Pharmacogenetics of methotrexate in patients with rheumatoid arthritis

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(1)Pharmacogenetics of methotrexate in patients with rheumatoid arthritis Wessels, J.A.M. Citation Wessels, J. A. M. (2007, October 11). Pharmacogenetics of methotrexate in patients with rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/12436 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/12436. Note: To cite this publication please use the final published version (if applicable)..

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(8) Table 1. Disease modifying anti-rheumatic drugs of interest for pharmacogenetic studies. DMARD. Polymorphic genes reported or likely to influence DMARD response and/or safety. Sulphasalazine. Metabolizing enzyme N-acetyltransferase 2 (NAT2) Drug transporter reduced folate carrier (RFC). Hydroxychloroquine. Drug transporter of the ATP-binding cassette type A (ABCA4). Azathioprine. Metabolizing enzyme thiopurine methyltransferase (TPMT) Drug targets such as enzymes in the purine synthesis. Ciclosporin. Metabolizing cytochrome P450 enzymes Drug transporter multi drug resistance protein (MRP). Leflunomide. Metabolizing cytochrome P450 enzymes Drug targets dihydroorotate dehydrogenase (DHODH) and enzymes in the pyrimidine syntheses. Methotrexate. Drug transporters reduced folate carrier, P-glycoprotein and multi resistant proteins (RFC, ABCB1, MRP) Drug targets such as enzymes in the pyrimidine and purine syntheses Biological milieu genes such as genes in the major histocompatibility complex region. Anakinra. Drug target interleukine-1 gene Biological milieu genes such as genes in the major histocompatibility complex region. Etanercept Infliximab Adalimumab. Drug target TNF gene and promoter region, TNF receptor gene Drug target immunoglobulin G fragment C receptor type IIa, type IIIa and b Biological milieu genes such as genes in the major histocompatibility complex region. Abatacept. Drug target CTLA4 Biological milieu genes such as genes in the major histocompatibility complex region. Rituximab. Drug target immunoglobulin G fragment C receptor type IIa and type IIIa Biological milieu genes such as genes in the major histocompatibility complex region. BG,I:MB>GMLPBMA-(*LBGMA>L>I:MAP:R@>G>LA:O>RB>E=>=FBQ>=K>LNEML57 .:;E> IK>L>GMLMA>IA:KF:<H@>G>MB<=:M:H?,I:MB>GMLMK>:M>=PBMA'.2FHGHMA>K:IR .A>;>LM LMN=B>=:LLH<B:MBHGBLMA>-(*BGMA>@>G>F>MARE>G>M>MK:AR=KH?HE:M>K>=N<M. :L> '." , :G >GSRF> MA:M <:M:ERS>L MA> ?HKF:MBHG H? F>MARE M>MK:AR=KH?HE:M> F>MARE ." : F>MARE=HGHK ?HK : O:KB>MR H? F>M:;HEB< K>:<MBHGL .PH <HFFHG IHER. FHKIABLFLBG'." ,>GSRF>:MIHLBMBHG PBE=MRI> :EE>E>K>IE:<>=;R:O:KB:GM . :EE>E> . :G= :K> :LLH<B:M>= PBMA =BFBGBLA>= >GSRF> :<MBOBMR E>:=BG@ MH AHFH<RLM>BG>FB: #G<K>:L>=AHFH<RLM>BG>IE:LF:E>O>ELA:O>;>>G:LLH<B:M>=PBMA'.2 MHQB<BMR 57 L : <HGL>JN>G<> L>O>K:E K>IHKML LMN=B>= MA> :LLH<B:MBHG ;>MP>>G MA> :G= IHERFHKIABLFL PBMA '.2 MHQB<BMR >LI><B:EER @:LMKHBGM>LMBG:E :G= EBO>K MHQB<BMR .:;E> 5 7 #G :==BMBHG MA> >??><ML H? MA>L> '." , IHER. FHKIABLFLHG'.2>?<:<RP>K>:LL>LL>=5 7 ->O>GLMN=B>L?HNG=GH:LLH<B:MBHGH?'." ,.PBMAHO>K:EE'.2 BG=N<>=MHQ. B<BMR5 7 PA>K>:LMAK>>LMN=B>L?HNG=:LLH<B:MBHGLPBMA!#MHQB<BMR?HK MA>.@>GHMRI>57 BG<K>:L>='.2=BL<HGMBGN:MBHG=N>MHBG<K>:L>=EBO>K>GSRF>E>O>EL ?HK. :EE>E><:KKB>KL57 :G=HO>K:EEMHQB<BMR5 7 .A>'." ,.P:L?HNG= GHMMH;>:LLH<B:M>=PBMAMA>=><K>:L>H?=BL>:L>:<MBOBMRL<HK>-:G= K>:<MBO>IKHM>BG E>O>EL,*:G=>KRMAKH<RM>L>=BF>GM:MBHGK:M>-,E>O>ELBG?HNKK>IHKML5 7 . IA:KF:<H@>G>MB<LH?BG?E:FF:MHKR:KMAKBMBL. .

