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Pharmacogenomics

Pharmacogenetics of inflammatory bowel disease

Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data.

Konstantinos H Katsanos1 & Konstantinos A Papadakis*,2 Division of Gastroenterology, Medical School, University of Ioannina, Greece 2 Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 293 2466 Fax: +1 507 284 0538 [email protected] mayo.edu  1

Keywords:  5-ASA • 6-MP • adalimumab • anti-TNF-α • azathioprine • genes polymorphisms • inflammatory bowel disease • infliximab • methotrexate • pharmacogenetics • TPMT

The ultimate goal of pharmacogenetic research is to find stable genetic predictors of drug response that enable the development of valuable genetic tests to reliably identify patients at risk of nonresponse or of develop­ ing an adverse reaction or toxicity. Pharmaco­ genetics could be of potential importance in inflammatory bowel disease (IBD) thera­ peutics. Several genes have been so far dem­ onstrated to influence the efficacy and side effects of drugs and reflect a complex interplay regarding absorption, transport, efficacy and toxicity [1] . Hypotheses including clinical observations on drug response in IBD patients will possi­ bly point to IBD etiology or whether the genes that control drug response are related to genes that control disease etiology, natural history and prognosis still remain unanswered [2–4] . TPMT deficiency represents a stable pharmaco­genetic factor that has been prospec­ tively and largely assessed before azathioprine (AZA) or mercaptopurine immunomodula­ tion is commenced in IBD patients. No other inherited determinant of drug response has

10.2217/PGS.14.154 © 2014 Future Medicine Ltd

been successively transferred from the bench to the clinic for the ­management of this disease. In this review, we summarize what is cur­ rently known about genetic determinants of drug therapy in IBD. We focus on genetic polymorphisms in predicting the response and intolerance of IBD patients to thiopurine drugs, methotrexate (MTX), aminosalicylates and anti-TNF-α inhibitors. On this basis, the concept of individualized medicine is analyzed and the rationale for future developments in the pharmacogenetics of i­nflammatory bowel disease is also presented. AZA metabolism & mechanism of action The thiopurine drugs AZA and 6-mercapto­ purine (6-MP) have been widely used in the treatment of IBD. AZA or 6-(1-methyl-4-ni­ troimidazol-5-ylthio) purine (Prepn: Hitch­ ings, Elion G, US patent 3,056,785 [1962]) after its ingestion can follow three com­ petitive pathways: the first is the pathway to 6-thioguanine nucleotide (6-TGN) catalyzed by HGPRT and the other two pathways are

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Review  Katsanos & Papadakis S-methylation to 6-methylmercaptopurine (6-MMP pathway) catalyzed by TPMT or oxidation to thiouric acid via the enzyme XO. TPMT and XO act as the com­ petitive catabolic pathways. The route of AOX is also regarded as an additional metabolic route [5–7] (Figure 1). AZA is metabolized via 6-MP and 6-TGN into 6-Thio-GTP. 6-Thio-GTP binds to the small GTPase Rac1. GTPases seem to coordinate many of the steps in the chemotactic response of leukocytes. Upon hydro­ lysis, 6-Thio-GDP bound to Rac1 inhibits Vav gua­ nosine exchange activity leading to accumulation of 6-Thio-GDP-bound inactive Rac1 molecules, blockade of GTP incorporation into Rac1 and, consecutively, suppression of Rac1 functions on T cell [8] (Figure 2) . Analytical data on the exact mechanisms of AZA intra­ cellular accumulation and action after oral ingestion still remains unclear. AZA efficacy & toxicity: the TPMT gene Genetic studies over the last two decades have demon­ strated that SNPs at the TPMT gene play an important role in the occurrence of myelosuppression and bone marrow toxicity (BMT), which represents a dose-related adverse event of thiopurines. The human TPMT gene, consisting of 10 exons, is located on chromosome 6p22.3. A pseudogene for this

locus is located on chromosome 18q. The hereditary nature of the TPMT deficiency was initially identified in a study investigating TPMT activity in red blood cells (RBC). Subsequent studies have clearly showed that the distribution of TPMT activity in RBC is tri­ modal; Almost 90% of individuals have high TPMT activity, 11% have intermediate activity and 0.3% have low or no detectable enzyme activity (Figure 3) . Indi­ vidual differences in TGN accumulation after AZA ingestion have been shown to be associated with BMT. The cellular accumulation of TGN is inversely propor­ tional to TPMT activity. In a patient with high TPMT activity AZA will metabolized preferentially to the methylation pathway, leaving less drug for TGN. Con­ versely, TPMT-deficient patients accumulate very high TGN concentrations in tissues, including RBC as the low TPMT enzyme activity refrains AZA to be metab­ olized to the methylation pathway. Subsequently, the use of standard doses of thiopurine drugs in patients with complete TPMT deficiency could be hazardous or even fatal due to BMT [9–12] . TPMT genotyping

Altered TPMT enzyme activity results from SNPs. Sev­ eral TPMT alleles have been identified, including three alleles (TPMT*2, TPMT*3A and TPMT*3C) which

5,10-MTHF MTHFR 6-MMP level

5-MTHF Me

6-MeMP

Inhibition of de novo purine synthesis

6-MeTG

6-MeTIMP

Homocysteine TPMT

Glutathione Cysteine Thiols Proteins

HPRT

6-MP

AZA

TPMT

IMPD 6-TIMP

XO/XDH

Aox1

TPMT

Thio-ITP

HPRT

GMPS 6-TXMP

6-TGMP

6-TG

MPK 6-TGDP

Thio-IDP Nitromethylimidazole

6-TU

8-OHTG

DPK

6-TU 6-TGTP Incorporation into DNA

Rac1 inhibition Figure 1. Enzymes involved in azathioprine/6-mercaptopurine/6-thioguanine nucleotide metabolization steps. 6-MP: 6-mercaptopurine; 6-TG: 6-thioguanine; 6-TU: 6-thiouric acid; AZA: Azathiopurine.

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Pharmacogenetics of inflammatory bowel disease 

Review

T lymphocyte Signaling complex

Rac1 Cytoskeletal machinery Focal adhesion Cdc42

Direction sensing

New contact formation

Contraction

Tail retraction

Figure 2. Regulation of chemotaxis of T lymphocytes. Rac1 sense the chemotactic factor gradient and polarize the cytoskeletal machinery to focal adhesion.

account for 80–95% of low or intermediate enzyme activity in Caucasian population. The TPMT*2 allele is defined by a single nucleotide transversion (G238C), which leads to an amino acid substitution at codon 80 (Ala80Pro). The allele TPMT*2 (G238C) results in a 100-fold reduction in TPMT catalytic activity. The second and more prevalent mutant allele, TPMT*3A, contains two nucleotide transition mutations (G460 and A719G), leading to amino acid substitutions at codon 154 (Ala154Thr) and codon 240 (Tyr240Cys). The allele TPMT*3B has only the G460A mutation and leads to a nine-fold reduction in catalytic activ­ ity. TPMT*3C has the only A719G mutation, which is associated with a 1.4-fold reduction in activity. The presence of both G460A and A719G, for example, TPMT*3A, leads to complete loss of TPMT activity. It should be noted here that the frequency of pattern of mutant TPMT alleles is different among various eth­ nic populations and except of the three more frequent TPMT alleles (TPMT*2, TPMT*3A and TPMT*3C) several other rare alleles have been so far reported. In addition, it seems that the prevalence of the three more frequent alleles may slightly vary among ethnicities [13] . A TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website [14] serves as a platform for this work [15] .

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TPMT enzyme activity

In most guidelines neither TPMT genotyping nor phe­ notyping is advised prior to the intitiation of therapy with thiopurine drugs. In case of normal TPMT activ­ ity (homozygous wild-type) a full dose of thiopurine drug can be administered at the start of therapy. In patients with indermediate TPMT activity result physicians should consider reducing the initial dose of a thiopurine medication to avoid complications. There are specific dosing recommendations for this phenotype/genotype result. In TPMT homozygous low (deficient patients) thiopurines should be avoided, or at most given in extremely low doses – for example, 10% of normal dose on 1–2 days per week. A dose reduction (up to 70%) of normal dose could be considered for TPMT heterozygotes. There are specific dosing recommendations for this phenotype/genotype

89.0% 0.3% 10.7%

89% high activity (WT) 10.7% intermediate (HTZ) 0.3% no activity (MT/MT) (in Caucasians)

Figure 3. TPMT activity is trimodal (high, intermediate, very low or absent). HTZ: Heterozygotes; MT: Mutated type; WT: Wild-type.

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Review  Katsanos & Papadakis result (i.e., the Mayo clinic expert – pharmacogenomics alert site – a decision support system). There is a clear advantage of TPMT testing pre­ treatment and, rather than considering delaying until result available, therapy can immediately start without TPMT (even if inadvisable), for example, starting at half dose and watching blood counts, and considering early TGN measurement if available. If the patient is currently receiving the thiopurine medication (i.e., con­ tinuation of therapy) doses can be adjusted on the basis of degree of myelosuppression and disease-specific guidelines during follow-up [16,17] . Recent research has refined our understanding of 6-MP/AZA metabolism. TGN measurement needs to be set into context with TPMT and it can potentially be used in clinical practice. The mono-, di- and triphosphated thioguanines (TGs) are of interest from a research point of view but the whole TGN is the mea­ surement in clinical practice and there is a lot of evi­ dence in the literature relevant to how this can improve outcome. It is important in terms of pharmacogenetics because it is an important interplay with TPMT. Levels of 6-TGN have been associated with a posi­ tive predictive value of clinical response in a great majority of patients. Of interest, AZA responsiveness was correlated to the relative concentrations of the different 6-TGNs (mono-, di- and tri-phosphates). 6-thioguanosine triphosphate (TGTP) and 6-thio­ guanosine diphosphate (TGDP) were the main metab­ olites within the 6-TGN molecule (Figure 4) . It was found that high TGTP levels correlated with both high 6-TGN and clinical response, whereas high TGDP was associated with worse clinical outcomes [18] . Still, TPMT enzyme testing is not the only predictor of clinical response in IBD patients treated with thio­ purines. HGPRT and other enzymes are also involved in the AZA activation pathway, which leads to the formation of the active 6-TGN metabolites. A signifi­ cant contribution of low HGPRT activity to clinical resistance to thiopurines is still investigated. Decreased activity of ITPA enzyme, has been associated to AZA intolerance but data is still conflicting [19–25] . TPMT testing: limitations & use in clinical practice

Conflicting data exist as to whether TPMT genotype or activity are useful in predicting adverse events to thio­ purines. There are many studies but not all, support­ ing the clinical importance of TPMT genotyping and TPMT enzyme activity measurement in AZA-treated patients. Although some cases of BMT are attributed to low TPMT enzyme activity, in a considerable percentage of cases leukopenia cannot be attributed to the most

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frequent TPMT variants (TPMT*2, TPMT*3A and TPMT*3C). Other factors possibly explaining AZA toxicity could be infrequent TPMT variants. For exam­ ple, TPMT*20, *21 and *22 variants have been associ­ ated with intermediate red blood cell TPMT activity. It is also important to consider individual differences in TGN accumulation as well as other predictors of TPMT activity including promoter polymorphisms, patient age viral infections, or other still unknown environmental factors. Other SNPs in other genes may be of importance in explaining many of the unex­ plained cases of BMT in IBD patients treated with thiopurines. Of importance, the discovery and charac­ terization of the TPMT polymorphisms grew directly out of pharmacogenomic studies of COMT [5] . In addition to this, there is a high degree of variability in TPMT activity within both the homozygous wildtype and heterozygous groups. In fact, some individuals with a heterozygous TPMT genotype exhibit high activ­ ity, whereas some homozygous wild-type subjects exhibit an intermediate phenotype, whereas TPMT enzyme activity may also be affected by blood transfusions. The induction of TPMT activity after commencement of AZA therapy remains controversial. After initiation of thiopurine therapy by a fixed dosing schedule, no general induction of TPMT enzyme activity occurs, however, TPMT gene expression is decreased. In addition, TPMT activity and the concentration of thioguanine nucleotides are higher in children than in adults. Genetic studies in large population samples have shown that the genotype which regulates TPMT activity accounted for two-thirds of the total variance in the level of RBC enzyme activity. Other factors including drug interactions and environ­ mental factors as well as promoter poly­morphisms, could play an important role in the TPMT phenotype. Never­ theless, TPMT polymorphism and TPMT enzyme activ­ ity represent ideal prototypes for the translation of gene information to tailor IBD therapeutics and thiopurine drug therapy in IBD patients. Some of the clinicians take a conservative approach with AZA, starting at a low dose and raising it slowly while others start at the standard dose and follow the patient carefully. All IBD patients must be monitored carefully with peripheral blood counts, regardless of prior testing for TPMT and dosage selected. Although TPMT testing is not widely available and cannot safely predict all myelotoxicity cases it seems that it has the potential to early warn for early severe leukopenia in TPMT homozygous recessive patients as well as to identify those who might benefit from higher AZA doses. We suggest that patients homozygous for one or more TPMT variants are at a very high risk of early severe leukopenia and thus, they have to avoid AZA treatment [26,27] .

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Pharmacogenetics of inflammatory bowel disease 

Blood circulation

Intracellular: 6-MP in bone marrow and other tissues

6-MMP inactive

6-MMP ribonucleotides

TPMT AZA

Review

Purine synthesis

TPMT 6-TGN nucleotides

6-MP HGPRT

DNA/RNA Cytotoxicity and immunosuppression

XO

6-TU inactive Figure 4. Azathioprine/6-mercaptopurine metabolization route in relation to TPMT enzyme. 6-MMP: 6-methylmercaptopurine; 6-MP: 6-mercaptopurine; 6-TGN: 6-thioguanine nucleotide; 6-TU: 6-thiouric acid; AZA: Azathioprine.

AZA toxicity: non-TPMT genetic determinants These limitations of TPMT testing have led investiga­ tors to study other genes and their variants involved in AZA metabolization steps which could probably alter the 6-TGN flow to target cells. These enzymes were investigated in the hope of explaining many of the unexplained cases of BMT in patients with IBD treated with AZA. Many genes have been so far inves­ tigated but their importance in clinical practice still remains controversial [28,29] . ITPA

The ITPA gene has eight exons. The protein encoded by this gene hydrolyzes inosine triphosphate and deoxy­ inosine triphosphate to the monophosphate nucleo­ tide and diphosphate. Defects in the encoded protein can result in ITPA deficiency. Two transcript variants encoding two different isoforms have been found for this gene [30] . Also, at least two other transcript vari­ ants have been identified which are probably regulatory rather than protein coding [31] . ITPase deficiency is not associated with any defined pathology other than the characteristic and abnormal accumulation of ITP in RBC. Nevertheless, ITPase deficiency may have phar­ macogenomic implications, and the abnormal metabo­ lism of 6-MP in ITPase deficient patients may lead to thiopurine drug toxicity. The 94C>A transversion in exon 2 results in a Pro32-to-Thr (P32T) substitution. The frequency of this polymorphism is higher in Japa­ nese, Chinese and east Indian origin populations com­ pared with Caucasians. Homozygous deficient indi­ viduals have complete deficient erythrocytre ITPAse

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activity accompanied by accumulation of ITP in RBC. In addition ITPase deficient heterozygotes showed a 22.5% ITPase activity of the control value, consistent of a dimeric structure of ITPase. There are studies in favor] or against the value of this SNP to predict toxicity or even BMT in AZA-treated IBD patients [32,33] . Regarding the IVS2 + 21A/C SNP the activities of IVS2+21A/C heterozygotes and 94C/A-IVS2A/C compound heterozygotes were 60 and 10%, respec­ tively, of the normal control mean suggesting that the intron mutation affects enzyme activity. However, it has been suggested that subjects with complete deficiency of ITPase activity have elevated ITP concentrations in erythrocytes but no obvious clinical abnormalities. Rac1

Rac1 is a member of the Rho family of small GTPases involved in signal transduction pathways that control proliferation, adhesion and migration of cells during embryonic development and invasiveness of tumor cells [34–36] . MTHFR

MTHFR catalyzes the conversion of 5,10-methylene­ tetrahydrofolate to 5-methyltetrahydrofolate, a cosub­ strate for homocysteine remethylation to methionine. Fourteen rare mutations of MTHFR have been asso­ ciated with severe MTHFR deficiency, hyperohomo­ cysteinemia, homocystinuria with many vascular and neurologic defects [37] . AOX & XO/XDH

AOX produces hydrogen peroxide and, under certain conditions, can catalyze the formation of superoxide.

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Review  Katsanos & Papadakis The XO/XDH enzyme system belongs to the group of molybdenum-containing hydroxylases and plays an important role in purine metabolism, iron uptake and transport as well as in the defence against microbial agents. XDH/XO catalyzes the oxidation of hypoxanthine to xanthine, and subsequently to uric acid [38] . HPRT1

HPRT maps to Xq26-q27.2 and consists of nine exons. HPRT enzyme activity is required for the phosphory­ lation of hypoxanthine and guanine, salvaging them for nucleic acid biosynthesis. It also phosphoribosyl­ ates purine analogs, which is a necessary step for their cytotoxicity [39] . Most recently HPRT is finding use in studies of in vivo selection for in vivo mutations arising in either somatic or germinal cells. Resistance to purine analogues provides a highly efficient selective system for HPRT mutant cells allowing them to grow while wild-type cells are killed [40] . The selection is pheno­ typic, cells with a nonfunctionning or poorly function­ ing enzyme will be resistant to the toxic effects of 6-TG or AZA. The rate of increase in mutant frequency is greater in children than in adults, consistent with the higher level of T-cell proliferation in children [41] . IMPD(H)1

IMPD[H]1 catalyzes the formation of xanthine mono­ phosphate from IMP. In the purine de novo synthetic pathway, IMPDH1 is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides [42] . AZA toxicity: nongenetic determinants Drugs for IBD that are concomitantly used with AZA have been also suggested to affect 6-TGN concentra­ tions and by consequence to predispose to AZA toxicity [43] . In vitro studies have suggested that 5-aminosali­ cylic acids (5-ASAs) could be potential TPMT inhibi­ tors and clinically higher thioguanine levels have been seen in patients concomitantly taking certain 5-ASAs along with AZA/6-MP [44] . However this has not observed in all studies. The administration of allopu­ rinol affects AZA metabolism by inhibiting XO/XDH enzyme and thus increasing the flow toward 6-TGN, furosemide increases BMT by TPMT inhibition while angiotensin converting enzyme inhibitors can increase BMT during AZA treatment by a still unknown mech­ anism [45] . A study showed that 6-TGN levels were sig­ nificantly higher and WBC significantly lower within 1–3 weeks after infliximab (IFX) infusion while the prolonged use of trimethoprim-sulfamethoxazole may result in life-threatening hematotoxicity [7,29] .

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MTX: pharmacogenetics of efficacy & toxicity MTX (also known as MTX-Glu1 because it is a mono­ glutamate) is converted to its active polyglutamated forms (MTXGlu2–5) by the enzyme FPGS [46] . MTX is an analog of dihydrofolic acid (DHF), enters cells primarily through the RFC1. This addition of gluta­ mate residues prevents MTX efflux from the cell via a wide range of multidrug resistance proteins. Glutama­ tion of MTX can be reversed by GGH. In fact, the bal­ ance between these two enzymes determines the time that MTX is retained within a cell and its efficacy. MTXGlu2–5 inhibits the folate pathway by displacing DHF as the preferred substrate of the folate-dependent enzymes which are DHFR, TYMS and ATIC. MTX when administered at high dose has an anti-proliferative effect and this has been due to MTXGlu2–5 [47] . Many genetic polymorphisms including also the MTHFR gene have been documented in the folate pathway and an considerable number of studies have reported an association of folate pathway polymorphisms with MTX toxicity [48–53] . Therapy with MTX results in a reduction of the reduced folate pool by inhibiting dehydrofolate reduc­ tase. The enzyme, MTHFR is crucial for folate homeo­ stasis by converting 5,10-methylene-tetrahydrofolate into 5-methyltetrahydrofolate, which is the carbon donor required for methionine synthesis. How MTX exerts its therapeutic effect is still unknown. Several mechanisms of action seem to play a role. First, MTX and its polyglu­ tamated form directly inhibit enzymes crucial for pyrim­ idine and purine synthesis. Furthermore, MTX inter­ feres with the folate cycle. Two nonsynonymous variants in this gene have been found to influence MTX toxicity and efficacy. The MTHFR SNP C677T has been asso­ ciated with increased MTX toxicity. The second SNP which is the A1298C, also leads to a reduced activity of the MTHFR and has been associated with an increased efficacy of MTX in rheumatoid arthritis patients [54] . In patients with IBD, the homo­zygous MTHFR 1298C variant was found to be associated with toxicity whereas the 677T variant was not. Discordance among studies is common, and associa­ tions observed in one cohort do not always replicate in another as MTX metabolism certainly depends on more SNPs in more genes than those included in these studies. For example, there have been reports on a tan­ dem repeat polymorphism in the 5´-untranslated pro­ moter region of the TYMS on MTX sensitivity in leu­ kemia and there is evidence from in vitro experiments that impaired VMcN1 activity may play a crucial role in MTX resistance [55–57] . Moreover, the dose as well as the scheme of MTX administration in IBD and other autoimmune diseases

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Pharmacogenetics of inflammatory bowel disease 

and heamatologic malignancies may differ, and extra­ polating pharmacogenetic associations from one disease to another may not be valid. 5-ASA formulations: pharmacogenetics of efficacy & toxicity Sulfasalazine (SASP) has been commonly used in the maintenance treatment for IBD. SASP is split into sul­ fapyridine (SP) and 5-ASA components by bacterial azo reductases in the colon and caecum, followed by acetylation of SP into AcSP by a polymorphic NAT in the liver. Mesalazine is also acetylated in the liver into N-ace­ tyl-5 aminosalicylates and excreted in the urine. For mesalazine, variability in drug acetylation was demon­ strated many years ago with patients divided in slow and rapid acetylators, because of polymorphisms in the NAT genes [58] . Arylamine NATs are polymorphic drug-metaboliz­ ing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. Two isoenzymes NAT1 and NAT2 have been identified in humans and more than 50% of Caucasians are NAT2 slow acetylators [59] . NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site modulating specificity. Polymorphisms in the NAT gene may cause unfolded protein. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite p-aminobenzoylglutamate (p-abaglu). Human NAT1 may contribute to folate and acetyl CoA homeostasis. Human NAT2 is mainly in liver and gut. NAT2 activity has been diagnosed by phenotyping that is, evaluating plasma concentrations or urinary excretions of tentatively administered test drugs for dose individ­ ualization and avoidance of serious adverse events [60] . Three point mutations in the NAT2 gene defined the wild-type allele NAT2*4 and three mutant alleles NAT2*5B, NAT2*6A and NAT2*7B. Patients can be stratified by this genotyping into three groups: the homozygote for the wild-type allele NAT2*4/*4 (rapid types), the compound heterozygote for the wild-type and mutant alleles NAT2*4/*5B, NAT2*4/*6A or NAT2*4/*7B (intermediate types) and the homozy­ gote for mutant alleles NAT2*5B/*5B, NAT2*5B/*6A, NAT2*5B/*7B, NAT2*6A/*6A, NAT2*6A/*7B or NAT2*7B/*7B (slow types) [61–63] . Genotyping for NAT has the theoretical advantage of avoiding the tentative administration of the test drugs, but there is inadequate information on its predictability for NAT2 activity.

