Endocrine Abstracts

In addition to the HLA gene region, two further genes involved in the inhibition of T cell signalling, CTLA-4 and PTPN22, have been consistently associated with autoimmune disease (AID), highlighting the important role played by molecules in this pathway in AID susceptibility. The Programmed Cell Death 1 gene (PDCD1) on chromosome 2q37.3 encodes PD-1 which is involved in providing a negative signal to activated T cells. Large case-control studies have shown association of PDCD1 with several AIDs including rheumatoid arthritis (RA) and type 1 diabetes (T1D) although, to date, no such studies have been performed for Graves’ disease (GD). The aim of this study was to investigate eight Tag SNPs representing all the common variation in PDCD1 within a well characterised large UK Caucasian GD dataset. In total 1058 patients with GD and 864 control subjects were genotyped for each SNP and any SNPs showing association were then screened in an additional 1613 GD patients. All subjects gave informed written consent and the project was approved by the local ethics committee. No association was seen for six of the SNPs genotyped in this study (+4163,+5049,+5318,+5640,+5678 and +7078). Association was detected between the +2375 SNP (OR=1.14 [95% CI=1.01-1.29]) and GD and a small protective effect was seen with the +6799 genotypes (P=0.028, OR=0.77 [95% CI=0.58-1.03]), however only a trend (P=0.073) was seen with the alleles. This study has for the first time shown that small effects within PDCD1 may contribute towards the development of GD, which supports the hypothesis that much of the remainder of the genetic contribution to GD could be due to several small genetic effects with ORs <1.2. Replication of this result is now needed to justify the more detailed and expensive fine-mapping of a primary aetiological variant in this gene region.