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
Summary 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 pol...
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| Veröffentlicht in: | Alimentary pharmacology & therapeutics 2019-04, Vol.49 (7), p.890-903 |
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| creator | Bank, Steffen Julsgaard, Mette Abed, Osama Karim Burisch, Johan Broder Brodersen, Jacob Pedersen, Natalia Konstantinovich Gouliaev, Anja Ajan, Rullah Nytoft Rasmussen, Ditlev Honore Grauslund, Camilla Roug, Stine Galsgaard, Julie Sprogøe Høyer Finsen, David Lindby, Karoline Sørensen, Jeanette Larsen, Lone Rohr Andersen, Malene Brandslund, Ivan Thomassen, Mads Green, Anders Bo Bojesen, Anders Bek Sørensen, Signe Vogel, Ulla Andersen, Vibeke Bergmann, Ann Christina Andersen, Paal Skytt Rashid, Shaista Lund, Britta Ørnfelt Rasmussen, Britt Kaiser Avlund, Sara Nielsen, Marie Ødum Nilsdotter Bramstång, Eva Karolina Poulsen, Anja Rudbeck‐Resdal, Ditte Aamann, Luise Alexandraki, Maria Joanna Foroutani, Ali Molzen, Line Hatrop, Anders Rittig, Charlotte Siggaard Stenbøg, Elisabeth Hedbäck, Nora Elisabeth Nielsen, Rasmus Gaardskaer Schiødt, Frank Vinholt Carlsen, Katrine Dessau, Ram Benny Hoffmann, Hans Jürgen Nexø, Bjørn Andersen Sode, Jacob |
| description | Summary
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. |
| doi_str_mv | 10.1111/apt.15187 |
| format | Article |
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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.</description><identifier>ISSN: 0269-2813</identifier><identifier>EISSN: 1365-2036</identifier><identifier>DOI: 10.1111/apt.15187</identifier><identifier>PMID: 30811631</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Cohort Studies ; Colon ; Crohn's disease ; Denmark - epidemiology ; Female ; Gene regulation ; Humans ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Inflammatory Bowel Diseases - drug therapy ; Inflammatory Bowel Diseases - epidemiology ; Inflammatory Bowel Diseases - genetics ; Interleukin 1 ; Interleukin 18 ; Interleukin-18 - genetics ; Interleukin-1beta - genetics ; Intestine ; Janus kinase 2 ; Male ; Middle Aged ; NF-kappa B - genetics ; NF-κB protein ; Patients ; Polymorphism, Single Nucleotide - genetics ; Retrospective Studies ; Signal transduction ; Single-nucleotide polymorphism ; TLR2 protein ; TLR4 protein ; Toll-like receptors ; Tumor necrosis factor ; Tumor Necrosis Factor Inhibitors - therapeutic use ; Tumor Necrosis Factor-alpha - genetics ; Tumor necrosis factor-TNF ; Ulcerative colitis ; Young Adult</subject><ispartof>Alimentary pharmacology & therapeutics, 2019-04, Vol.49 (7), p.890-903</ispartof><rights>2019 John Wiley & Sons Ltd</rights><rights>2019 John Wiley & Sons Ltd.</rights><rights>Copyright © 2019 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-3070-8950 ; 0000-0002-3916-4710 ; 0000-0002-3312-5139</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fapt.15187$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fapt.15187$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30811631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bank, Steffen</creatorcontrib><creatorcontrib>Julsgaard, Mette</creatorcontrib><creatorcontrib>Abed, Osama Karim</creatorcontrib><creatorcontrib>Burisch, Johan</creatorcontrib><creatorcontrib>Broder Brodersen, Jacob</creatorcontrib><creatorcontrib>Pedersen, Natalia