The Pharmacogenomics Journal (2013) 13, 297–305 & 2013 Macmillan Publishers Limited All rights reserved 1470-269X/13 www.nature.com/tpj

REVIEW polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases

R Prieto-Pe´ rez1, T Cabaleiro1, E Daude´n2 and F Abad-Santos1

Psoriasis (Ps) is a chronic inflammatory disease with an important genetic component. It shares pathophysiological mechanisms with other autoimmune diseases such as psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn’s disease (CD). These conditions can be treated using biological drugs such as infliximab, adalimumab and , which selectively block the proinflammatory (TNF)-a. Although these agents have greatly improved the prognosis of Ps, PsA, RA and CD, they do not cure the disease and are expensive; in addition, significant proportions of patients do not respond or develop serious adverse effects. Therefore, it is important to investigate biomarkers, such as gene polymorphisms, that can predict which patients will respond best to a specific drug. Some polymorphisms in TNF, TNF receptor superfamily 1B (TNFR1B) and TNFa-induced 3 gene (TNFAIP3) have been associated with response to anti-TNF therapy in patients with Ps. The present article reviews other polymorphisms that could also play a role in prediction of response to these treatments.

The Pharmacogenomics Journal (2013) 13, 297–305; doi:10.1038/tpj.2012.53; published online 22 January 2013 Keywords: gene polymorphisms; psoriasis; etanercept; adalimumab; infliximab

INTRODUCTION Medicines Agency, an 8-to-12-weeks study is generally sufficient 11,12 Psoriasis (Ps) is a chronic inflammatory disease with a multi- to show short-term efficacy. factorial origin that has a considerable impact on health-care. The anti-TNF agents are effective in the treatment of Ps (XPASI- have an important role in the pathogenesis of the 75 in 50–80% of patients at 12 weeks). However, these drugs are disease by mediating intercellular communication between not effective in all patients and do not cure the disease. Moreover, 13,14 immune cells that infiltrate the skin and .1 The they are expensive and can also produce long-term toxicity. prevalence of Ps varies with geographic location and has been Consequently, it is necessary to further investigate the reported to range from 1%–3%.2,3 pathogenesis of Ps to find new therapeutic targets that enable Family and twin studies show that genetic predisposition the development of more effective drugs. It is also important to has a major role in the development of Ps.4 In addition, several search for new biomarkers, in particular, genetic polymorphisms studies have reported that environmental factors can trigger that can predict which patients will respond to a specific drug. the disease.5 Identification of pharmacogenetic markers that allow us to treat Genome-wide association studies (GWAS) have uncovered only those patients who will respond without the risk of adverse several Ps-related chromosomal regions, such as the receptors events would significantly optimize the efficiency of therapy and for (IL)-23 and IL-12B.6,7 The major histocompatibility reduce costs. complex human leukocyte antigen-Cw6 region, however, has This review is based on current knowledge of the genetic basis been consistently associated with Ps (present in 67% of patients of the pathogenesis of Ps and of the relationship between Ps and versus 15% of the general population).8 other autoimmune diseases (PsA, RA and CD). We examined the Ps is a complex disease that can occur simultaneously with association between these diseases and response to biological other inflammatory disorders such as psoriatic arthritis (PsA) in treatments. We propose to identify genetic biomarkers that could 10–30% of cases.2 In addition, Ps shares pathophysiological possibly be associated with response to the treatment of Ps with mechanisms with PsA, rheumatoid arthritis (RA) and Crohn’s anti-TNF. disease (CD). These disorders involve a strong genetic component and can be treated with the drugs used to treat Ps.9,10 Several agents are available for the treatment of Ps, including biologics that selectively block tumor necrosis factor (TNF)-a (infliximab, IMMUNOPATHOGENESIS AND GENETICS OF PS AND RELATED adalimumab and etanercept). AUTOIMMUNE DISEASES The regular tool for assessing efficacy of treatment of Ps in Failure of the immune system to recognize autologous tissues or clinical trials is Ps area and severity index (PASI) score. The components of the immune system as self leads to inflammation, European Medicines Agency has recognized PASI-75 response injury and death of healthy cells, as well as onset of autoimmune (75% improvement from baseline PASI) as an indicator for severe diseases such as Ps, PsA, RA and CD. The exact cause of loss of Ps response to treatment in clinical trials. According to European recognition of self is not well known.

1Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teo´ filo Hernando, Universidad Auto´noma de Madrid, Instituto de Investigacio´ n Sanitaria Princesa (IP), Madrid, Spain and 2Service of Dermatology, Hospital Universitario de la Princesa, Instituto de Investigacio´n Sanitaria Princesa (IP), Madrid, Spain. Correspondence: R Prieto- Pe´rez Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teo´filo Hernando, Instituto de Investigacio´n Sanitaria Princesa (IP), C/Diego de Leo´n, 62, Madrid 28006, Spain. E-mail: [email protected] Received 6 August 2012; revised 24 October 2012; accepted 16 November 2012; published online 22 January 2013 Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 298 Several studies have associated Ps, PsA, RA and CD with an activation into Th1 that produce IFN-g. Other cytokines produced immune response involving the helper T cells Th1 and Th17 that is by APCs include IL-19, IL-20 and IL-24, which cause alteration of triggered by bacterial infection or an environmental stimulus.15 keratinocytes in psoriatic skin.1 Antigens cross the epithelium through cells and are phagocytized IL-18 maintains the response of Th1, whose production is by antigen-presenting cells (APCs) such as macrophages and increased in CD.23 Th1 cells develop mainly as a result of cytokine dendritic cells. Naive CD4 þ T cells become activated by cytokines IL-12 production by macrophages and increased production such as TNF-a, IL-1, IL-6 and and inflammatory of IFN-g by T cells.16 Recent studies have associated polymor- molecules released by APCs after an environmental stimulus or phisms in IL-12B (rs6887695 and rs3212227) with Ps in Caucasian infection (Figure 1). patients.7 These findings have been confirmed elsewhere,6,24–26 The influx of activated leukocytes and monocytes leads to the and single-nucleotide polymorphisms (SNPs) have been detected production of inflammatory mediators that amplify inflammation in Caucasian patients with CD,27,28 PsA29,30 and RA.31 However, and cause tissue injury.16 IL-1, IL-6 and TNF-a are the major APCs Varade et al.32 found no association between these SNPs and RA, derived from the cytokines present in the rheumatoid joint. All of although their data suggest that IL-23R contributes to the etiology these agents cause aberrant activation of osteoclasts and joint of RA (Table 1). erosion in patients with RA.15,17,18 Activated Th1 also increase production of TNF-a, which acts on Increased levels of proinflammatory cytokines (TNF-a, IL-6 and intestinal fibroblasts and leads to the release of IL-13 and IL-1b), favoring the recruitment of leukocytes intensify the transforming -b (TGF-b), which causes fibrosis and inflammatory response.19 These cytokines have a major role in stricture formation in CD.33 the perpetuation of intestinal inflammation in CD, resulting in an The role of IL-13 and IL-4 is unclear, although genetic variations imbalance between proinflammatory and anti-inflammatory may result in deregulation of the Th1 and Th17 pathways.34 SNPs in cytokines.20 They also have an important role in the mechanism the IL-13 gene (rs2054, rs848 and rs1800925) have been associated of arthritic bone destruction, because they induce the receptor with Ps31,35,36 and PsA.37 Eder et al.38 associated these polymorphisms activator of NF-kB (RANK) in synovial fibroblasts, which require with increased susceptibility to PsA in patients with Ps. RANK ligand (RANKL) to trigger the differentiation of osteoclast The SNPs rs20541 and rs1800925 were found to be closely precursor cells into activated osteoclasts. This process results in associated with susceptibility to PsA. However, Bowes et al.39 bone resorption and the eventual manifestation of PsA.21 T cells found that neither was significantly associated with susceptibility also express RANKL. In contrast, levels of -g (IFN-g), a to Ps vulgaris. Li et al.40 suggested that the most significant 5q31 potent RANKL inhibitor produced by T cells, are very low. This variants (including rs1800925 in the IL-13 gene) associated with Ps imbalance may be responsible for the aberrant activation of were not significant in CD. Therefore, association with CD and Ps osteoclast formation in arthritis.22 in this region seems to result from the presence of different Activated APCs release other proinflammatory cytokines such as variants. As for RA, the results of Marinou et al.41 indicated that IL-12, IL-18, IL-15, IL-6 and IL-8, and, together with TNF-a and IL-1, common variants of the IL-4/IL-13 pathway did not significantly they acquire the ability to drive T-cell differentiation and contribute to susceptibility to this disease.

