediatr Obes. 2010;5:327–333

  • Chen TC, Turner AK, Holick MF. Methods for the determination of the circulating concentration of 25-hydroxyvitamin D. J Nutr Biochem. 1990;1:315–319

  • Wallace AM, Gibson S, de la Hunty A, Lamberg-Allardt C, Ashwell M. Measurement of 25-hydroxyvitamin D in the clinical laboratory: current procedures, performance characteristics and limitations. Steroids. 2010;75:477–488

  • Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Statistical applications in genetics and molecular biology. 2004;3:Article3

  • Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med. 1990;9:811–818

  • Smith NL, Hindorff LA, Heckbert SR, Lemaitre RN, Marciante KD, Rice K, et al. Association of genetic variations with nonfatal venous thrombosis in postmenopausal women. JAMA. 2007;297:489–498

  • Al-Shahrour F, Diaz-Uriarte R, Dopazo J. FatiGO: a web tool for finding significant associations of gene ontology terms with groups of genes. Bioinformatics. 2004;20:578–580

  • Morrison EE. Action and interactions at microtubule ends. Cell Mol Life Sci. 2007;64:307–317

  • Musch A. Microtubule organization and function in epithelial cells. Traffic. 2004;5:1–9

  • Valiron O, Caudron N, Job D. Microtubule dynamics. Cell Mol Life Sci. 2001;58:2069–2084

  • Carvalho P, Tirnauer JS, Pellman D. Surfing on microtubule ends. Trends Cell Biol. 2003;13:229–237

  • Renner C, Pfitzenmeier JP, Gerlach K, Held G, Ohnesorge S, Sahin U, et al. RP1, a new member of the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells. J Immunol. 1997;159:1276–1283

  • Wang Y, Zhou X, Zhu H, Liu S, Zhou C, Zhang G, et al. Overexpression of EB1 in human esophageal squamous cell carcinoma (ESCC) may promote cellular growth by activating β-catenin/TCF pathway. Oncogene. 2005;24:6637–6645

  • Kelly K, Siebenlist U. Immediate-early genes induced by antigen receptor stimulation. Curr Opin Immunol. 1995;7:327–332

  • Abiatari I, Gillen S, DeOliveira T, Klose T, Bo K, Giese NA, et al. The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells. Int J Oncol. 2009;35:1111–1116

  • Hernandez A, Martinez ME, Fiering S, Galton VA, St Germain D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest. 2006;116:476–484

  • Meulenbelt I, Bos SD, Chapman K, van der Breggen R, Houwing-Duistermaat JJ, Kremer D, et al. Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility. Ann Rheum Dis. 2011;70:164–167

  • Martin-Subero JI, Ammerpohl O, Bibikova M, Wickham-Garcia E, Agirre X, Alvarez S, et al. A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms. PLoS One. 2009;4:e6986

  • Figueroa ME, Wouters BJ, Skrabanek L, Glass J, Li Y, Erpelinck-Verschueren CA, et al. Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/T-lymphoid features. Blood. 2009;113:2795–2804

  • Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776

  • Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77:903–910

  • Carlberg C, Seuter S. Dynamics of nuclear receptor target gene regulation. Chromosoma. 2010;119:479–484

  • Pike JW. Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand. Mol Cell Endocrinol. 2011;347:3–10

  • Kim MS, Kondo T, Takada I, Youn MY, Yamamoto Y, Takahashi S, et al. DNA demethylation in hormone-induced transcriptional derepression. Nature. 2009;461:1007–1012

  • Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature. 2002;416:552–556

  • Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, Munoz A. Genetic signatures of differentiation induced by 1α,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63:7799–7806

  • Larriba MJ, Ordonez-Moran P, Chicote I, Martin-Fernandez G, Puig I, Munoz A, et al. Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer. PLoS One. 2011;6:e23524

  • Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K. CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev. 2007;23:631–636

  • Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U.S.A. 2004;101:7711–7715

  • Wang X, Zhu H, Snieder H, Su S, Munn D, Harshfield G, et al. Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med. 2010;8:87

  • Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B, et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet. 2012;21:371–383

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