Konstantinovich</creatorcontrib><creatorcontrib>Gouliaev, Anja</creatorcontrib><creatorcontrib>Ajan, Rullah</creatorcontrib><creatorcontrib>Nytoft Rasmussen, Ditlev</creatorcontrib><creatorcontrib>Honore Grauslund, Camilla</creatorcontrib><creatorcontrib>Roug, Stine</creatorcontrib><creatorcontrib>Galsgaard, Julie</creatorcontrib><creatorcontrib>Sprogøe Høyer Finsen, David</creatorcontrib><creatorcontrib>Lindby, Karoline</creatorcontrib><creatorcontrib>Sørensen, Jeanette</creatorcontrib><creatorcontrib>Larsen, Lone</creatorcontrib><creatorcontrib>Rohr Andersen, Malene</creatorcontrib><creatorcontrib>Brandslund, Ivan</creatorcontrib><creatorcontrib>Thomassen, Mads</creatorcontrib><creatorcontrib>Green, Anders</creatorcontrib><creatorcontrib>Bo Bojesen, Anders</creatorcontrib><creatorcontrib>Bek Sørensen, Signe</creatorcontrib><creatorcontrib>Vogel, Ulla</creatorcontrib><creatorcontrib>Andersen, Vibeke</creatorcontrib><creatorcontrib>Bergmann, Ann Christina</creatorcontrib><creatorcontrib>Andersen, Paal Skytt</creatorcontrib><creatorcontrib>Rashid, Shaista</creatorcontrib><creatorcontrib>Lund, Britta Ørnfelt</creatorcontrib><creatorcontrib>Rasmussen, Britt Kaiser</creatorcontrib><creatorcontrib>Avlund, Sara</creatorcontrib><creatorcontrib>Nielsen, Marie Ødum</creatorcontrib><creatorcontrib>Nilsdotter Bramstång, Eva Karolina</creatorcontrib><creatorcontrib>Poulsen, Anja</creatorcontrib><creatorcontrib>Rudbeck‐Resdal, Ditte</creatorcontrib><creatorcontrib>Aamann, Luise</creatorcontrib><creatorcontrib>Alexandraki, Maria Joanna</creatorcontrib><creatorcontrib>Foroutani, Ali</creatorcontrib><creatorcontrib>Molzen, Line</creatorcontrib><creatorcontrib>Hatrop, Anders</creatorcontrib><creatorcontrib>Rittig, Charlotte Siggaard</creatorcontrib><creatorcontrib>Stenbøg, Elisabeth</creatorcontrib><creatorcontrib>Hedbäck, Nora Elisabeth</creatorcontrib><creatorcontrib>Nielsen, Rasmus Gaardskaer</creatorcontrib><creatorcontrib>Schiødt, Frank Vinholt</creatorcontrib><creatorcontrib>Carlsen, Katrine</creatorcontrib><creatorcontrib>Dessau, Ram Benny</creatorcontrib><creatorcontrib>Hoffmann, Hans Jürgen</creatorcontrib><creatorcontrib>Nexø, Bjørn Andersen</creatorcontrib><creatorcontrib>Sode, Jacob</creatorcontrib><creatorcontrib>Danish IBD Genetics Working Group</creatorcontrib><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</title><title>Alimentary pharmacology & therapeutics</title><addtitle>Aliment Pharmacol Ther</addtitle><description>Summary
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.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Cohort Studies</subject><subject>Colon</subject><subject>Crohn's disease</subject><subject>Denmark - epidemiology</subject><subject>Female</subject><subject>Gene regulation</subject><subject>Humans</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Inflammatory Bowel Diseases - drug therapy</subject><subject>Inflammatory Bowel Diseases - epidemiology</subject><subject>Inflammatory Bowel Diseases - genetics</subject><subject>Interleukin 1</subject><subject>Interleukin 18</subject><subject>Interleukin-18 - genetics</subject><subject>Interleukin-1beta - genetics</subject><subject>Intestine</subject><subject>Janus kinase 2</subject><subject>Male</subject><subject>Middle Aged</subject><subject>NF-kappa B - genetics</subject><subject>NF-κB protein</subject><subject>Patients</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Retrospective