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(11) Table 2. Pharmacogenetic association studies of methotrexate with treatment outcome in rheumatoid arthritis. Gene. Role in pathways, relation with MTX. SNP. MTHFR. Catalyzes methylene 677C>T THF to methyl-THF; indirect target MTX. Postulated effect SNP. Clinical effects. Thermolibale MTHFR with decreased activity and increased homocysteine levels. Increases homocysteine level [42]; No increased homocysteine level [44]; Effect on GI toxicity [42]; T-allele associated with increased liver enzyme levels [39]; T-allele associated with toxicity [46]; No association with toxicity [32,35,37,38,40,42,45]; No association with efficacy [39,40,40,45]; Association with efficacy [32,35]. 1298 A>C May further decrease MTHFR activity and increase homocysteine levels. . ATIC. Conversion of AICAR 347C>G to 10-formyl-AICAR; target of polyglutamated MTX. DHFR. Reduction of DHF to –473G>A Possibly affecting mRNA No effect on efficacy or toxicity THF; target of MTX 35389G>A transcription, affinity of [32] MTX. MTHFD1. catalyzes interconversion of 1-carbon derivatives of THF; indirect target MTX. 1958G>A. May decrease enzyme activity. AA associated with inefficacy [51]. SHMT1. catalyzes conversion 1420C>T of serine and THF to glycine and methylene-THF: indirect target MTX. May decrease enzyme activity. No association with efficacy [51]; CC associated with efficacy [35]; No association with toxicity [35,37]; CC associated with alopecia and CNS side effects [37]. TSER. Enhancer region of ’5 UTR TYMS; indirect target 28bp of MTX repeat. May increase enzyme activity. No association with efficacy [35,40,51]; No association with toxicity [35,40]; Association with toxicity and alopecia [37]. TYMS. Conversion of dUMP ’3 UTR May decrease TYMS to dTMP; target of 6bp dele- mRNA stability and MTX tion expression. AMPD1. Conversion of AMP to ADP and ATP; indirect target MTX. MTR. Methylation of 2756A>G homocysteine to methionine; indirect target MTX. May decrease enzyme activity; increase homocysteine levels. No association with efficacy [33,35]; AA associated with toxicity [35]; No association with toxicity [33]. MTRR. Methylation of 66A>G cofactors required for MTR action; indirect target MTX. May decrease MTRR activity; increase homocysteine levels. No effect on efficacy [33,35]; No association with toxicity [33]; Association with toxicity [35]. 34C>T. May decrease ATIC activity, affect AICAR accumulation and adenosine release. A-allele associated with toxicity [38,45]; C-allele associated with toxicity and GI toxicity [32,35]; No association with toxicity [40]; No association with efficacy [35,40,45]; Association with efficacy [32,46] Association with efficacy [33,37,51]; No association with efficacy [35]; GG associated with toxicity and GI toxicity [33,35,37]; No effect on toxicity [49]. May affect MTX efficacy [40]; No effect on efficacy as defined by MTX dose [49]; No effect on toxicity [49]. Decreased enzyme activ- T-allele associated with efficacy ity, may enhance conver- [33,51]; No association with toxicsion to adenosine ity [33].

