The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-α activity and low tumor necrosis factor a levels in patients with lupus

Objective. The C1858T polymorphism in PTPN22 has been associated with the risk of systemic lupus erythematosus (SLE) as well as multiple other autoimmune diseases. We have previously shown that high serum interferon-alpha (IFN alpha) activity is a heritable risk factor for SLE. The aim of this study was to determine whether the PTPN22 risk variant may shift serum cytokine profiles to higher IFN alpha activity, resulting in risk of disease. Methods. IFN alpha was measured in 143 patients with SLE, using a functional reporter cell assay, and tumor necrosis factor alpha (TNF alpha) was measured by enzyme-linked immunosorbent assay. The rs2476601 single-nucleotide polymorphism in PTPN22 (C1858T) was genotyped in the same patients. Patients were grouped, using a clustering algorithm, into 4 cytokine groups (IFN alpha predominant, IFN alpha and TNF alpha correlated, TNF alpha predominant, and both IFN alpha and TNF alpha low). Results. SLE patients carrying the risk allele of PTPN22 had higher serum IFNa activity than patients lacking the risk allele (P = 0.027). TNFa levels were lower in carriers of the risk allele (P = 0.030), and the risk allele was more common in patients in the IFN alpha-predominant and IFN alpha and TNF alpha-correlated groups as compared with patients in the TNF alpha-predominant and both IFN alpha and TNF alpha-low groups (P = 0.001). Twenty-five percent of male patients carried the risk allele, compared with 10% of female patients (P = 0.024); however, cytokine skewing was similar in both sexes. Conclusion. The autoimmune disease risk allele of PTPN22 is associated with skewing of serum cytokine profiles toward higher IFN alpha activity and lower TNF alpha levels in vivo in patients with SLE. This serum cytokine pattern may be relevant in other autoimmune diseases associated with the PTPN22 risk allele.