Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

Krintel, Sophine B.; Palermo, G.; Johansen, Julia S.; Germer, Søren; Essioux, Laurent; Benayed, Ryma; Badi, Laura; Østergaard, Mikkel; Hetland, Merete Lund

doi:10.1097/fpc.0b013e3283544043

Cited by 60 publications

(59 citation statements)

References 44 publications

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“…We did not find any evidence for association for the loci identified from previously published GWAS on anti-TNF response [18][19][20] or for the PTPRC gene (table 3) 16 17 in the Dutch patients included in our stage 1 GWAS, suggesting that these genes do not play a major role in anti-TNF treatment outcome in our population. However, the power of our study to detect an association with PTPRC loci at p<0.0005 in a set size of 882 patients was 26%.…”

Section: Figurementioning

confidence: 53%

“…16 17 A number of additional potential candidate loci have been suggested on the basis of results from three genome-wide association studies (GWAS). [18][19][20] In a GWAS of 566 patients with RA, Plant et al 19 found evidence of association at seven genetic loci with response to TNF blockade, two of which mapped within genes: PDZ domain-containing protein 2 (PDZD2) and eyes absent homologue 4 (EYA4). In a small study (n=89) by Liu et al, 18 association was reported for markers in the MAFB and PON1 gene regions as well as in a region of chromosome 9 that contains the interferon kappa (IFN-κ), MOBKL2B and C9orf72 loci.…”

Section: Introductionmentioning

confidence: 99%

“…21 However, these results could not be replicated by others. 20 22 Krintel et al 20 reported associations of singlenucleotide polymorphisms (SNPs) within a non-coding region surrounded by the TLR4 gene and the DBC1 gene and a marker within the FOXP1 gene with treatment outcome in a cohort of 196 Danish patients.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

et al. 2012

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Background Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently there are no means of identifying these patients prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach. Methods We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity. Results Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. Conclusion Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

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Section: Figurementioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

et al. 2012

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“…Recently, a genome-wide association studies of anti-TNF response in rheumatoid arthritis in the Danish population identified a large group of candidate regions. 17 Using an independent cohort of rheumatoid arthritis patients from the Spanish population, we were able to replicate the association between PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus on chromosome 12p12.2 and anti-TNF response. 18 Combining the evidence between the two patient cohorts, PDE3A-SLCO1C1 association was the first pharmacogenetic locus to reach the genome-wide level of significance in rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 82%

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis

Juliá¹,

Ferrándiz

Daudén

et al. 2014

Pharmacogenomics J

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Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

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“…8 It was replicated in the first genomewide association study (GWAS) of response to TNFi, 9 but not in subsequent GWAS on this phenotype. [10][11][12][13] The second replicated biomarker, in the PTPRC gene, was identified in a study considering the RA susceptibility loci as candidate genes. 14 The RA risk allele of this locus was associated with improved response to TNFi.…”

Section: Introductionmentioning

confidence: 99%

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis

et al. 2015

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Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

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Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

Cited by 60 publications

References 44 publications

Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis

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