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

Sophine B Krintel; Giuseppe Palermo; Julia S Johansen; Søren Germer; Laurent Essioux; Ryma Benayed; Laura Badi; Mikkel Østergaard; Merete L Hetland

doi:10.1097/fpc.0b013e3283544043

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

Sophine B Krintel, Giuseppe Palermo, Julia S Johansen, Søren Germer, Laurent Essioux, Ryma Benayed, Laura Badi, Mikkel Østergaard, Merete L Hetland

54 Citations (Scopus)

Abstract

Objective: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. Methods: TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. Results: After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. Conclusion: In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

Original language	English
Journal	Pharmacogenetics and Genomics
Volume	22
Issue number	8
Pages (from-to)	577-89
Number of pages	13
ISSN	1744-6872
DOIs	https://doi.org/10.1097/fpc.0b013e3283544043
Publication status	Published - Aug 2012

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Krintel, S. B., Palermo, G., Johansen, J. S., Germer, S., Essioux, L., Benayed, R., Badi, L., Østergaard, M., & Hetland, M. L. (2012). Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis. Pharmacogenetics and Genomics, 22(8), 577-89. https://doi.org/10.1097/fpc.0b013e3283544043

Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis. / Krintel, Sophine B; Palermo, Giuseppe; Johansen, Julia S et al.

In: Pharmacogenetics and Genomics, Vol. 22, No. 8, 08.2012, p. 577-89.

Research output: Contribution to journal › Journal article › Research › peer-review

Krintel, SB, Palermo, G, Johansen, JS, Germer, S, Essioux, L, Benayed, R, Badi, L, Østergaard, M & Hetland, ML 2012, 'Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis', Pharmacogenetics and Genomics, vol. 22, no. 8, pp. 577-89. https://doi.org/10.1097/fpc.0b013e3283544043

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abstract = "Objective: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. Methods: TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. Results: After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. Conclusion: In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.",

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T1 - Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

AU - Krintel, Sophine B

AU - Palermo, Giuseppe

AU - Johansen, Julia S

AU - Germer, Søren

AU - Essioux, Laurent

AU - Benayed, Ryma

AU - Badi, Laura

AU - Østergaard, Mikkel

AU - Hetland, Merete L

PY - 2012/8

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N2 - Objective: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. Methods: TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. Results: After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. Conclusion: In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

AB - Objective: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. Methods: TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. Results: After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. Conclusion: In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

U2 - 10.1097/fpc.0b013e3283544043

DO - 10.1097/fpc.0b013e3283544043

M3 - Journal article

SN - 1744-6872

VL - 22

SP - 577

EP - 589

JO - Pharmacogenetics

JF - Pharmacogenetics

IS - 8

ER -

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

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