Environmental factors, Bacteria

Epithelium -Defensin-2 Joint inflammation, enthesitis, cytokine-induced + Antigen osteoclastogenesis, bone resorption by CD68 IL-4, IL-13 osteoclast in PsA. IL-23R IL-1B IL-17 IL-22 Hyperproliferation of skin, poor IL-23, IL-6 differentiation of keratinocytes and Macrophage IL-21 IL-6 robust mononuclear inflammation in Ps. IL-12,IL-18 IL-26 keratinocytes   INF- IL-1, IL-15 LT h17 TNF- TNF-β Dendritic cell TNF- IL-22 IL-6 IL-6 IL-1, IL-6 IL-8 TNF- IL-10 TGB-β LT h1 IL-1, IL-6, IL-17 LT reg LT h1  Synovial fibroblast TNF-

IL-19, IL-20, IL-24 INF- TNF- Matrix-degrading proteases Prostanoids IL-6 IL-8 IL-1, IL-6 GM-CSF TNF- RANK Bone resorption in PsA. Aberrant activation Intestinal fibroblasts Matrix degradation, Osteoclast of osteoclastin RA IL-13 epithelial damage, TGF- endothelial activation, Joint erosion Fibrosis, stricture formation in CD vascular disruption in CD Figure 1. Schematic representation of the association between Ps and related autoimmune diseases. Cytokines have an important role in the pathogenesis of Psoriasis (Ps), psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn’s disease (CD). The figure illustrates the interaction between APCs, T cells and other cells such as fibroblasts. These interactions are facilitated by the actions of cytokines produced by the cells themselves or other cells nearby. Cytokines that stimulate (-) and inhibit (B) other cells are indicated. Tumor necrosis factor (TNF)-a and subunit p40 of interleukin (IL)-23 or IL-12 are the targets of the biological agents used in the treatment of these autoimmune diseases. IFN, interferon; Th1, type 1 helper T cell; Treg, regulatory T cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; TGF, transforming growth factor; RANK, receptor activator of nuclear factor kB.

The Pharmacogenomics Journal (2013), 297 – 305 & 2013 Macmillan Publishers Limited Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 299 Table 1. Association between SNPs in genes encoding cytokines and autoimmune diseases

Gene Role gene SNP MAF Allele Ps PsA RA CD References

IL-23R Receptor of IL-23.mhyperproliferation of rs7530511 0.125 T   7*,24#,27#,29#,31#,42#,44#,120# psoriatic skin.mmononuclear inflammation. Expansion and maintenance of Th17 cells

rs2201841 0.275 C 36*,47*,49#,50# rs11209026 0.067 A    7*,24#,27#,29#,30*,31*, 42–46#,47*,48* TNF-a Mediate numerous inflammatory and rs1800629 0.217 A    21#,58#,67#,77–81#,83–85#, immunoregulatory activities 87–89#,92#,94–97#,119#,121# rs361525 0.131 A   77–80#,83–87#,91–93#,95# rs1799724 0.158 A    82#,95#,98#,99# IL-12B Activated Th1.mproduction INF-g and TNF-a. rs6887695 0.217 T    7*,24#,26–29#,30*,31* Expansion and maintenance of Th17 cells rs3212227 0.225 C    6#,7*,24#,25#, 27–29#,30*,31*,120#,122# IL-13 Role unclear. Involved in B-cell differentiation. rs20541 0.233 T  35*,36*,35–39# Regulation Th1 and Th17 pathways rs848 0.242 T  35*,37–39# rs1800925 0.196 T  31#,35*,38–40# IL-21 m hyperproliferation of psoriatic rs6822844 0.146 T    73*,74#,75#,76# skin.mmononuclear inflammation IL-1B Recruitment of leukocytes.minflammatory rs16944 0.358 A   51#,52#,54#,56# response IL-1A rs1143634 0.208 A   51–53#,60# IL-10 Inhibit Th1 differentiation. Promoting Treg rs1800896 0.467 A 62#,65–71#,118* differentiation rs1800871 0.173 T 62#,65#,66# rs1800872 0.202 A 62#,65#,66#,71#

Abbreviations: CD, Crohn’s disease; IFN, interferon; IL, interleukin; MAF, minor allele frequency (data from web page Hapmap123); Ps, psoriasis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SNP, single-nucleotide polymorphisms; Th1, type-1 helper T cell; TNF, tumor necrosis factor; Treg, regulatory T cells. mindicates ‘increase’; K indicates an association between the disease and an SNP. *indicates that the data come from GWAS and #indicates that the data come from candidate genes studies.

APCs also secrete IL-23. Overexpression of IL-23, which induces a significant association between rs16944 and increased risk of epidermal proliferation, has been detected in lesional psoriatic PsA. However, other authors found no evidence for an association skin. Some GWAS have identified IL-23R and other genes involved between these polymorphisms and PsA.9,55 One meta-analysis in the differentiation of Th17 cells (for example, Ps, PsA, RA and CD showed a significant association between the rs16944 allele G susceptibility genes). The SNP rs11209026 has been associated variant and RA in a Caucasian population.56 The results of Celik with Ps7,24,27,42 and PsA.29,30,43,44 However, Huffmeier et al.45 et al.57 suggested that this polymorphism was not an important indicated that this polymorphism is relevant for susceptibility to Ps risk factor in susceptibility to inflammatory bowel diseases, such as in general, even though it is not a specific risk factor for arthritis. In CD. However, Ferreira et al.58 found no association between this contrast, other authors found associations between rs11209026 SNP and an increased risk of CD. The polymorphism rs1143634 in and RA.31 Moreover, this uncommon coding variant (Arg4Gln) the IL-1b gene has been associated with RA and with severity of confers strong protection in CD.46–48 The polymorphisms and susceptibility to inflammatory bowel disease,59,60 and rs7530511 and rs2201841 in IL-23R have also been associated rs1143634 has been described as a potentially important marker with autoimmune diseases. rs7530511 was associated with Ps, PsA of the severity of joint destruction in patients with RA.61 and RA, although no references were found for CD. rs2201841 has Treg can produce IL-10 and TGF-b, which inhibit Th1 been associated with susceptibility to Ps36 and CD.47 Several differentiation while promoting Treg differentiation.19 Several studies suggest that IL-23 is an essential promoter of chronic joint studies have suggested that polymorphisms in the IL-10 promoter inflammation in RA; however, Park et al.49 found no statistically (position–1082 (rs1800896), position–819 (rs1800871) and significant differences in this SNP of the IL-23R gene. Other position–592 (rs1800872)), but not in IL-1b, have a role in the authors, however, reported that rs2201841 was a risk factor for RA etiology of CD. Other authors have not found any association as well as CD50 (Table 1). between these polymorphisms and CD, Ps or PsA.62–65 In Ps, high concentrations of TGF-b inhibit expression of IL-23R Nevertheless, the results of Kingo et al.66 show that the IL-10 and favor the development of T regulatory (Treg) cells.34 IL-23, IL-6 ACC haplotype (–1082, –819 and –592) has a role in determining and IL-1b inhibit the development of Treg cells but are necessary the severity and course of plaque Ps. Settin et al.67 showed a for differentiation of Th17.19 significantly higher frequency of the IL-10 –1082 GG genotype in The IL-1b promoter region polymorphisms rs16944 and patients with Ps than in healthy controls. Other studies have rs1143634 have been associated with increased susceptibility to suggested that patients with late-onset Ps (over 40 years) were Ps51 and RA.52 In addition, Ravindran et al.53 noted an increased more likely to be heterozygous at position –1082 (P ¼ 0.02).68 In frequency of IL-1b rs1143634 among Caucasian PsA patients. The addition, this SNP has been described as a relevant risk factor for results of univariate tests to establish associations between developing CD in a Spanish population69 and has been implicated genotypes and diseases performed by Rhaman et al.54 revealed in susceptibility to RA (GG þ GA genotypes had a 25% decreased

