Endocrine Abstracts

Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the initiation and regulation of the cytokine cascade during an inflammatory response and is, therefore, a good candidate for involvement in the development of autoimmune disease. The TNF-alpha gene has been mapped to chromosome 6p21.3 and many single nucleotide polymorphisms (SNPs) have been detected within the gene that could affect its function. The allele frequencies of these SNPs and their relationship to autoimmune disease remain largely unknown. The aims of this study were (i) generate UK Caucasian population allele frequencies for 13 published TNF-alpha SNPs and (ii) examine for association with Graves' disease (GD). Following informed consent, allele frequencies were determined in 96 control subjects with no family history of autoimmune disease using either PCR-RFLP or Allele Specific PCR. Using a power of study threshold of 80%, 7 SNPs (+1304, +851, +489, -238, -308, -857 & -863) had mutant allele frequencies above 5% and were taken forward for the association study in 864 subjects with GD and 864 controls. The -238 SNP showed evidence for association with GD (chi-square = 8.685, p = 0.003) with an OR of 1.46, which was independent of the known HLA association with GD. A previous study on U937 and Raji cells expressing the -238A mutant allele showed consistent increases in basal and inducible activity compared to the -238G wild-type (Bayley, et al, 2001), suggesting the -238A could disrupt a known TNF-alpha repression site. Our study has provided useful allele frequency data for the published TNF-alpha SNPs in a UK control population and produced preliminary data suggesting association of a functional SNP with GD. Further studies with at least a similar number of cases and controls, which could be provided by a novel ongoing UK wide national collection of DNA, are required to confirm these data.