Association of the thyrotrophin receptor gene (TSHR) with Graves disease: evidence from independent UK population based case control and family studies
OJ Brand, JM Heward, T Brix, JD Carr-Smith, JM Connell, L Hegedus, PJ Hunt, BG Robinson, JAH Wass, WM Wiersinga, JA Franklyn, A Weetman & SCL Gough
Genetic variants consistently associated with the development of Graves disease (GD) have, to date, been general autoimmunity loci including those within the HLA region, the CTLA-4 gene and most recently the PTPN22 gene encoding lymphoid tyrosine phosphatase (LYP). The thyrotophin receptor gene (TSHR) has recently however, been identified as the first Graves disease specific susceptibility locus. To further refine association with disease and exclude population stratification we have performed a case control (n=1536) and independent family based (n=>600 subjects including 209 with Graves) association study of 32 single nucleotide polymorphisms (SNPs) spanning 610 kb of genomic DNA including the TSHR. Eleven SNPs associated with disease in the case control study fell within two distinct blocks of linkage disequilibrium either side of the TSHR start codon. The first block, 5′ of the TSHR (88.5 Kb) contained the most associated SNPs, rs759916 (P=5×10−6) and rs1025253 (P=5×10−5) located 48 Kb and 32.5 Kb upstream of TSHR start codon respectively. The second block extended approximately 37 Kb into intron 1 with the maximum association at rs2268458 (P=5×10−4) and rs2300521 (P=4×10−4). Preferential transmission of the associated alleles (T) of rs759916 (P=0.04) and (C) of rs2300521 (P=0.01) was seen in the family study respectively. These data from two independent UK case-control and family cohorts confirm the TSHR region as a Graves disease specific susceptibility locus. They further show two clear peaks of association either side of the TSHR start codon and exclude population stratification as an alternative explanation for association with disease. Further studies are now underway to identify the primary aetiological variant(s) within this region, and to understand the mechanism by which disease susceptibility is conferred.