& 2013 Macmillan Publishers Limited The Pharmacogenomics Journal (2013), 297 – 305 Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 300 risk).70 The meta-analysis by Lee et al.71 suggested that the –592 homozygous for the TNF-a –308G allele respond to etanercept CA polymorphism confers susceptibility to RA in Asians and that better than patients who are heterozygous for this allele. Seitz the IL-10 –1082 GA polymorphism is associated with susceptibility et al.97 confirmed that patients with the –308 GG genotype respond to RA. better to anti-TNF treatment than those with the AA or AG Activated Th17 cells, mainly those activated by IL-23, secrete genotypes in RA and even in PsA. proinflammatory cytokines (IL-17, IL-22, IL-21, IL-6, IL-26 and The differences in the therapeutic effects of infliximab among TNF-a) that cause hyperproliferation and poor differentiation of patients with CD may be explained in part by the presence of the keratinocytes and robust mononuclear inflammation in Ps. In TNF-a –857 C4T polymorphism.98 As stated above, evidence of a patients with PsA, secretion of these cytokines by Th17 cells led to strong association between the TNF-a promoter polymorphisms at joint inflammation, enthesitis, cytokine-induced osteoclastogen- positions –238 and –308 and Ps and PsA has been found.77,79 esis and bone resorption by CD68 þ osteoclasts.34,72 Several Moreover, other meta-analyses suggested that both studies have found an association between specific SNPs in the polymorphisms could be used as biomarkers to predict the risk IL-21 gene (rs6822844) and susceptibility to Ps, PsA,73 RA74 and of Ps and PsA.78,80 CD.75,76 Other authors have found an association between the TNF-a is generated and expressed by several types of immune polymorphism TNF-a –857 (C allele) and rs1061622 in TNFRSF1B cells, namely, dendritic cells, macrophages, Th1 cells and Th17 (T allele) and good response to etanercept in patients with Ps cells. It mediates numerous inflammatory and immunoregulatory (P ¼ 0.002 and P ¼ 0.001, respectively); however, they did not find activities. The important role of this proinflammatory cytokine in the same association for infliximab or adalimumab.99 Therefore, the pathogenesis of Ps, PsA, RA and CD is also supported by TNF-a polymorphisms may be a useful tool for predicting response GWAS, which have demonstrated that the SNPs in the TNF-a gene to anti-TNF treatment in patients with Ps. (rs1800629, rs361525 and rs1799724), also known as TNF-a –308, SNPs of TNF receptor superfamily 1A (TNFR1A) (rs767455) and TNF-a –238 and TNF-a –857, respectively, have been linked to a TNFR1B (rs1061624 and rs3397) were evaluated in Japanese wide variety of conditions. patients with CD.100 The minor allele of rs767455 was associated The SNPs rs1800629 and rs361525 are strongly associated with with a lack of efficacy of infliximab than the major genotype. This Ps and PsA,67,77–80 and the results of several studies suggest that finding was confirmed by Pierik et al.101 In addition, the AT rs1800629 is associated with an increased risk of early-onset Ps, haplotype (rs1061622 A allele and rs3397 T allele) also showed presence of joint erosions in PsA (Po0.0001) and progression of significant differences in their distribution between responders joint erosions in early PsA.51,81,82 Other authors confirmed the and nonresponders (P ¼ 0.01).100 In contrast, a previous study association between TNF-a –238 and early-onset Ps.83,84 In conducted in Caucasian population concluded that TNFR1A and addition, Arias et al.85 suggested that heterozygosity at the TNFR1B polymorphisms could be thoroughly excluded as TNF-a –238 locus is associated with increased susceptibility to pharmacogenomic markers for a treatment response to type I Ps. According to these results, polymorphisms in TNF-a may infliximab in CD.102 These controversial results may be explained be useful prognostic markers in Ps and PsA, although this by the possible genetic differences between races. hypothesis requires further evaluation.86 In contrast, Kim et al.87 The SNP rs1061622 (mutant 196Arg allele) on the TNFR1B gene found no significant differences in the polymorphisms TNF-a –238 has been associated with a poorer response to anti-TNF therapy, and TNF-a –308 between Ps patients and controls in the Korean independently of the specific agent used. This polymorphism population. could prove to be a useful genetic marker for predicting the Other authors have reported an association between rs1800629 degree of response to anti-TNF therapy.103 In this sense, the and an increased risk of RA or CD.58,88 Moreover, Nemec et al.89 response to infliximab in CD and RA was associated with suggested an association between–308 GA and the severity rs1061622, but not with other polymorphisms (TNF-a promoter of RA. –238, –308, –857 and rs767455).104 However, larger studies are In summary, Ps shares pathological mechanisms with PsA, RA needed to confirm the relevance of these associations. and CD. Attention has focused on inhibition of TNF-a, which can The TNFAIP3 gene has been associated with Ps,36 PsA and RA, as be a successful mean of treating these diseases when an well as with other autoimmune disorders.105,106 The G allele of abnormality of the LTh1 pathway has an important role in its rs610604 located in the TNFAIP3 gene was associated with a good pathogenesis.18 Table 1 shows several polymorphisms in TNF-a response to therapy all anti-TNF agents (P ¼ 0.05) and etanercept and IL-23, IL-12B, IL-13, IL-21, IL-1A, IL-1B and IL-10 that have been (P ¼ 0.016).107 Its haplotype with the T allele of rs2230926 are associated with these diseases in GWAS or candidate gene studies. markers of a positive response to anti-TNF agents107 in Ps. Nevertheless, in a study performed in RA patients no association was found between other polymorphisms in this gene and good GENETIC POLYMORPHISMS ASSOCIATED WITH RESPONSE TO response to anti-TNF treatment.108 ANTI-TNF TREATMENT Polymorphism in the LTA gene (rs909253) has been associated To date, no highly specific and/or sensitive genetic predictors of with poorer response to anti-TNF treatment in CD (homozygotes the outcome of anti-TNF therapy have been identified.90 for LTA NcoI-TNFc-aa13L-aa26 haplotype 1-1-1-1).109 This SNP has Pharmacogenetic studies focusing on the genes involved in the also been significantly associated with the presence of joint etiology of Ps, PsA, RA and CD and on the pharmacokinetics of erosions in PsA.81 The LTA gene has been associated with anti-TNF agents have identified markers that could be associated response to etanercept in RA,92 but no association was found with the outcome of anti-TNF treatment (Table 2). with response to infliximab in CD.110 Polymorphisms in the TNF-a gene promoter are significantly Polymorphisms in the fraction constant gamma receptor gene associated with severity and response to treatment of RA.89,91,92 Lee (FCGR) affect the affinity of the receptor for immunoglobulin, et al.93 found an association between response to infliximab and which may in turn affect the efficacy of immunoglobulin-based the TNF-a –238 A4Gpolymorphism(P ¼ 0.039) in RA, but not with therapies. The response to infliximab in patients with RA is the TNF-a –308 A4G polymorphism. In contrast, Mugnier et al.94 affected by the FCGR2A (rs1801274, 131 H4R) and FCGR3A suggested that patients with the –308 GG genotype respond (rs396991, 158 V4F) genotypes in RA.111 Lee et al.112 found no better to infliximab than patients with the AA or AG genotypes. relation between the polymorphism in FCGR2A and susceptibility Other authors have associated –238G, –308G and –857C to RA in Europeans or Asians. However, the polymorphism in alleles in the TNF-a gene with a lower response to adalimumab FCGR3A was associated with RA in Europeans but not in Asians. in RA.95 Moreover, Guis et al.96 concluded that RA patients who are This polymorphism in the FCGR3A gene (FF genotype) may be

