Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy

S Bank, P S Andersen, Johan Burisch, N Pedersen, S Roug, J Galsgaard, S Y Turino, J B Brodersen, S Rashid, B K Rasmussen, S Avlund, T B Olesen, H.J. Hoffmann, Bjørn A Nexø, J Sode, U. Vogel, V Andersen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-' 3), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

OriginalsprogEngelsk
TidsskriftThe Pharmacogenomics Journal
Vol/bind18
Udgave nummer1
Sider (fra-til)87–97
ISSN1470-269X
DOI
StatusUdgivet - jan. 2018

Fingeraftryk

Interleukin-18
Ulcerative Colitis
Crohn Disease
Single Nucleotide Polymorphism
Inflammatory Bowel Diseases
Interferon-gamma
Interleukin-6
Tumor Necrosis Factor-alpha
Logistic Models

Citer dette

Bank, S ; Andersen, P S ; Burisch, Johan ; Pedersen, N ; Roug, S ; Galsgaard, J ; Turino, S Y ; Brodersen, J B ; Rashid, S ; Rasmussen, B K ; Avlund, S ; Olesen, T B ; Hoffmann, H.J. ; Nexø, Bjørn A ; Sode, J ; Vogel, U. ; Andersen, V. / Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy. I: The Pharmacogenomics Journal. 2018 ; Bind 18, Nr. 1. s. 87–97.
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title = "Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy",
abstract = "Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-' 3), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF na{\"i}ve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95{\%} CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Child, Cohort Studies, Colitis, Ulcerative/drug therapy, Crohn Disease/genetics, Female, Humans, Inflammatory Bowel Diseases/drug therapy, Interferon-gamma/genetics, Interleukin-12/genetics, Interleukin-18/genetics, Male, Middle Aged, Polymorphism, Single Nucleotide/genetics, Toll-Like Receptor 5/genetics, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Young Adult",
author = "S Bank and Andersen, {P S} and Johan Burisch and N Pedersen and S Roug and J Galsgaard and Turino, {S Y} and Brodersen, {J B} and S Rashid and Rasmussen, {B K} and S Avlund and Olesen, {T B} and H.J. Hoffmann and Nex{\o}, {Bj{\o}rn A} and J Sode and U. Vogel and V Andersen",
year = "2018",
month = "1",
doi = "10.1038/tpj.2016.84",
language = "English",
volume = "18",
pages = "87–97",
journal = "The Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "1",

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Bank, S, Andersen, PS, Burisch, J, Pedersen, N, Roug, S, Galsgaard, J, Turino, SY, Brodersen, JB, Rashid, S, Rasmussen, BK, Avlund, S, Olesen, TB, Hoffmann, HJ, Nexø, BA, Sode, J, Vogel, U & Andersen, V 2018, 'Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy', The Pharmacogenomics Journal, bind 18, nr. 1, s. 87–97. https://doi.org/10.1038/tpj.2016.84

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy. / Bank, S; Andersen, P S; Burisch, Johan; Pedersen, N; Roug, S; Galsgaard, J; Turino, S Y; Brodersen, J B; Rashid, S; Rasmussen, B K; Avlund, S; Olesen, T B; Hoffmann, H.J.; Nexø, Bjørn A; Sode, J; Vogel, U.; Andersen, V.

I: The Pharmacogenomics Journal, Bind 18, Nr. 1, 01.2018, s. 87–97.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy

AU - Bank, S

AU - Andersen, P S

AU - Burisch, Johan

AU - Pedersen, N

AU - Roug, S

AU - Galsgaard, J

AU - Turino, S Y

AU - Brodersen, J B

AU - Rashid, S

AU - Rasmussen, B K

AU - Avlund, S

AU - Olesen, T B

AU - Hoffmann, H.J.

AU - Nexø, Bjørn A

AU - Sode, J

AU - Vogel, U.

AU - Andersen, V

PY - 2018/1

Y1 - 2018/1

N2 - Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-' 3), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

AB - Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-' 3), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Child

KW - Cohort Studies

KW - Colitis, Ulcerative/drug therapy

KW - Crohn Disease/genetics

KW - Female

KW - Humans

KW - Inflammatory Bowel Diseases/drug therapy

KW - Interferon-gamma/genetics

KW - Interleukin-12/genetics

KW - Interleukin-18/genetics

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

KW - Toll-Like Receptor 5/genetics

KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors

KW - Young Adult

U2 - 10.1038/tpj.2016.84

DO - 10.1038/tpj.2016.84

M3 - Journal article

VL - 18

SP - 87

EP - 97

JO - The Pharmacogenomics Journal

JF - The Pharmacogenomics Journal

SN - 1470-269X

IS - 1

ER -