Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment.
BACKGROUND
Anti-tumour necrosis factor (anti-TNF) therapy has proved to be highly successful in treating rheumatoid arthritis (RA), although 30-40% of patients have little or no response. The authors hypothesise that this may be genetically determined. In other complex diseases, susceptibility genes have been shown to influence treatment response. The aim of the current study was to investigate the association of markers within confirmed RA susceptibility loci with the response to anti-TNF treatment.


METHODS
Eighteen single nucleotide polymorphisms (SNPs) mapping to 11 genetic loci were genotyped in 1012 patients with RA receiving treatment with etanercept, infliximab or adalimumab. Multivariate linear regression analyses were performed using the absolute change in 28 joint count disease activity score (DAS28) between baseline and 6-month follow-up as the outcome variable, adjusting for confounders. p Values <0.05 were considered statistically significant and associated markers were genotyped in an additional 322 samples. Analysis was performed in the combined cohort of 1334 subjects with RA treated with anti-TNF.


RESULTS
In the combined analysis, SNPs mapping to AFF3 and CD226 had a statistically significant association with the response to anti-TNF treatment under an additive model. The G allele at rs10865035, mapping to AFF3, was associated with an improved response to anti-TNF treatment (coefficient -0.14 (95% CI -0.25 to -0.03), p=0.015). At the CD226 SNP rs763361, the C allele conferred reduced response to treatment (coefficient 0.11 (95% CI 0.00 to 0.22), p=0.048).


CONCLUSIONS
These results suggest that AFF3 and CD226, two confirmed RA susceptibility genes, have an additional role in influencing the response to anti-TNF treatment.
Tan
Rachael J L
RJ
Arthritis Research Campaign Epidemiology Unit, Stopford Building, Oxford Road, University of Manchester, Manchester M13 9PT, UK.
Gibbons
Laura J
LJ
Potter
Catherine
C
Hyrich
Kimme L
KL
Morgan
Ann W
AW
Wilson
Anthony G
AG
Isaacs
John D
JD
Barton
Anne
A
D000328:Adult; D000368:Aged; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000098862:T Lineage-Specific Activation Antigen 1
C097738:AFF3 protein, human; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; D000098862:T Lineage-Specific Activation Antigen 1; D005819:Genetic Markers; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha
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