Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci.
OBJECTIVE
Anti-tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30-40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts.


METHODS
Data from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF-treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10(-3) ) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed.


RESULTS
Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient -0.27, P = 5.67(-05) ). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37(-04) ). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12.


CONCLUSIONS
Using a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.
University of Manchester, Manchester, UK.
Darren
D
Plant
John
J
Bowes
Catherine
C
Potter
Kimme L
KL
Hyrich
Ann W
AW
Morgan
Anthony G
AG
Wilson
John D
JD
Isaacs
Anne
A
Barton
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D015815:Cell Adhesion Molecules; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine / Q000379:methods*; D011237:Predictive Value of Tests; D015534:Trans-Activators / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; C117736:EYA4 protein, human; D005819:Genetic Markers; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha