Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease

Table 1 Genetic factors that influence the response to biological therapy for patients with inflammatory bowel disease

Genetic markers	Patients	Clinical consequences	Ref.
Polymorphisms in TLR2, rs11938228, TLR4, TLR9, TNFRSF1A, IFNG, IL-6, and IL-1B (rs4848306, NOD-like receptor thermal protein domain associated protein 3, Janus kinase 2)	IBD	Clinical response in to anti-TNF	Bek et al[53], 2016; Salvador-Martín et al[87], 2019; Steenholdt et al[101], 2012; Medrano et al[102], 2013; Bank et al[88], 2014
Polymorphisms in TNF-α promoter (-308 A/G and -857 C/T)	IBD and spondylarthritis	Clinical response to anti-TNF	Tong et al[86], 2013; Song et al[103], 2015
Polymorphisms implicated in NF-kB pathway: TLR2, TLR4, TLR9, LY96 (MD-2), CD14, mitogen-activated protein kinase 14 (NIK), TNF-α, TNFRSF1A, TNFAIP3 (A20), IL-1B, IL-1RN, IL-6, IL-17A, IFNG	IBD	Clinical response to anti-TNF (adalimumab)	Bank et al[88], 2014; Song et al[103], 2015; Bek et al[53], 2016
Polymorphisms in IL-23R	UC	Early response to infliximab	Jürgens et al[56], 2010
HLA-DQA1*05	CD	Development of ADA against infliximab and adalimumab	Sazonovs et al[89], 2020; Salvador-Martín et al[87], 2023
HLA-DRB1	IBD	Development of ADA against infliximab	Billiet et al[90], 2015
Polymorphisms in FcγRIIIa	CD	Development of ADA against infliximab	Louis et al[91], 2004
Polymorphisms in NOD2	CD	Clinical response to anti-TNF	Niess et al[98], 2012
Polymorphisms in NOD2	CD	Loss of response to anti-TNF	Juanola et al[99], 2015
Polymorphisms in NOD2	CD	Lower anti-TNF trough levels	Schäffler et al[100], 2018
Polymorphisms in ATG16L1 (C11orf30; rs7927894 CC, CCNY; rs12777960 CC) (rs10210302)	IBD and CD	Clinical response to adalimumab	Koder et al[84], 2015; Zapata-Cobo et al[28], 2023
Polymorphisms in FAS, FASL, and CASP9 (apoptotic pharmacogenetic index)	CD	Clinical response to infliximab and adalimumab	Hlavaty et al[104], 2007; Koder et al[84], 2015
Multiple polymorphisms (combined clinical-genetic model)	CD and UC	Short-term and long-term to clinical response anti-TNF	Barber et al[58], 2016; Burke et al[105], 2018
Polymorphisms in TNFSF4/18, perilipin 2, rs762787, rs9572250, rs144256942, rs523781	IBD	Clinical response to anti-TNF	Wang et al[106], 2019
PHACTR3 (rs6100556)	UC and CD	Response to anti-TNF in children	Zapata-Cobo et al[28], 2023
CNTN5	CD		Thomas et al[107], 2014
FCGR3A	CD and UC	Antibody-dependent immune responses	Curci et al[41], 2021
PTGER4 (rs10512734)	CD	Response to adalimumab	Koder et al[84], 2015
IL-27	CD	Response to adalimumab	Koder et al[84], 2015
NR12	CD	Response to adalimumab	Koder et al[84], 2015
FASL (rs763110 )	CD	Clinical response in patients with CD treated with infliximab	Zapata-Cobo et al[28], 2023; Steenholdt et al[101], 2012
IRF1-AS1	UC	Response to anti-TNF in children	Zapata-Cobo et al[28], 2023
Polymorphisms in IL-1B	IBD	Response to anti-TNF-α	Bank et al[88], 2014
Polymorphisms in IL-18	IBD	Response to anti-TNF-α	Bek et al[53], 2016
TLR2 (rs1816702 CC and rs3804099 TT)		Clinical response to infliximab	Salvador-Martín et al[87], 2019
Polymorphisms in CXCL12	IBD	Response to anti-TNF-α in children	Zapata-Cobo et al[28], 2023
Polymorphisms in IL-10	IBD	Response to anti-TNF-α in children	Salvador-Martín et al[108], 2020; Salvador-Martín et al[109], 2023
Polymorphisms in IL-17	IBD	Response to anti-TNF-α in children	Salvador-Martín et al[108], 2020; Salvador-Martín et al[109], 2023; Bank et al[88], 2014
Polymorphisms in IL-6	IBD	Response to anti-TNF-α in children	Salvador-Martín et al[108], 2020
Gene protein tyrosine phosphatase non-receptor type 2 (rs7234029 AG + GG, CASP9)	IBD	Non-response to anti-TNF and ustekinumab	Hoffmann et al[110], 2021

ADA: Anti-drug antibodies; ATG16L1: Autophagy-related 16-like 1; CASP9: Caspase-9; CCNY: Cyclin Y; CD: Crohn’s disease; CD14: Cluster of differentiation 14; CNTN5; Contactin 5; CXCL12: C-X-C motif chemokine ligand 12; FASL: Fas ligand; FCGR3A: Fc gamma receptor 3A: FcγRIIIa: Immunoglobulin G Fc receptor IIIa; HLA: Human leukocyte antigen; IBD: Inflammatory bowel disease; IFNG: Interferon gamma; IL: Interleukin; IL-1RN: Interleukin 1 receptor antagonist; IRF1-AS1; Interferon regulatory factor 1 antisense RNA 1; LY96: Lymphocyte antigen 96; NF-kB: Nuclear factor kappa B; NOD: Nucleotide-binding oligomerization domain-containing protein; NR12: Hemopoietin receptor gene; PHACTR3: Phosphatase and actin regulator 3; PTGER4: Prostaglandin E receptor 4; TLR: Toll-like receptor; TNF: Tumor necrosis factor; TNFAIP3: Tumor necrosis factor alpha-induced protein 3; TNFR: Tumor necrosis factor receptor; TNFRSF1A: TNF receptor superfamily member 1A; UC: Ulcerative colitis.