Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Genome-Wide Association Study of Genetic Predictors of Anti-Tumour Necrosis Factor (TNF) Treatment in Rheumatoid Arthritis (RA) Identifies Associations with Polymorphisms at Five Loci

Gibbons1,  Laura J., Potter2,  Catherine, Hyrich1,  K. L., Morgan3,  Ann W., Wilson4,  Anthony G., Isaacs2,  John D., Braggss,  

arc Epidemiology Unit, University of Manchester, Manchester, United Kingdom
arc Epidemiology Unit, University of Manchester, Manchester, United Kingdom
Musculoskeletal Research Group, Newcastle University, Newcastle Upon Tyne, United Kingdom
University of Leeds, Leeds, United Kingdom
Sheffield Uni/Medical School, Sheffield, United Kingdom

Purpose:

Anti-tumour necrosis factor (TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30–40% of patients treated. Knowledge of genetic factors influencing response may facilitate personalised therapy. The aim of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts.

Method:

Genome-wide association (GWA) data from the WTCCC1 was analysed in terms of treatment response for 595 anti-TNF-treated RA patients. Multivariate linear regression analysis of change in 28 joint count disease activity score (DAS28) at 6 months was conducted at each single nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10-3) were genotyped in two independent validation cohorts (n = 403 and n = 332) and a combined analysis was performed.

Results:

Of 193 markers associated with treatment response in the GWA data, 5 were replicated in both validation cohorts. In the combined analysis, the strongest effect was at rs9292156, an intergenic SNP on chromosome 5q11.2: the minor allele conferred improved response (Table 1), with a clinically relevant improvement of 0.61 units between the minor and major allele homozygotes. Association was also replicated at intronic SNPs in PDZD2 and EYA4, and at intergenic SNPs at chromosomal regions 1q23.3 and 12p12.3.

Table 1. Treatment response data in the combined cohort

    All cohorts combined (n = 1,330)
       Additive model
SNPLocusGenotypeCountMean baseline DAS28 (SD)Mean change in DAS28 (SD)Genotypic global PGlobal PCoefficient (95% CI)
rs12081765Chr1q23.3113996.61 (0.95)-2.70 (1.47)5.12 × 10-42.26 × 10-40.20 (0.10, 0.31)
  126616.68 (1.01)-2.44 (1.47)   
  222676.64 (0.95)-2.33 (1.54)   
rs1532269PDZD2115406.61 (1.03)-2.57 (1.49)6.54 × 10-44.04 × 10-40.21 (0.09, 0.32)
  126356.70 (0.94)-2.52 (1.47)   
  221536.59 (0.98)-2.16 (1.54)   
rs9292156Chr5q11.2119176.67 (0.97)-2.42 (1.50)9.76 × 10-51.97 × 10-5-0.31 (-0.45, -0.17)
  123676.60 (0.99)-2.62 (1.43)   
  22446.66 (1.18)-3.03 (1.50)   
rs17301249EYA4118756.64 (0.97)-2.39 (1.46)9.93 × 10-55.87 × 10-5-0.27 (-0.41, -0.14)
  124006.64 (1.01)-2.69 (1.57)   
  22546.86 (0.95)-2.85 (1.25)   
rs7305646Chr12p12.3113466.76 (0.99)-2.36 (1.46)4.18 × 10-48.41 × 10-5-0.22 (-0.33, -0.11)
  126656.65 (0.98)-2.49 (1.49)   
  223096.55 (0.98)-2.68 (1.52)   

Conclusion:

Using a genome-wide strategy, we have identified and replicated association at 5 genetic loci with response to anti-TNF treatment in RA patients. Adding these loci to known clinical variables improves the predictive model by ~25%, but additional predictors have yet to be identified.

1Wellcome Trust Case Control Consortium: Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007 Nov 39(11):1329–37.

To cite this abstract, please use the following information:
Gibbons, Laura J., Potter, Catherine, Hyrich, K. L., Morgan, Ann W., Wilson, Anthony G., Isaacs, John D., et al; Genome-Wide Association Study of Genetic Predictors of Anti-Tumour Necrosis Factor (TNF) Treatment in Rheumatoid Arthritis (RA) Identifies Associations with Polymorphisms at Five Loci [abstract]. Arthritis Rheum 2009;60 Suppl 10 :573
DOI: 10.1002/art.25653

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