Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Genome Wide Association Analysis of Rheumatoid Arthritis Patients Treated with Anti-TNF Medication
Coenen1, Marieke JH, Toonen1, Erik JM, Lee2, Annette T., Batliwalla2, Franak, Kievit1, Wietske, Scheffer1, Hans, Radstake1, Timothy RDJ
Treatment strategies blocking tumour necrosis factor (TNF) have proven very successful in patients with rheumatoid arthritis (RA) showing beneficial effects in at least 60% of the patients. However, a significant subset of patients does not respond for reasons that are unknown, and there is currently no means of identifying these patients.
In this study we performed a genome-wide association (GWA) analysis on 213 patients with RA treated with antibodies directed to TNF (anti-TNF) from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. For patient selection, we used an extreme groups approach, limiting inclusion to only very good responders (n=96) and total non-responders (n=117) to anti-TNF, based on the EULAR response criteria. Single nucleotide polymorphisms (SNPs) markers were genotyped using the Illumina HumanHap550-Duo BeadChip. Association analysis was performed using the whole genome association analysis toolset PLINK.
496.659 SNPs and 207 patients passed quality control. Thirty-three SNPs showed association (uncorrected p-value < 0.0001) with anti-TNF treatment response. The top 10 associated markers were located in regions including the nardilysin (NRD1) gene on chromosome 1; the solute carrier family 35, member F3 (SLC35F3) gene on chromosome 1; the latrophilin 3 (LPHN3) gene on chromosome 4; the translocation associated membrane protein 1-like 1 (TRAM1L1) gene on chromosome 4; the ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) gene on chromosome 5; the glutamate receptor, metabotropic 4 (GRM4) gene on chromosome 16; and a region on chromosome 14 that includes the beta-spectrin (SPTB) gene.
Solute carrier family 35, member F3 latrophilin 3 translocation associated membrane protein 1-like 1 (ADAM metallopeptidase with thrombospondin type 1 motif, 16 (glutamate receptor, metabotropic 4 beta-spectrin
The most interesting candidate is NRD1 for which it is documented that it is involved in TNF alpha shedding. To validate the present results we will extend the GWA analysis with an additional 362 patients from the DREAM registry. Significant findings will be replicated in other patient cohorts. The identified genes may serve as new biomarkers predicting anti-TNF response.
To cite this abstract, please use the following information:
Coenen, Marieke JH, Toonen, Erik JM, Lee, Annette T., Batliwalla, Franak, Kievit, Wietske, Scheffer, Hans, et al; Genome Wide Association Analysis of Rheumatoid Arthritis Patients Treated with Anti-TNF Medication [abstract]. Arthritis Rheum 2009;60 Suppl 10 :394