Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome

Jacob Sode, Ulla Vogel, Steffen Bank, Paal Skytt Andersen, Marianne Kragh Thomsen, Merete Lund Hetland, Henning Locht, Niels Heegaard, Vibeke Andersen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

OBJECTIVE: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.

METHODS: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.

RESULTS: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).

CONCLUSIONS: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.

OriginalsprogEngelsk
Artikelnummere100361
TidsskriftPLOS ONE
Vol/bind9
Udgave nummer6
Antal sider9
ISSN1932-6203
DOI
StatusUdgivet - 2014

Fingeraftryk

Inflammasomes
rheumatoid arthritis
Genes
Polymorphism
genetic variation
Rheumatoid Factor
single nucleotide polymorphism
Immunoglobulin M
genes
Nucleotides
Rheumatic Diseases
alleles
Pattern Recognition Receptors
joint diseases
Single Nucleotide Polymorphism
tumor necrosis factors
interferons
Alleles
odds ratio
Interferons

Citer dette

Sode, Jacob ; Vogel, Ulla ; Bank, Steffen ; Andersen, Paal Skytt ; Thomsen, Marianne Kragh ; Hetland, Merete Lund ; Locht, Henning ; Heegaard, Niels ; Andersen, Vibeke. / Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome. I: PLOS ONE. 2014 ; Bind 9, Nr. 6.
@article{dcd7dcd1dd4c437fbc16aa512df1e65b,
title = "Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome",
abstract = "OBJECTIVE: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.METHODS: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.RESULTS: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95{\%} confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).CONCLUSIONS: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.",
author = "Jacob Sode and Ulla Vogel and Steffen Bank and Andersen, {Paal Skytt} and Thomsen, {Marianne Kragh} and Hetland, {Merete Lund} and Henning Locht and Niels Heegaard and Vibeke Andersen",
year = "2014",
doi = "10.1371/journal.pone.0100361",
language = "English",
volume = "9",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

Sode, J, Vogel, U, Bank, S, Andersen, PS, Thomsen, MK, Hetland, ML, Locht, H, Heegaard, N & Andersen, V 2014, 'Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome', PLOS ONE, bind 9, nr. 6, e100361. https://doi.org/10.1371/journal.pone.0100361

Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome. / Sode, Jacob; Vogel, Ulla; Bank, Steffen; Andersen, Paal Skytt; Thomsen, Marianne Kragh; Hetland, Merete Lund; Locht, Henning; Heegaard, Niels; Andersen, Vibeke.

I: PLOS ONE, Bind 9, Nr. 6, e100361, 2014.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome

AU - Sode, Jacob

AU - Vogel, Ulla

AU - Bank, Steffen

AU - Andersen, Paal Skytt

AU - Thomsen, Marianne Kragh

AU - Hetland, Merete Lund

AU - Locht, Henning

AU - Heegaard, Niels

AU - Andersen, Vibeke

PY - 2014

Y1 - 2014

N2 - OBJECTIVE: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.METHODS: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.RESULTS: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).CONCLUSIONS: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.

AB - OBJECTIVE: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.METHODS: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.RESULTS: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).CONCLUSIONS: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.

U2 - 10.1371/journal.pone.0100361

DO - 10.1371/journal.pone.0100361

M3 - Journal article

VL - 9

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 6

M1 - e100361

ER -