Endocrine Abstracts (2002) 3 OC7

The vitamin D receptor gene is associated with susceptibility to development of Graves' disease in the UK

JE Collins1, JM Heward1, A Allahabadia2, JA Franklyn1, SCL Gough2 & R Nithiyananthan1,2


1Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK; 2Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Birmingham. UK.


A number of candidate genes have been investigated as susceptibility loci for the development of Graves' disease. Those which appear to be consistently associated with disease include the HLA and the CTLA-4 gene regions. Polymorphisms of the VDR gene have been shown to increase susceptibility to autoimmune diseases including type 1 diabetes, multiple sclerosis, and Crohn's disease. Recently, an association has also been reported between the VDR gene and autoimmune thyroid disease in Japanese females. We have investigated three VDR gene polymorphisms in 672 Caucasian patients with Graves' disease and 864 control subjects. Genotyping of three single nucleotide polymorphisms was performed by PCR-RFLP using the restriction enzymes FokI, BsmI and ApaI. The ApaI polymorphism was found to be associated with Graves' disease. There was a significant difference in the genotype distribution with an increase frequency of the AA genotype in patients with Graves' disease compared with the controls (30.6% versus 22.7; Chi sq. = 11.78, 2 degrees of freedom, p = 0.003). Similarly, there was a significant excess of the A allele in patients with Graves' disease compared with the control subjects (61% versus 57% respectively; Chi sq. = 4.45, 1 degree of freedom, p = 0.035, odds ratio = 1.2; confidence limits = 1.01-1.37). No association was found between Graves' disease and either the Fok1 or Bsm1 polymorphism. In an attempt to replicate the Apa1 association and exclude population stratification we performed the transmission disequilibrium test in an independent data set of 218 families. The results showed a significant excess in transmission of the A allele from heterozygous parents to the affected offspring compared to the unaffected offspring (56% versus 44% respectively; Chi sq. = 5.34; p = 0.021). These findings suggest that polymorphism of the VDR gene is associated with susceptibility to development of Graves' disease in the UK.

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