Studies</subject><subject>Signal transduction</subject><subject>Single-nucleotide polymorphism</subject><subject>TLR2 protein</subject><subject>TLR4 protein</subject><subject>Toll-like receptors</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor Inhibitors - therapeutic use</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor necrosis factor-TNF</subject><subject>Ulcerative colitis</subject><subject>Young Adult</subject><issn>0269-2813</issn><issn>1365-2036</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9u1DAQxi1ERZfCgRdAlrhwaFr_SbLOsRQWKq1KD8s5msSziksSG9urVW48Ak_CQ_EkON1tD7Ulz1j-fTPWfIS84-yCp3UJLl7wgqvlC7LgsiwywWT5kiyYKKtMKC5PyesQ7hlj5ZKJV-RUMsV5KfmC_L2z_TRY7zoThkDNSGOH9Hb189M53dyu_v3-A73r4JzerFPOG4wph1Ef74o6iN0epkDBI4UQbGsgoqZ7EzvqMTg7BqTRJlE0SZKKzi08uGnu9hlGE7q5isExhoPMjNsehgGi9RNt7B57qk1ACPiGnGyhD_j2GM_Ij9WXzfW3bP3968311TpzkufLLEfRpp23XChgUIhWtkIIVWiOuWxkKaQuZANbXTUSodou83Q0QueFzlWh5Bn5eKjrvP21wxDrwYQW-x5GtLtQizTsebr5jH54ht7bnR_T7xJVMcU4r8pEvT9Su2ZAXTtvBvBT_ehEAi4PwN70OD29c1bPFtfJ4vrB4vrqbvOQyP9chJyc</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Bank, Steffen</creator><creator>Julsgaard, Mette</creator><creator>Abed, Osama Karim</creator><creator>Burisch, Johan</creator><creator>Broder Brodersen, Jacob</creator><creator>Pedersen, Natalia 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Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7T5</scope><scope>7TK</scope><scope>7U9</scope><scope>H94</scope><scope>M7N</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3070-8950</orcidid><orcidid>https://orcid.org/0000-0002-3916-4710</orcidid><orcidid>https://orcid.org/0000-0002-3312-5139</orcidid></search><sort><creationdate>201904</creationdate><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</title><author>Bank, Steffen ; Julsgaard, Mette ; Abed, Osama Karim ; Burisch, Johan ; Broder Brodersen, Jacob ; Pedersen, Natalia Konstantinovich ; Gouliaev, Anja ; Ajan, Rullah ; Nytoft Rasmussen, Ditlev ; Honore Grauslund, Camilla ; Roug, Stine ; Galsgaard, Julie ; Sprogøe Høyer Finsen, David ; Lindby, Karoline ; Sørensen, Jeanette ; Larsen, Lone ; Rohr Andersen, Malene ; Brandslund, Ivan ; Thomassen, Mads ; Green, Anders ; Bo Bojesen, Anders ; Bek Sørensen, Signe ; Vogel, Ulla ; Andersen, Vibeke ; Bergmann, Ann Christina ; Andersen, Paal Skytt ; Rashid, Shaista ; Lund, Britta Ørnfelt ; Rasmussen, Britt Kaiser ; Avlund, Sara ; Nielsen, Marie Ødum ; Nilsdotter Bramstång, Eva Karolina ; Poulsen, Anja ; Rudbeck‐Resdal, Ditte ; Aamann, Luise ; Alexandraki, Maria Joanna ; Foroutani, Ali ; Molzen, Line ; Hatrop, Anders ; Rittig, Charlotte Siggaard ; Stenbøg, Elisabeth ; Hedbäck, Nora Elisabeth ; Nielsen, Rasmus Gaardskaer ; Schiødt, Frank Vinholt ; Carlsen, Katrine ; Dessau, Ram Benny ; Hoffmann, Hans Jürgen ; Nexø, Bjørn Andersen ; Sode, Jacob</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p3147-4e2c2c24c128a0a52c3c22285d1e43b3623d53bafd9b3ea9f74a9fb2d45d48583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Cohort Studies</topic><topic>Colon</topic><topic>Crohn's disease</topic><topic>Denmark - epidemiology</topic><topic>Female</topic><topic>Gene regulation</topic><topic>Humans</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory bowel diseases</topic><topic>Inflammatory Bowel Diseases - drug therapy</topic><topic>Inflammatory Bowel Diseases - epidemiology</topic><topic>Inflammatory Bowel Diseases - genetics</topic><topic>Interleukin 1</topic><topic>Interleukin 18</topic><topic>Interleukin-18 - genetics</topic><topic>Interleukin-1beta - genetics</topic><topic>Intestine</topic><topic>Janus kinase 2</topic><topic>Male</topic><topic>Middle Aged</topic><topic>NF-kappa B - genetics</topic><topic>NF-κB protein</topic><topic>Patients</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Retrospective Studies</topic><topic>Signal transduction</topic><topic>Single-nucleotide polymorphism</topic><topic>TLR2 protein</topic><topic>TLR4 protein</topic><topic>Toll-like receptors</topic><topic>Tumor necrosis factor</topic><topic>Tumor Necrosis Factor Inhibitors - therapeutic use</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor necrosis factor-TNF</topic><topic>Ulcerative colitis</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bank, Steffen</creatorcontrib><creatorcontrib>Julsgaard, Mette</creatorcontrib><creatorcontrib>Abed, Osama Karim</creatorcontrib><creatorcontrib>Burisch, Johan</creatorcontrib><creatorcontrib>Broder Brodersen, Jacob</creatorcontrib><creatorcontrib>Pedersen, Natalia Konstantinovich</creatorcontrib><creatorcontrib>Gouliaev, Anja</creatorcontrib><creatorcontrib>Ajan, Rullah</creatorcontrib><creatorcontrib>Nytoft Rasmussen, Ditlev</creatorcontrib><creatorcontrib>Honore Grauslund, Camilla</creatorcontrib><creatorcontrib>Roug, Stine</creatorcontrib><creatorcontrib>Galsgaard, Julie</creatorcontrib><creatorcontrib>Sprogøe Høyer Finsen, David</creatorcontrib><creatorcontrib>Lindby, Karoline</creatorcontrib><creatorcontrib>Sørensen, Jeanette</creatorcontrib><creatorcontrib>Larsen, Lone</creatorcontrib><creatorcontrib>Rohr Andersen, Malene</creatorcontrib><creatorcontrib>Brandslund, Ivan</creatorcontrib><creatorcontrib>Thomassen, Mads</creatorcontrib><creatorcontrib>Green, Anders</creatorcontrib><creatorcontrib>Bo Bojesen, Anders</creatorcontrib><creatorcontrib>Bek Sørensen, Signe</creatorcontrib><creatorcontrib>Vogel, Ulla</creatorcontrib><creatorcontrib>Andersen, Vibeke</creatorcontrib><creatorcontrib>Bergmann, Ann Christina</creatorcontrib><creatorcontrib>Andersen, Paal Skytt</creatorcontrib><creatorcontrib>Rashid, Shaista</creatorcontrib><creatorcontrib>Lund, Britta Ørnfelt</creatorcontrib><creatorcontrib>Rasmussen, Britt Kaiser</creatorcontrib><creatorcontrib>Avlund, Sara</creatorcontrib><creatorcontrib>Nielsen, Marie Ødum</creatorcontrib><creatorcontrib>Nilsdotter Bramstång, Eva Karolina</creatorcontrib><creatorcontrib>Poulsen, Anja</creatorcontrib><creatorcontrib>Rudbeck‐Resdal, Ditte</creatorcontrib><creatorcontrib>Aamann, Luise</creatorcontrib><creatorcontrib>Alexandraki, Maria Joanna</creatorcontrib><creatorcontrib>Foroutani, Ali</creatorcontrib><creatorcontrib>Molzen, Line</creatorcontrib><creatorcontrib>Hatrop, Anders</creatorcontrib><creatorcontrib>Rittig, Charlotte Siggaard</creatorcontrib><creatorcontrib>Stenbøg, Elisabeth</creatorcontrib><creatorcontrib>Hedbäck, Nora Elisabeth</creatorcontrib><creatorcontrib>Nielsen, Rasmus Gaardskaer</creatorcontrib><creatorcontrib>Schiødt, Frank Vinholt</creatorcontrib><creatorcontrib>Carlsen, Katrine</creatorcontrib><creatorcontrib>Dessau, Ram Benny</creatorcontrib><creatorcontrib>Hoffmann, Hans Jürgen</creatorcontrib><creatorcontrib>Nexø, Bjørn Andersen</creatorcontrib><creatorcontrib>Sode, Jacob</creatorcontrib><creatorcontrib>Danish IBD Genetics Working