Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease

The Danish IBD Genetics Working Group

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Background: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC. Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response. Methods: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). Results: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04)). Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.

OriginalsprogEngelsk
TidsskriftAlimentary Pharmacology and Therapeutics
Vol/bind49
Udgave nummer7
Sider (fra-til)890-903
ISSN0269-2813
DOI
StatusUdgivet - apr. 2019

Fingeraftryk

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

Citer dette

@article{f55f3ddc03a14ba5901d40184ffe3aab,
title = "Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease",
abstract = "Background: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC. Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response. Methods: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). Results: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95{\%} CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95{\%} CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95{\%} CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95{\%} CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95{\%} CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95{\%} CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95{\%} CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95{\%} CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95{\%} CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95{\%} CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95{\%} CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95{\%} CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95{\%} CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95{\%} CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95{\%} CI: 1.01-1.53, P = 0.04)). Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82{\%} (in 9{\%} of the CD patients) and 75{\%} (in 15{\%} of the UC patients), compared to 71{\%} and 64{\%} in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.",
author = "Steffen Bank and Mette Julsgaard and Abed, {Osama Karim} and Johan Burisch and {Broder Brodersen}, Jacob and Pedersen, {Natalia Konstantinovich} and Anja Gouliaev and Rullah Ajan and {Nytoft Rasmussen}, Ditlev and {Honore Grauslund}, Camilla and Stine Roug and Julie Galsgaard and {Sprog{\o}e H{\o}yer Finsen}, David and Karoline Lindby and Jeanette S{\o}rensen and Lone Larsen and {Rohr Andersen}, Malene and Ivan Brandslund and Mads Thomassen and Anders Green and {Bo Bojesen}, Anders and {Bek S{\o}rensen}, Signe and Ulla Vogel and Vibeke Andersen and {The Danish IBD Genetics Working Group}",
year = "2019",
month = "4",
doi = "10.1111/apt.15187",
language = "English",
volume = "49",
pages = "890--903",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell",
number = "7",

}

Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease. / The Danish IBD Genetics Working Group.

I: Alimentary Pharmacology and Therapeutics, Bind 49, Nr. 7, 04.2019, s. 890-903.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease

AU - Bank, Steffen

AU - Julsgaard, Mette

AU - Abed, Osama Karim

AU - Burisch, Johan

AU - Broder Brodersen, Jacob

AU - Pedersen, Natalia Konstantinovich

AU - Gouliaev, Anja

AU - Ajan, Rullah

AU - Nytoft Rasmussen, Ditlev

AU - Honore Grauslund, Camilla

AU - Roug, Stine

AU - Galsgaard, Julie

AU - Sprogøe Høyer Finsen, David

AU - Lindby, Karoline

AU - Sørensen, Jeanette

AU - Larsen, Lone

AU - Rohr Andersen, Malene

AU - Brandslund, Ivan

AU - Thomassen, Mads

AU - Green, Anders

AU - Bo Bojesen, Anders

AU - Bek Sørensen, Signe

AU - Vogel, Ulla

AU - Andersen, Vibeke

AU - The Danish IBD Genetics Working Group

PY - 2019/4

Y1 - 2019/4

N2 - Background: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC. Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response. Methods: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). Results: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04)). Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.

AB - Background: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC. Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response. Methods: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). Results: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04)). Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.

U2 - 10.1111/apt.15187

DO - 10.1111/apt.15187

M3 - Journal article

VL - 49

SP - 890

EP - 903

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 7

ER -