Vitamin D-Binding Protein (DBP) Gene Polymorphism is Associated with Graves' Disease and the Vitamin D Status in a Polish Population Study

Abstract

Objective: Vitamin D-binding protein (DBP) genetic variants have an influence on vitamin D status and, therefore, they may contribute to the development of autoimmune diseases. In this case-control study, we investigated the association of DBP gene polymorphisms with susceptibility to Graves' disease (GD) in a Polish population. Furthermore, we analyzed the distribution of DBP genotypes in GD patients divided according to the clinical (gender, age of onset, ophthalmopathy, family history, smoking habits) and genetic parameters (CTLA4 49G and HLA-DRB1*03 alleles), as well as the vitamin D serum levels. Methods: 332 polish patients with GD and 185 healthy controls were genotyped for the DBP gene single nucleotide polymorphisms (SNPs) at codon 420 ACG → AAG (Thr → Lys) and at codon 416 GAT → GAG (Asp → Glu) by the PCR-RFLP method. The variable (TAAA)_N repeat polymorphism in the intron 8 was analyzed in 332 patients and 164 controls by the PCR amplification followed by the PAGE. In addition, 25(OH)D₃ serum levels were measured in 110 patients. Results: In patients with GD, the frequency of the Lys allele (34.2 % vs. 25.7 %, p = 0.005; OR = 1.50; 95 % CI: 1.13 - 1.99) at codon 420 was significantly higher compared to controls. The distribution of codon 420 genotypes also differed significantly (p = 0.01), with the frequency of the Lys/Lys homozygotes (9.3 % vs. 5.9 %; OR = 1.63; 95 % CI: 0.80 - 3.32) being higher in GD. The distribution of codon 416 alleles and genotypes did not differ in both studied groups (p = 0.59 and p = 0.81, respectively). Analysis of the intron 8 (TAAA)_N repeat polymorphism led to the identification of a novel variant in the Polish population, described as 7 repeats, but no association between the intron 8 alleles and GD was observed. The 420 Lys allele was associated with lower 25(OH)D₃ serum levels (p = 0.01). No correlation between the DBP genotypes and other susceptibility alleles or the GD clinical phenotype was observed. Conclusions: (i) The DBP gene Lys allele at codon 420 confers susceptibility to GD in the Polish population, (ii) the codon 416 alleles and intron 8 (TAAA)_N variants are not associated with susceptibility to and clinical phenotype of GD, and (iii) the codon 420 Lys allele correlates with lower 25(OH)D₃ serum concentration.

Key words

Graves' disease (GD) - vitamin D - vitamin D-binding protein (DBP) - genetic polymorphism

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