Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: The Diabetes Autoimmunity Study in the Young (DAISY)
Highlights
► We investigated the association between T1D and variants in VDR and PTPN2 genes. ► VDR and PTPN2 variants are not associated with risk of development of IA. ► VDR and PTPN2 variants interact to influence progression from IA to T1D. ► This study offers insight concerning the role of vitamin D in the etiology of T1D.
Introduction
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells of the pancreas are destroyed. There is typically a preclinical phase of circulating autoantibodies, called islet autoimmunity (IA) that precedes the clinical diagnosis of T1D.
Vitamin D deficiency has been associated with a number of diseases, including multiple sclerosis [1], rheumatoid arthritis, and T1D [2], although not consistently. The mechanism by which vitamin D may exert its effects on these diseases is still not understood completely, particularly with regard to underlying genetic risk. The gene for the vitamin D receptor (VDR), through which vitamin D acts, has long been a candidate gene for T1D. Initial small studies found VDR polymorphisms to be associated with T1D [3], [4], [5], [6], [7], [8], [9]. However, Nejentsev et al. analyzed association of the 98 VDR single nucleotide polymorphisms (SNPs) in up to 3763 type 1 diabetic families and found no evidence of association with T1D in the populations tested [10]. Moreover, in a meta-analysis, Guo et al. found no evidence of an association between VDR gene polymorphisms (FokI, BsmI, ApaI, and TaqI) and T1D risk [11]. Finally, in a recent analysis of 19 genes for association with T1D in the Type 1 Diabetes Genetics Consortium families, none of the forty SNPs genotyped in the VDR region were associated with T1D [12]. A recent study [13] showed that the vitamin D receptor binds to a number of genomic positions across the genome, including a novel intronic binding site in the protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), which has also been associated with T1D through a genome-wide association scan in 2007 [14], [15]. This suggests the possibility of a more complex relationship in which variation in both VDR and PTPN2 is necessary to have an effect on diabetes risk, which may explain why previous findings regarding VDR have been inconsistent.
The Diabetes Autoimmunity Study in the Young (DAISY) has been prospectively following children at increased T1D risk for the development of IA and progression to T1D since 1993. The purpose of this study was to examine the associations between 5 particular VDR and PTPN2 SNPs and the development of IA and progression to T1D in the prospective DAISY cohort. We also aimed to explore a potential gene–gene interaction between VDR and PTPN2 polymorphisms and the risk of IA and progression to T1D.
Section snippets
Subjects
DAISY is a prospective study composed of two groups of children at increased risk for T1D who were recruited between 1993 and 2004 and are being followed prospectively for the development of IA and T1D. One group is made up of first degree relatives of patients with type 1 diabetes mellitus, recruited between birth and eight years of age. The second group consists of infants born at St. Joseph's Hospital in Denver, Colorado, whose umbilical cord blood was screened for diabetes-susceptibility
Development of persistent islet autoimmunity
We first examined whether variants in VDR were associated with development of persistent islet autoimmunity, and whether these interacted with variants in PTPN2. Table 1 describes the children by whether or not they developed persistent IA. Of a total of 122 IA positive children in DAISY, 11 had to be excluded from the subsequent proportional hazards analyses of IA because they tested autoantibody positive on their first study visit (i.e., they were left-censored). The mean age at first IA
Discussion
In the DAISY population, the three VDR SNPs, VDR rs1544410, VDR rs2228570, and VDR rs11568820 we tested were not significantly associated with the appearance of IA. However, VDR rs2228570 was found to be associated with progression to T1D in IA positive children, and VDR rs1544410 significantly interacted with PTPN2 rs1893217 on risk of progression to T1D, suggesting that the role of VDR in risk of T1D is complex. Besides the aforementioned interaction between PTPN2 rs1893217 and VDR rs1544410,
Acknowledgements
This research was supported by NIH grants R01-DK49654, R01-DK32493, DERC Molecular Biology Core NIH P30 DK57516, R21 DK84568, and JDRF Grant 11-2010-206. We acknowledge Cisca Wijmenga for providing us with the PTPN2 genotypes.
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