Cytokine responses for two associated variants (R231W, rs201917359; and R703W, rs55882956) in <i>TYK2</i> as well as a previously reported risk variant (P1004A, rs34536443) for multiple autoimmune diseases were evaluated by reporter assays.
Genome wide association studies have linked a SNP (rs34536443) within <i>TYK2</i> encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS).
Our MD results provided information, at atomic level, on the consequences of the Pro1104 to Ala substitution on the structure and dynamics of the kinase domain of Tyk2 and suggested reduced enzymatic activity of the resulting protein variant due to stabilization of inactive conformations, thus adding to knowledge towards the elucidation of the protection mechanism against autoimmune diseases associated with this point mutation.
Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD.