Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis

Liu, Chunyu; Batliwalla, Franak; Li, Wentian; Lee, Annette; Roubenoff, Ronenn; Beckman, Evan M.; Khalili, Houman; Damle, Aarti; Kern, Marlena; Furie, Richard; Dupuis, Josée; Plenge, Robert M.; Coenen, Marieke J. H.; Behrens, Timothy W.; Carulli, John P.; Gregersen, Peter K.

doi:10.2119/2008-00056.liu

Cited by 198 publications

(148 citation statements)

References 42 publications

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“…It is supported by the large size of the three studies showing significant association with rs10919563 (3003 patients in total), and their PTPRC genetic biomarker of response to TNFi A Ferreiro-Iglesias et al combined P-value (P = 9.08 × 10 − 8 ), which approaches the GWAS significance threshold in fixed-effect meta-analysis. In contrast, previous studies showing association of the IL10 rs1800896 SNP were small (123 and 89 patients, respectively), and their P-values were modest (P = 0.04 and 0.01), 8,9 as in the present study (P = 0.01). Even more limited is the support for the CHUK rs11591741 SNP, which is replicated here for the first time.…”

Section: Discussioncontrasting

confidence: 99%

“…This result replicated an early study of selected cytokine polymorphisms in patients treated with ETC, 8 and the first genome-wide association study (GWAS) of response to TNFi. 9 The two studies found association with the same direction of change and at the same time of follow-up as we have found here. However, drug stratified analysis did not show an effect of this SNP in the subset of our patients treated with ETC (B = 0.04 ± 0.18; P = 0.8).…”

Section: Resultssupporting

confidence: 87%

“…The PTPRC and IL10 associations are specially remarkable, because they were already the most replicated biomarkers of the 14 explored. 8,9,14,15 In addition, the three biomarkers have reproduced the same genotype/ response relationships previously reported. 8,9,14,15,18 Therefore, these promising results should encourage further studies in this field, including those aiming to their confirmation in additional samples.…”

Section: Discussionsupporting

confidence: 76%

“…The first one, in the IL10 gene, was identified in an early study addressing selected single nucleotide polymorphisms (SNPs) in cytokine genes. 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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 99%

Section: Resultssupporting

confidence: 87%

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Dans une approche différente, Liu et al [36] ont réalisé, chez 102 PR actives débutant un traitement anti-TNF, une cartographie du génome, par genome wide association scan (GWAS). Plus de 280 000 SNP ont été analysés en fonction de la réponse clinique (évaluation du DAS) des malades.…”

Section: Phamacogénomique Et Gènes Du Tnfunclassified