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Review

Of interest, NAT inhibitors co-administration with 5-ASAs in IBD has prompted ongoing investigations of azoreductases in gut bacteria which release 5-ASA from prodrugs including balsalazide [64,65] . Anti-TNF-α therapies: pharmacogenetics of efficacy & toxicity Pharmacogenetic studies on IFX in IBD and other autoimmune diseases have adopted a candidate gene approach, focusing primarily on variants that have the potential to influence monocyte and T-cell apoptosis, or the expression, metabolism and signal transduc­ tion of TNF. Variants that have been associated with IFX response in IBD are listed in Table 1. Of these, the polymorphisms within the genes coding for TNF and TNFAIP3, the cell surface receptors TNFRSF1A and TNFRSF1B, the apoptosis-inducing ligand FasL and the receptor FCGR3A, have been associated with response to anti-TNF therapy [66–75] . Investigators hypothesized that genetic poly­ morphisms of FCGR3A, the gene coding for the FcγRIIIa receptor, may influence the efficacy of IFX. An initial study reported that the FCGR3A-158V/V polymorphism was associated with better biologic and perhaps clinical responses to IFX. A larger follow-up study of a subset of patients from the ACCENT I trial showed a trend towards a greater decrease in C-reactive protein after IFX in V/V homozygotes versus carriers of one or no V alleles. However, no association with clinical response was seen. Other studies have found no association between response to IFX and several genetic variants, including TNF-α and TNF receptor gene polymorphisms, NOD2/CARD15 gene mutations and a haplotype in the TNF-β (lymphotoxin-α) gene [76] . The chimeric anti-TNF-α antibody IFX is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma1 chain may also be implicated and this allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype. FcγRIIIa recep­ tors on cytotoxic cells recognize the immunoglobulin G1 portion of IFX that is bound to TNF-α-expressing cells. However, the IGHG1 polymorphism does not seem to play a major role in the induction of ATI. Fur­ ther analyses will be required to determine whether it is also the case for humanized or fully human antibodies that have the same G1m allotypes [77] . Clinical response to biologics based on genotyping The introduction of anti-TNF therapy has dramati­ cally improved the outlook for patients suffering from IBD. Despite this, a substantial proportion of patients

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Review  Katsanos & Papadakis fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; how­ ever, variation in genes or their expression may identify those most likely to respond [78] . By testing variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have been replicated consistently between studies. These negative findings in anti-TNF-α pharmaco­ genetics reflect the complexity of IBD, as well as the complexity of the drug’s therapeutic effects. In fact, concomitant immunosuppressive medication, younger age and colonic disease location have been confirmed as clinical predictors of IFX response. There is some evidence to suggest that shorter disease duration , non­ smoking and higher baseline C-reactive protein levels are also predictors of response.

Emerging genome-wide association studies sug­ gest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect [79–86] . MDR, other genes & IBD pharmacogenetics MDR is a highly polymorphic stress-response gene and of interest the majority of the detected polymorphisms are intronic or silent. In humans, two MDR gene fam­ ily members (MDR1 and MDR3) exist, whereas in rodents three genes are present named as mdr1a, mdr1b and mdr2 [87] . The MDR1 gene product is the P-gp, which has been initially described as a transport protein which was overexpressed in tumors developing resistance to chemotherapeutic agents. P-gp is expressed in many tissues including enterocytes, brain choroids plexus,

Table 1. Gene polymorphisms related to inflammatory bowel disease therapy.

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Gene

Inflammatory bowel disease therapy

TPMT (thiopurine methyl-transferase)

Purines

ITPA (inosine-triphosphate-pyrophosphatase)

Purines

Rac1 (a small guanine triphosphatase)

Purines

XO/XDH (xanthine oxidase)

Purines and allopurinol

AOX (aldehyde oxidase)

Purines

MOCOS (the product that activates the cofactor for AOX and XDH)

 

GST (glutathione-S-transferase)

Purines

HPGRT (hypoxanthine phosphoribosyltransferase)

Purines

MDR1 (multidrug resistance)

Purines and steroids

MTHFR (methylene tetrahydrofolate reductase)

Purines and methotrexate

GGH (γ-glutamyl hydrolase)

Methotrexate

RFC (reduced folate carrier)

Methotrexate

TYMS/MS (thymidylate/methionine synthase)

Methotrexate

ATIC (aminoimidazole-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase)

