PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes

Bahram Namjou, Xana Kim-Howard, Celi Sun, Adam Adler, Sharon A. Chung, Kenneth M. Kaufman, Jennifer A. Kelly, Stuart B. Glenn, Joel M. Guthridge, Robert H. Scofield, Robert P. Kimberly, Elizabeth E. Brown, Graciela S. Alarcón, Jeffrey C. Edberg, Jae Hoon Kim, Jiyoung Choi, Rosalind Ramsey-Goldman, Michelle A. Petri, John D. Reveille, Luis M. ViláSusan A. Boackle, Barry I. Freedman, Betty P. Tsao, Carl D. Langefeld, Timothy J. Vyse, Chaim O. Jacob, Bernardo Pons-Estel, Timothy B. Niewold, Kathy L. Moser Sivils, Joan T. Merrill, Juan Manuel Anaya, Gary S. Gilkeson, Patrick M. Gaffney, Sang Cheol Bae, Marta E. Alarcón-Riquelme, John B. Harley, Lindsey A. Criswell, Judith A. James, Swapan K. Nath

Research output: Contribution to journalResearch Articlepeer-review

54 Scopus citations


Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10-9, OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10-5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.

Original languageEnglish (US)
Article numbere69404
Issue number8
StatePublished - Aug 7 2013

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General


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