The Pharmacogenomics Journal (2013), 297 – 305 & 2013 Macmillan Publishers Limited Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 301 Table 2. Association between SNPs and response to anti-TNF therapy

Gene SNP Minor allele and MAF Related response to anti-TNF therapy Drug Ps PsA RA CD References

TNF-a rs1800629 A 0.217 Gk95m94,96,97,100 A, E, I. — K 21#,88#,94–97# TNF-a rs361525 A 0.131 G k A, E, I. K 91–93#,95#,124# TNF-a rs1799724 A 0.158 C k A, E, I. K 95# I K 98# C k E K 99# LMO4 rs983332 A 0.192 A k A, E, I. K 118* GBP6 rs928655 G 0.288 A k A, E, I. K 118* LASS6 rs133933173 A 0.292 A k A, E, I. K 118* PON1 rs854555 A 0.358 A k A, E, I. K 118* PON1 rs854548 A 0.250 A k A, E, I. K 118* PON1 rs854547 G 0.375 A k A, E, I. K 118* TNFR1A rs767455 T 0.485 T k I K 100#,101# TNFR1B rs1061622 G 0.239 G k A, E, I. K 100#,102#,103#,125# T k E K 99# R aminoacid k I K 104# TNFR1B rs3397 C 0.484 ** I K 100# TNFR1B rs1061624 G 0.482 ** I K 100# LTA rs909253 G 0.354 *** I K 109# FCGR3A rs396991 F aminoacid m A, E, I. K 113#,114# FCGR2A rs1801274 A 0.491 R aminoacid m I K 111#,114# TTP rs4962153 A 0.156 G m I K 115# MAP3K1 rs96844 G 0.257 G m A, E, I. K 116# MAP3K14 rs4792847 A 0.367 A k A, E, I. K 116# TLR2 rs2289318 C 0.223 C k A, E, I. K 117# TLR10/1/6 rs11096957 G 0.354 G m A, E, I. K 117# MyD88 rs7744 G 0.146 G m A, E, I. K 117# CHUK rs11591741 C 0.423 C k A, E, I. K 117# IKBKB rs11986055 C 0.031 C m A, E, I. K 117# IRAK-3 rs11541076 T 0.199 T m A, E, I. K 117# NFKBIB rs3136645 C 0.199 C k A, E, I. K 117# NFKBIB rs9403 G 0.381 G k A, E, I. K 117# PTGS2 rs2206593 A 0.045 A k A, E, I. K 117# EPS15 rs437943 C 0.308 G k A, E, I. K 118* QKI rs10945919 G 0.336 G k A, E, I. K 118* IFNK rs7046653 A 0.288 A k A, E, I. K 118* MOBKL2B rs868856 A 0.288 T k A, E, I. K 118* MOBKL2B rs2814707 T 0.239 A k A, E, I. K 118* C9orf72 rs774359 C 0.265 C k A, E, I. K 118* C9orf72 rs3849942 T 0.235 A k A, E, I. K 118* MAFB rs6028945 T 0.170 T k A, E, I. K 118* MAFB rs6071980 C 0.164 C k A, E, I. K 118* CST5 rs6138150 C 0.168 T k A, E, I. K 118* TGFB1 rs1800471 C 0.080 Ck(haplotype with allele 2 IL1-R) E K 119# PTPRC rs10919563 A 0.097 G m A, E, I. K 108# TNFAIP3 rs610604 C 0.408 G m E K 107# Abbreviations: A, adalimumab; CD, Crohn’s disease; E, etanercept; I, infliximab; IL, interleukin; MAF, minor allele frequency (data from web page Hapmap123 and Alfred126 in Caucasian population); Ps, psoriasis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SNP, single-nucleotide polymorphism; TNF, tumor necrosis factor. kindicates allele associated with non-response andmindicates a greater chance of achieving a moderate/good response with anti-TNF therapy. K indicates an association between the disease and an SNP. *indicates that the data come from GWAS and #indicates that the data come from candidate genes studies. **rs1061624 (A allele) and rs3397 (T allele) did not independently associate with infliximab efficacy, but the AT haplotype had a significant differencein distribution in responders and nonresponders.100 ***LTA NcoI-TNFc-aa13L-aa26 haplotype 1-1-1-1k.109

associated with positive response after 12 weeks treatment with duration than patients with the AA/AG genotypes and, therefore, a anti-TNF agents in RA. However, patients with RR genotype in higher probability of response to infliximab.115 FCGR2A gene showed a good and moderate response at 30 week Two SNPs in MAP3K gene were involved in the response to anti- of treatment.113 The authors concluded that the influence of these TNF therapy in a sample of 428 patients with RA.116 Carrying the genes are complex and dynamic and requires an exhaustive minor allele of rs96844 was associated with good treatment evaluation of patients at different time points. Other authors have response, whereas carrying the minor allele of rs4792847 was reported that the mechanism of the reduced clearance of associated with a reduced treatment response. However, in a infliximab in patients with RA could be explained in part by replication study of association with a complete cohort (n ¼ 1070) polymorphisms in FCGR.114 neither of these associations were found.116 Other study has concluded that the SNP rs4962153 in the A study evaluates the association between response to promoter region of the TTP (tristetraprolin) gene mildly affects etanercept and nine SNPs in patients with RA (Table 2).117 The promoter activity and, thus, disease duration in patients with RA. results of this study indicated that patients carrying the minor Specifically, patients with the GG genotype had a shorter disease allele in rs11986055 (IKBKB), rs11541076 (IRAK-3) and rs7744

& 2013 Macmillan Publishers Limited The Pharmacogenomics Journal (2013), 297 – 305 Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 302 (MyD88) had a greater chance of achieving a moderate/good CONFLICT OF INTEREST response with anti-TNF therapy compared with major The authors declare no conflict of interest. homozygotes. In contrast, lower probability of good response was associated with the minor allele of rs11591741 in CHUK gene.117 ACKNOWLEDGEMENTS In a prospective GWAS performed on 89 RA patients who This study was partially funded by Instituto de Salud Carlos III (FIS PI10/01740) and started treatment with anti-TNF agents, significant associations Fundacio´nTeo´filo Hernando. We are grateful to Mr. Thomas O’Boyle for editorial with treatment response were observed with multiple SNPs assistance. 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