Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population
Introduction
Vitamin D is a potent modulator of the immune system and is involved in the regulation of cell proliferation and differentiation [1]. Vitamin D is an effective immunosuppressant via inhibition of lymphocyte activation and cytokine production [1] and prevents or markedly suppresses the development of several autoimmune diseases in animal models [1]. The administration of vitamin D protects against the development of insulitis and type 1 diabetes in nonobese diabetic mice [2]. In humans, epidemiological studies indicated that dietary vitamin D supplementation during early childhood decreases the risk of type 1 diabetes [3], [4] and that maternal intake of vitamin D during pregnancy may have a protective effect on the appearance of islet autoantibodies in offspring [5].
Because vitamin D exerts its effects through the vitamin D receptor (VDR), the VDR gene has become a candidate susceptibility gene for type 1 diabetes. The VDR gene is located on chromosome 12q12–q14 and includes eight protein-coding exons (exons 2–9) and six untranslated exons (exons 1a–1f), which are alternatively spliced [6]. Four common single nucleotide polymorphisms (SNPs) in the VDR gene have been investigated extensively: FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI G>T (rs7975232), and TaqI C>T (rs731236). Allele T of the FokI SNP creates an alternative ATG initiation codon in exon 2 leading to a VDR protein that is three amino acids longer [7]. The BsmI and ApaI SNPs are both located in intron 8, and the TaqI is a silent SNP in exon 9. The four SNPs were tested for association with various human diseases [8] and affected the risk of endocrine immune-mediated disorders such as Graves’ disease, Hashimoto’s thyroiditis and Addison’s disease [8], [9], [10]. Several studies also reported the association of type 1 diabetes with one or more of the four SNPs. However, the reported associations are inconsistent among studies [11].
The aim of this study was to assess the contribution of these VDR polymorphisms to the susceptibility to type 1 diabetes in the Portuguese population.
Section snippets
Subjects
The study group consisted of 207 Caucasian Portuguese patients with type 1 diabetes mellitus (113 males and 94 females; mean age at time of study ± SD = 27.5 ± 10.2 years) who attended the outpatient clinics at the University Hospital of Coimbra (Portugal). Diabetes was diagnosed according to World Health Organization criteria [12] and classified as type 1 on the basis of classical clinical presentation [12], low or undetectable levels of serum C-peptide, and the presence of one or more
Results
All frequencies were in Hardy–Weinberg equilibrium. The distribution of VDR genotype and allele frequencies did not differ significantly between patients with type 1 diabetes mellitus and controls (Table 1). No single genotype or allele was associated with an altered risk for type 1 diabetes mellitus. Because there were three possible genotypes for each of the four SNPs, each individual was classified as having one of the 81 possible combinations of genotypes. The distribution of these genotype
Discussion
The VDR locus has been studied in different populations for association with susceptibility to immune-mediated diseases, but with inconsistent findings in type 1 diabetes mellitus [11]. To clarify the contribution of VDR polymorphisms to genetic susceptibility to type 1 diabetes mellitus among Portuguese patients, we conducted a retrospective case–control study by analyzing four well-characterized VDR polymorphisms. We reported no evidence of allelic or genotypic association of the FokI T>C
Acknowledgment
This work was supported, in part, by “Bolsa Dr. M. M. Almeida Ruas–Sociedade Portuguesa de Diabetologia/Novo Nordisk, em Diabetes (2003).”
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