Group</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Alimentary pharmacology & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bank, Steffen</au><au>Julsgaard, Mette</au><au>Abed, Osama Karim</au><au>Burisch, Johan</au><au>Broder Brodersen, Jacob</au><au>Pedersen, Natalia Konstantinovich</au><au>Gouliaev, Anja</au><au>Ajan, Rullah</au><au>Nytoft Rasmussen, Ditlev</au><au>Honore Grauslund, Camilla</au><au>Roug, Stine</au><au>Galsgaard, Julie</au><au>Sprogøe Høyer Finsen, David</au><au>Lindby, Karoline</au><au>Sørensen, Jeanette</au><au>Larsen, Lone</au><au>Rohr Andersen, Malene</au><au>Brandslund, Ivan</au><au>Thomassen, Mads</au><au>Green, Anders</au><au>Bo Bojesen, Anders</au><au>Bek Sørensen, Signe</au><au>Vogel, Ulla</au><au>Andersen, Vibeke</au><au>Bergmann, Ann Christina</au><au>Andersen, Paal Skytt</au><au>Rashid, Shaista</au><au>Lund, Britta Ørnfelt</au><au>Rasmussen, Britt Kaiser</au><au>Avlund, Sara</au><au>Nielsen, Marie Ødum</au><au>Nilsdotter Bramstång, Eva Karolina</au><au>Poulsen, Anja</au><au>Rudbeck‐Resdal, Ditte</au><au>Aamann, Luise</au><au>Alexandraki, Maria Joanna</au><au>Foroutani, Ali</au><au>Molzen, Line</au><au>Hatrop, Anders</au><au>Rittig, Charlotte Siggaard</au><au>Stenbøg, Elisabeth</au><au>Hedbäck, Nora Elisabeth</au><au>Nielsen, Rasmus Gaardskaer</au><au>Schiødt, Frank Vinholt</au><au>Carlsen, Katrine</au><au>Dessau, Ram Benny</au><au>Hoffmann, Hans Jürgen</au><au>Nexø, Bjørn Andersen</au><au>Sode, Jacob</au><aucorp>Danish IBD Genetics Working Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Alimentary pharmacology & therapeutics</jtitle><addtitle>Aliment Pharmacol Ther</addtitle><date>2019-04</date><risdate>2019</risdate><volume>49</volume><issue>7</issue><spage>890</spage><epage>903</epage><pages>890-903</pages><issn>0269-2813</issn><eissn>1365-2036</eissn><abstract>Summary
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.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30811631</pmid><doi>10.1111/apt.15187</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-3070-8950</orcidid><orcidid>https://orcid.org/0000-0002-3916-4710</orcidid><orcidid>https://orcid.org/0000-0002-3312-5139</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0269-2813 |
| ispartof | Alimentary pharmacology & therapeutics, 2019-04, Vol.49 (7), p.890-903 |
| issn | 0269-2813 1365-2036 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2187026948 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Adult Aged Aged, 80 and over Child Child, Preschool Cohort Studies Colon Crohn's disease Denmark - epidemiology Female Gene regulation Humans Inflammatory bowel disease Inflammatory bowel diseases Inflammatory Bowel Diseases - drug therapy Inflammatory Bowel Diseases - epidemiology Inflammatory Bowel Diseases - genetics Interleukin 1 Interleukin 18 Interleukin-18 - genetics Interleukin-1beta - genetics Intestine Janus kinase 2 Male Middle Aged NF-kappa B - genetics NF-κB protein Patients Polymorphism, Single Nucleotide - genetics Retrospective Studies Signal transduction Single-nucleotide polymorphism TLR2 protein TLR4 protein Toll-like receptors Tumor necrosis factor Tumor Necrosis Factor Inhibitors - therapeutic use Tumor Necrosis Factor-alpha - genetics Tumor necrosis factor-TNF Ulcerative colitis Young Adult |
| 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 |
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