Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves' ophthalmopathy

• Published in: Clinical endocrinology (Oxford) 2007-11, Vol.67 (5), p.663-667
• Main Authors: Syed, A. A., Simmonds, M. J., Brand, O. J., Franklyn, J. A., Gough, S. C. L., Heward, J. M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Case-Control Studies; Chi-Square Distribution; Endocrinopathies; European Continental Ancestry Group; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genotype; Graves Ophthalmopathy - genetics; Humans; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 12 - genetics; Receptors, Thyrotropin - genetics; Thyroid. Thyroid axis (diseases); Vertebrates: endocrinology
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2007.02942.x

Summary Objective  Protein tyrosine phosphatases (PTPs), such as PTPN22, are important regulators of signal transduction from the T cell receptor and have been associated with autoimmunity. PTPN12 interacts with the same T cell activation accessory molecules, Grb2 and Csk kinase, as the Graves’ disease (GD) associated PTPN22 encoded lymphoid tyrosine phosphatase (LYP) molecule and also plays a key role in T cell receptor signalling, leading to the hypothesis that it too may be involved in GD susceptibility. Design  PTPN12 was tested for association in a large well‐characterized UK Caucasian case control cohort using seven tagging single nucleotide polymorphisms (SNPs). Patients  A total of 1058 GD patients and 864 controls. Measurements  Tests for association with the disease. Results  Despite adequate statistical power to detect an effect if present, none of the seven tag SNPs were associated with GD (P = 0·925–0·089). Three SNPs (rs1468682, rs4729535 and rs17467232), however, demonstrated association with the presence of ophthalmopathy NOSPECS classes 2–4 (P = 0·039–0·004). Four SNPs (rs1468682, rs4729535, rs17155601 and rs17467232) revealed evidence of interaction with the previously associated thyrotropin hormone receptor (TSHR) rs2268458 SNP (P = 0·035–0·002). Conclusions  No association was detected between individual PTPN12 tag SNPs and GD but preliminary evidence suggests PTPN12 confers an increased risk of mild/moderate ophthalmopathy (NOSPECS classes 2–4) and that PTPN12 interacts with the TSHR. Replication of these preliminary results is now required in larger independent datasets to validate these findings.