Methotrexate

FPGS (folylpolyglutamate synthase)

Methotrexate

BCRP/ABCG2 (breast cancer resistance protein)

Methotrexate

TNFRSF (TNF receptor superfamily 1A and 1B)

Infliximab

TNFAIP3 (TNFα-induced protein 3 gene)

Infliximab

FcGR3A (Fc-gamma receptor)

Infliximab

IL-23 (interleukin-23)

Infliximab

FASLG (Fas ligand)

Infliximab

IGHG1 (IgG1 heavy chain-coding gene)

Infliximab

NOD2 (nucleotide-binding oligomerization domain-containing protein 2)

Infliximab and antibiotics

IL-10 (interleukin-10)

Adalimumab

NAT (N-acetyltransferase, NAT1, NAT2)

Mesalazine and 5-aminosalicylic acid

Pharmacogenomics (2014) 15(16)

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Pharmacogenetics of inflammatory bowel disease 

placenta, ovaries, hepatocytes and testes. Gender dif­ ferences have also been noted in the MDR1 hepatic expression with women displaying only one third to one half of the hepatic P-gp level of men. The physiological role of P-gp involves hormone and metabolite secretion, bacterial product detoxification and transport of various drugs to the extracellular space, thus inhibiting their toxic or therapeutic effects (Figure 5). The human MDR gene is composed of 28 exons and various SNPs have been reported in the MDR1 gene. Various reports have suggested that one or the other are associated with altered transporter or gene expression activity. Preliminary studies showing that the TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of cyclosporine failure in patients with evidence of steroid-resistant ulcerative colitis [88] . The G2677T variant in the MDR1 gene was predicting of gastrointestinal and also of the socalled unspecified intolerance to MTX and AZA in IBD [89] . Furthermore, patients carrying the wild-type C3435 allele were more able in steroid tapering, com­ pared with patients with the 3435T variant, emphasiz­ ing the functional effect of this variant on the P-gp pump function. To minimize the chance of a spurious association between MDR1 genotypes and in vivo phe­ notypes, careful attention must be paid to haplotypes, gender, environmental factors and sample size. Indeed, such studies should try to ensure that demographic data of subjects selected for the various MDR1 SNPs do not differ [90] . Pharmacogenetic studies have found no association between NOD2 variants and prediction of response to IBD therapies. In addition, responses to steroids, AZA and IFX seem not to be related to NOD2 [91] . Of note, NOD2 was related to antibiotic failure in IBD patient. The HLA-DR region has been associated with failure to budesonide and DLG5-R30Q and MIF (macro­ phage migration inhibition)predicted a good response to steroids [92] . Finally, the 1082 AA IL-10 genotype was associated with steroid dependency, whereas the 113A variant of the DLG5 gene predicted resistance to steroids [93,94] . Pharmacogenetics & individualized IBD therapy Instead of anticipating that single drug will be affective in all patients with IBD, an approach to individualize therapy seems more promising. With the progress in genetics research in IBD, genetic markers are increas­ ingly being proposed to improve stratification of patients into more homogenous subgroups in reference to dis­ ease pathogenesis and response to certain therapeutics. Genetics have the major advantage of being stable over time and not prone to subjective interpretation.

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Review

MDR1 gene codes for P-gp pump that regulates drug influx into the cell P-gp is expressed in enterocytes

D

P-gp

NF-κB

MDR1 gene polymorphisms can change P-gp structure inhibiting drug influx into the cell D

P-gp

N F-κ NF-κB

Figure 5. The MDR1 gene codes for a P-gp pump that regulates drug influx into the target cells (NF-κB). In the presence of MDR1 gene polymorphisms the P-gp pump is dysregulated and its normal function is altered. D: Drug. 

Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimiza­ tion of individualized therapy [94] . Nevertheless, except of TPMT none of the pharmacogenetic variants associ­ ated with particular therapeutic molecules have shown sufficient sensitivity or specificity to have been imple­ mented in daily clinical management and tailoring of IBD therapy. Along the same line of thinking, pharmacogenet­ ics or the study of association between variability in drug response and genetic variation has also received more attention as part of the endeavor for personalized medicine. The ultimate goal in this area of medicine is to adapt medication to a patient’s specific genetic back­ ground and therefore improve on efficacy and safety rates [95] . Although it is clear that genetic research in IBD has advanced our understanding of the clinical hetero­

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Review  Katsanos & Papadakis geneity of the disease, new efforts are required and point towards the complex combination of a panel of clinical, biochemical, serological and genetic factors, in order to achieve the optimal prediction of both clinical behaviour and response to therapy. Drug effects depend on a variety of variables includ­ ing its uptake, metabolism and disposition to target organs. The genes of many of the metabolizing enzymes involved are polymorphic resulting in functional alter­ ation of the encoded protein hence influencing desired as well as unwanted drug effects. It will then be essen­

tial to investigate the functional consequences of poly­ morphisms in these genes so the molecular and cellular mechanisms can be better characterized. Although nanostrategies for IBD therapeutics inves­ tigated animal and in vitro models of IBD have shown promise and need further investigation on many issues related to the safety and uptake of the different nano­ medical therapeutics acting on various pathways and phases in the GI tract of patients suffering from IBD [96] . Prospective randomized trials including large patient populations are warranted to provide strong evidence of

Executive summary Azathioprine metabolization & mechanism of action • Azathioprine (AZA) after its ingestion can follow three metabolic routes: the first is the route to 6-thioguanine nucleotide catalyzed by TPMT and the other two routes are S-methylation to methylmercaptopurine catalyzed also by TPMT or oxidation to thiouric acid via XO.

AZA efficacy & toxicity: the TPMT gene • The hereditary nature of the TPMT deficiency in humans was initially identified in a study of TPMT activity in red blood cells (RBCs). • The distribution of TPMT activity in RBC is trimodal; 90% of persons have high activity, 10% have intermediate activity and 0.3% have low or no enzyme activity. • TPMT-deficient patients accumulate very high thioguanine nucleotide concentrations in tissues, including RBCs leading to bone marrow toxicity. • Current guidelines recommend consideration of TPMT genotype and TPMT enzyme testing prior to the intitiation of therapy with thiopurine drugs.

AZA toxicity: non-TPMT genetic determinants • Limitations of TPMT testing lead investigators to other gene variants involved in AZA metabolization steps.

Methotrexate: pharmacogenetics of efficacy & toxicity • Methotrexate, an analog of dihydrofolic acid (DHF), enters cells through the reduced folate carrier 1 and is converted to polyglutamated forms (MTXGlu2–5) by folylpolyglutamate synthase. • MTXGlu2–5 inhibit the folate pathway by displacing DHF as the preferred substrate of the folatedependent enzymes DHF reductase, thymidylate synthase 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase and methylenetetrahydrofolate reductase.

5-ASA formulations: pharmacogenetics of efficacy & toxicity • Sulfasalazine is split into sulfapyridine and 5-aminosalicylic acid components followed by acetylation by a polymorphic NAT. • NATs are polymorphic drug-metabolizing enzymes, and two isoenzymes NAT1 and NAT2 have been identified in humans.

Anti-TNF-α therapies: pharmacogenetics of efficacy & toxicity • Gene variants that have been associated with infliximab response in inflammatory bowel disease (IBD) are those coding for TNF and TNFAIP3, the cell surface receptors TNFRSF1A and TNFRSF1B, the apoptosis ligand FasL and the receptor FCGR3A.

Clinical response to biologics based on genotyping • By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported.

MDR, other genes & IBD pharmacogenetics • Various reports suggested a role of MDR1 polymorphisms in IBD pharmacogenetics.

Pharmacogenetics & individualized IBD therapy • Studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics may be helpful for individualized therapy.

Future perspective • TPMT deficiency remains the only genetic test to be used clinically. • The clinical relevance of other genetic variants found in the purine biosynthesis, folate pathways and anti-TNF-α therapies remain to be established. • Clinical validation of newly identified biomarkers is necessary before implementation into routine clinical practice.

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Pharmacogenomics (2014) 15(16)

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Pharmacogenetics of inflammatory bowel disease 

the clinical utility of pharmacogenetic-based individu­ alised therapy. Nevertheless, the importance and neces­ sity of pharmacogenetic studies will increase further as more therapeutic classes are being developed. Future perspective Despite intensive pharmacogenetic research, the study of the inherited TPMT deficiency remains the only genetic test to be used clinically to guide thiopurine therapy in IBD. The clinical relevance of other genetic variants found in folate pathways or the purine biosynthesis still remain to be elucidated. Validation of new bio­markers is necessary before translating research into clinical practice. In addition, no polymorphism predicted to influence the TNF-α expression, metabolism and signal transduction has been consistently associated with IFX response. The lack of independent replication of associa­ tions is influenced by the complexity of the metabolic pathways involved, gene–gene interactions, gene–envi­ ronment interactions, small cohort size of IBD popula­ tions under investigation, existence of heterogeneity in IBD cohorts and the difficulty of clearly identifying the genetic variants which contribute to disease and those that contribute to adverse events. Prediciting future developments in the pharmaco­ genetics of IBD is rather a difficult task. Functional

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Examines the arena of the evolving inflammatory bowel disease nanomedicine, studied so far in animal and in vitro models, before comprehensive clinical testing in humans.

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Pharmacogenomics (2014) 15(16)

future science group

Pharmacogenetics of inflammatory bowel disease.

Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings...
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