Abstract
Type I diabetes (T1D) results from interactions between environmental exposures and genetic susceptibility leading to immune dysfunction and destruction of the insulin-producing β cells of the pancreas. Vitamin D deficiency is likely to be one of the many environmental factors influencing T1D development and diagnosis, and, hence, the hormone receptor gene, VDR, was examined for association with T1D risk. The Type I Diabetes Genetics Consortium genotyped 38 single nucleotide polymorphisms (SNPs) in 1654 T1D nuclear families (6707 individuals, 3399 affected). Genotypes for 38 SNPs were assigned using the Illumina (ILMN) and Sequenom (SQN) technology. The analysis of data release as of July 2008 is reported for both platforms. No evidence of association of VDR SNPs with T1D at P<0.01 was obtained in the overall sample set, nor in subgroups analyses of the parent-of-origin, sex of offspring and HLA risk once adjusted for multiple testing.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857–864.
Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57: 1084–1092.
van Etten E, Verlinden L, Giulietti A, Ramos-Lopez E, Branisteanu DD, Ferreira GB et al. The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur J Immunol 2007; 37: 395–405.
Giulietti A, Gysemans C, Stoffels K, van Etten E, Decallonne B, Overbergh L et al. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia 2004; 47: 451–462.
Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R . Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia 1994; 37: 552–558.
Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM . Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358: 1500–1503.
Mohr SB, Garland CF, Gorham ED, Garland FC . The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia 2008; 51: 1391–1398.
Greer RM, Rogers MA, Bowling FG, Buntain HM, Harris M, Leong GM et al. Australian children and adolescents with type 1 diabetes have low vitamin D levels. Med J Aust 2007; 187: 59–60.
Brekke HK, Ludvigsson J . Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes 2007; 8: 11–14.
Holick MF . Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79: 362–371.
Gysemans C, van Etten E, Overbergh L, Giulietti A, Eelen G, Waer M et al. Unaltered diabetes presentation in NOD mice lacking the vitamin D receptor. Diabetes 2008; 57: 269–275.
Mathieu C, van Etten E, Gysemans C, Decallonne B, Kato S, Laureys J et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res 2001; 16: 2057–2065.
Pani MA, Knapp M, Donner H, Braun J, Baur MP, Usadel KH et al. Vitamin D receptor allele combinations influence genetic susceptibility to IDDM in Germans. Diabetes 2000; 49: 504–507.
Nejentsev S, Cooper JD, Godfrey L, Howson JM, Rance H, Nutland S et al. Analysis of the vitamin D receptor gene sequence variants in type 1 diabetes. Diabetes 2004; 53: 2709–2712.
Lemos MC, Fagulha A, Coutinho E, Gomes L, Bastos M, Barros L et al. Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population. Hum Immunol 2008; 69: 134–138.
Mimbacas A, Trujillo J, Gascue C, Javiel G, Cardoso H . Prevalence of vitamin D receptor gene polymorphism in a Uruguayan population and its relation to type 1 diabetes mellitus. Genet Mol Res 2007; 6: 534–542.
Guo SW, Magnuson VL, Schiller JJ, Wang X, Wu Y, Ghosh S . Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies. Am J Epidemiol 2006; 164: 711–724.
Nguyen M, d’Alesio A, Pascussi JM, Kumar R, Griffin MD, Dong X et al. Vitamin D-resistant rickets and type 1 diabetes in a child with compound heterozygous mutations of the vitamin D receptor (L263R and R391S): dissociated responses of the CYP-24 and rel-B promoters to 1,25-dihydroxyvitamin D3. J Bone Miner Res 2006; 21: 886–894.
Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988; 85: 3294–3298.
Ponsonby AL, Pezic A, Ellis J, Morley R, Cameron F, Carlin J et al. Variation in associations between allelic variants of the vitamin D receptor gene and onset of type 1 diabetes mellitus by ambient winter ultraviolet radiation levels: a meta-regression analysis. Am J Epidemiol 2008; 168: 358–365.
Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes 2005; 54: 2995–3001.
Rich SS, Concannon P, Erlich H, Julier C, Morahan G, Nerup J et al. The Type 1 Diabetes Genetics Consortium. Ann N Y Acad Sci 2006; 1079: 1–8.
Dudbridge F, Gusnanto A . Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 2008; 32: 227–234.
Dudbridge F . Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008; 66: 87–98.
Acknowledgements
This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. The work was also supported by grants to JAT from the Wellcome Trust, Juvenile Diabetes Research Foundation and the National Institute for Health Research Biomedical Research Centre award to Cambridge. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
Kahles, H., Morahan, G., Todd, J. et al. Association analyses of the vitamin D receptor gene in 1654 families with type I diabetes. Genes Immun 10 (Suppl 1), S60–S63 (2009). https://doi.org/10.1038/gene.2009.93
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2009.93
Keywords
This article is cited by
-
Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept
Reviews in Endocrine and Metabolic Disorders (2017)
-
The Role of Vitamin D in the Metabolic Homeostasis of Diabetic Bone
Clinical Reviews in Bone and Mineral Metabolism (2013)
-
Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study
Breast Cancer Research (2012)
-
Overview of the Type I Diabetes Genetics Consortium
Genes & Immunity (2009)
-
The Type I Diabetes Genetics Consortium ‘Rapid Response’ family-based candidate gene study: strategy, genes selection, and main outcome
Genes & Immunity (2009)