PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes.
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.
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Bahram
B
Namjou
Xana
X
Kim-Howard
Celi
C
Sun
Adam
A
Adler
Sharon A
SA
Chung
Kenneth M
KM
Kaufman
Jennifer A
JA
Kelly
Stuart B
SB
Glenn
Joel M
JM
Guthridge
Robert H
RH
Scofield
Robert P
RP
Kimberly
Elizabeth E
EE
Brown
Graciela S
GS
Alarcón
Jeffrey C
JC
Edberg
Jae-Hoon
JH
Kim
Jiyoung
J
Choi
Rosalind
R
Ramsey-Goldman
Michelle A
MA
Petri
John D
JD
Reveille
Luis M
LM
Vilá
Susan A
SA
Boackle
Barry I
BI
Freedman
Betty P
BP
Tsao
Carl D
CD
Langefeld
Timothy J
TJ
Vyse
Chaim O
CO
Jacob
Bernardo
B
Pons-Estel
Timothy B
TB
Niewold
Kathy L
KL
Moser Sivils
Joan T
JT
Merrill
Juan-Manuel
JM
Anaya
Gary S
GS
Gilkeson
Patrick M
PM
Gaffney
Sang-Cheol
SC
Bae
Marta E
ME
Alarcón-Riquelme
John B
JB
Harley
Lindsey A
LA
Criswell
Judith A
JA
James
Swapan K
SK
Nath
D001741:Black or African American / Q000235:genetics; D017153:Antibodies, Anticardiolipin / Q000276:immunology; D001213:Asian / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D044465:White People / Q000235:genetics
D017153:Antibodies, Anticardiolipin; D007074:Immunoglobulin G; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22