Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes
- Jason D. Cooper1,
- Deborah J. Smyth1,
- Neil M. Walker1,
- Helen Stevens1,
- Oliver S. Burren1,
- Chris Wallace1,
- Christopher Greissl2,
- Elizabeth Ramos-Lopez2,
- Elina Hyppönen3,
- David B. Dunger4,
- Timothy D. Spector5,
- Willem H. Ouwehand6,7,
- Thomas J. Wang8,9,10,
- Klaus Badenhoop2 and
- John A. Todd1⇓
- 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
- 2Department of Internal Medicine I, Division of Endocrinology, Diabetes, and Metabolism, University Hospital Frankfurt, Frankfurt am Main, Germany
- 3University College London Institute of Child Health, Medical Research Council Centre of Epidemiology for Child Health and Centre for Paediatric Epidemiology and Biostatistics, London, U.K.
- 4Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
- 5Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.
- 6Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, U.K.
- 7Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, U.K.
- 8Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 9Harvard Medical School, Boston, Massachusetts
- 10Framingham Heart Study, Framingham, Massachusetts
- Corresponding author: John A. Todd, .
OBJECTIVE Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.
RESEARCH DESIGN AND METHODS We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.
RESULTS Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3).
CONCLUSIONS Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.
- Received November 30, 2010.
- Accepted February 27, 2011.
- © 2011 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.