Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.
Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P=.0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.
Plenge
Robert M
RM
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Padyukov
Leonid
L
Remmers
Elaine F
EF
Purcell
Shaun
S
Lee
Annette T
AT
Karlson
Elizabeth W
EW
Wolfe
Frederick
F
Kastner
Daniel L
DL
Alfredsson
Lars
L
Altshuler
David
D
Gregersen
Peter K
PK
Klareskog
Lars
L
Rioux
John D
JD
D000328:Adult; D017668:Age of Onset; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009656:North America / Q000453:epidemiology; D016017:Odds Ratio; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D012189:Retrospective Studies; D012196:Review Literature as Topic; D012737:Sex Factors; D013548:Sweden / Q000453:epidemiology; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006867:Hydrolases; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases