Abstract
Vitamin D deficiency is a common public health problem in the US. It is related to the high risk of rickets, osteoporosis and other diseases. Currently, serum 25-hydroxy vitamin D [25(OH)D] concentration is the best indicator of vitamin D status, and determination of its deficiency or sufficiency. This level has high heritability (28–80%). However, genes contributing to the wide variation in serum 25(OH)D are generally unknown. In this study, we screened nine important genes in vitamin D metabolic pathways using 49 single nucleotide polymorphism (SNP) markers in a group of 156 unrelated healthy Caucasian subjects. Significant confounding factors that may affect serum 25(OH)D variations were used as covariates for the association analyses. An association test for quantitative trait was performed to evaluate the association between candidate genes and serum 25(OH)D levels. Permutation was conducted for correcting multiple testing problems. Evidence of association was observed at SNPs in the CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1) and the GC (vitamin D binding protein) gene. Next, we performed a replication study for six promising SNPs in the gene CYP2R1 and GC, using another group of 340 unrelated healthy Caucasian subjects. Association analyses were conducted in the replication cohort (n = 340) and the pooled cohort (n = 496). The CYP2R1 gene and the GC gene remain significant in the pooled cohort. The results suggest that the CYP2R1 and GC genes may contribute to the variation of serum 25(OH)D levels in healthy populations.
Similar content being viewed by others
References
Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, Weinstein SJ, Chanock SJ, Schatzkin A, Hayes RB (2009) Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 30:769–776
Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745
Akiba T, Endou H, Koseki C, Sakai F, Horiuchi N, Suda T (1980) Localization of 25-hydroxyvitamin D3-1 alpha-hydroxylase activity in the mammalian kidney. Biochem Biophys Res Commun 94:313–318
Arguelles LM, Langman CB, Ariza AJ, Ali FN, Dilley K, Price H, Liu X, Zhang S, Hong X, Wang B, Xing H, Li Z, Liu X, Zhang W, Xu X, Wang X (2009) Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins. J Clin Endocrinol Metab 94:3273–3281
Bang UC, Semb S, Nordgaard-Lassen I, Jensen JE (2009) A descriptive cross-sectional study of the prevalence of 25-hydroxyvitamin D deficiency and association with bone markers in a hospitalized population. Nutr Res 29:671–675
Borkar VV, Verma S, Bhalla A (2009) Low levels of vitamin D in North Indian children with newly diagnosed type 1 diabetes. Pediatr Diabetes 11:345–350
Bosse Y, Lemire M, Poon AH, Daley D, He JQ, Sandford A, White JH, James AL, Musk AW, Palmer LJ, Raby BA, Weiss ST, Kozyrskyj AL, Becker A, Hudson TJ, Laprise C (2009) Asthma and genes encoding components of the vitamin D pathway. Respir Res 10:98
Carter GD, Carter CR, Gunter E, Jones J, Jones G, Makin HL, Sufi S (2004) Measurement of vitamin D metabolites: an international perspective on methodology and clinical interpretation. J Steroid Biochem Mol Biol 89–90:467–471
Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 278:38084–38093
Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101:7711–7715
De La Vega FM, Isaac HI, Scafe CR (2006) A tool for selecting SNPs for association studies based on observed linkage disequilibrium patterns. Pac Symp Biocomput 2006:487–498
Downie D, McFadyen MC, Rooney PH, Cruickshank ME, Parkin DE, Miller ID, Telfer C, Melvin WT, Murray GI (2005) Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers. Clin Cancer Res 11:7369–7375
Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, Giovannucci EL (2004) Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13:1502–1508
Gottfried E, Rehli M, Hahn J, Holler E, Andreesen R, Kreutz M (2006) Monocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite. Biochem Biophys Res Commun 349:209–213
Gupta RP, He YA, Patrick KS, Halpert JR, Bell NH (2005) CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. J Clin Endocrinol Metab 90:1210–1219
Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281
Kilkkinen A, Knekt P, Aro A, Rissanen H, Marniemi J, Heliovaara M, Impivaara O, Reunanen A (2009) Vitamin D status and the risk of cardiovascular disease death. Am J Epidemiol 170:1032–1039
Lappe JM, Davies KM, Travers-Gustafson D, Heaney RP (2006) Vitamin D status in a rural postmenopausal female population. J Am Coll Nutr 25:395–402
Melamed ML, Astor B, Michos ED, Hostetter TH, Powe NR, Muntner P (2009) 25-hydroxyvitamin D levels, race, and the progression of kidney disease. J Am Soc Nephrol 20:2631–2639
Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E (2007) Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D, and prostate cancer risk. Prostate 67:911–923
Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang YM, Affleck P, Elliott F, Chan M, Leake S, Karpavicius B, Haynes S, Kukalizch K, Whitaker L, Jackson S, Gerry E, Nolan C, Bertram C, Marsden J, Elder DE, Barrett JH, Bishop DT (2009) Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J Clin Oncol 27:5439–5444
Orton SM, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, Chao MJ, Vieth R, Sadovnick AD, Ebers GC (2008) Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am J Clin Nutr 88:441–447
Pita Martin Portela ML, Monico A, Barahona A, Dupraz H, Sol Gonzales-Chaves MM, Zeni SN (2009) Comparative 25-OH-vitamin D level in institutionalized women older than 65 years from two cities in Spain and Argentina having a similar solar radiation index. Nutrition 26:283–289
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K (2007) CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 23:631–636
Rovner AJ, Miller RS (2008) Vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis. Pediatrics 122:907–908 (author reply 908–909)
Sahota O (2000) Osteoporosis and the role of vitamin D and calcium—vitamin D deficiency, vitamin D insufficiency and vitamin D sufficiency. Age Ageing 29:301–304
Sawada N, Kusudo T, Sakaki T, Hatakeyama S, Hanada M, Abe D, Kamao M, Okano T, Ohta M, Inouye K (2004) Novel metabolism of 1 alpha, 25-dihydroxyvitamin D3 with C24–C25 bond cleavage catalyzed by human CYP24A1. Biochemistry 43:4530–4537
Shea MK, Benjamin EJ, Dupuis J, Massaro JM, Jacques PF, D’Agostino RB Sr, Ordovas JM, O’Donnell CJ, Dawson-Hughes B, Vasan RS, Booth SL (2009) Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr 63:458–464
Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K (2004) Metabolism of vitamin D by human microsomal CYP2R1. Biochem Biophys Res Commun 324:451–457
Simonelli C (2005) The role of vitamin D deficiency in osteoporosis and fractures. Minn Med 88:34–36
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376:180–188
Wharton B, Bishop N (2003) Rickets. Lancet 362:1389–1400
Wjst M, Altmuller J, Faus-Kessler T, Braig C, Bahnweg M, Andre E (2006) Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res 7:60
Wjst M, Altmuller J, Braig C, Bahnweg M, Andre E (2007) A genome-wide linkage scan for 25-OH-D(3) and 1, 25-(OH)2–D3 serum levels in asthma families. J Steroid Biochem Mol Biol 103:799–802
Acknowledgments
We thank Darin Jensen for his constructive input during the preparation of the manuscript. Investigators of this work were supported by grants from Cancer and Smoking Disease Research Bone Biology Program, the Nebraska Tobacco Settlement Biomedical Research Development Award, an NIH grant (3R01CA129488-01A2S2), and a grant from State of Nebraska Cancer and Smoking Disease Research Program (LB595).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bu, FX., Armas, L., Lappe, J. et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet 128, 549–556 (2010). https://doi.org/10.1007/s00439-010-0881-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-010-0881-9