(12) Table 2. Pharmacogenetic association studies of methotrexate with treatment outcome in rheumatoid arthritis. (continued) Gene. Role in pathways, relation with MTX. SNP. Postulated effect SNP. Clinical effects. ITPA. Conversion ITP to IMP; indirect target MTX. 94C>A. Decreased enzyme activity; may enhance conversion to AMP and adenosine. CC associated with efficacy [33,51]; Association with toxicity [33]. FPGS. Adding polyglutamates to MTX; prolonging cellular retention MTX. 1994A>G 114G>A. May affect MTX polyglutamation. No association with efficacy [41]; No association with toxicity [41]. GGH. Conversion of long chain polyglutamated MTX into short chain by removing polyglutamates. 452C>T 16C>T –401C>T. Decreased binding affinity for polyglutamated MTX May affect polyglutamated MTX levels. May affect efficacy [41]; No association with efficacy [51]; No association with toxicity [41] No association with efficacy [35]; May affect efficacy [36]; CC associated with toxicity [35]. ABCB1. Efflux transporter on 3435C>T cells; efflux of MTX. May decrease enzyme expression or mRNA stability; may increase intracellular MTX levels. TT associated with increased MTX dose [49]; T-allele associated with inefficacy [50]. RFC. Folate entry in the cell. May affect transcriptional No effect efficacy as defined by activity and increased MTX dose [49]; No association MTX entry in the cell with efficacy [32,35]; No association with toxicity [32,35,49]. 80G>A. ABCB1 = P-glycoprotein; ADP = adenosine diphosphate; AICAR = aminoimidazole-4-carboxamide ribonucleotide; AMP = adenosine monophosphate; AMPD1 = adenosine monophosphate deaminase; ATIC = 5aminoimidazole-4-carboxamide ribo-nucleotide transformylase; ATP = adenosine triphosphate; CNS= central nervous system; DHF = dihydrofolate; DHFR = dihydrofolate reductase; dTMP = deoxy thymidine monophosphate; dUMP = deoxy-uridine monophosphate; FPGS = folylpoly-glutamate synthetase; GI= gastrointestinal; GGH = -glutamyl hydrolase; IMP = inosine monophosphate; ITP = inosine triphosphate; ITPA = inosine triphosphatase; MTHFD1 = methylenetetrahydrofolate dehydrogenase; MTHFR = methylene tetrahydrofolate reductase; MTR = methyltetrahydrofolate-homocysteine methyltransferase; MTRR = 5methyltetrahydrofolate-homocysteine methyltransferase reductase; MTX= methotrexate; RFC1 = reduced folate carrier; SHMT1 = serine hydroxymethyltransferase; THF = tetrahydrofolate; TSER = thymidylate synthetase enhancer region; TYMS = thymidylate synthetase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

(13) Table 3. Pharmacogenetic association studies of anti-TNF agents and their efficacy of treatment in rheumatoid arthritis. Gene. Function. TNF. TNF produc- –308 G>A promotor May increase trantion and regula- region scriptional activity; tion May increase TNF levels. SNP. Postulated effect SNP Clinical effects GG associated with efficacy INF [59–61]; No effect on efficacy INF [62,78]; No effect on efficacy ETA [51,64,66]; GA associated with increased TNF levels after INF [78]. –857C>T, promoter See above region. T-allele associated with efficacy ETA [64]. –863C>A, promoter See above region –238G>A, promoter region. No effect on efficacy ETA[64]; No effect on efficacy ETA [51,64]; No effect on efficacy INF [62]. –1031T>C promoter region. See above. No effect on efficacy ETA [64]. +488 intronic region Unknown +2018 Unknown. No effect on efficacy ETA [51] No effect on efficacy INF [62]. –609 –580 –383. May affect TNF binding. No effect on efficacy ETA [51]. May increase interleukine 6 production and affect TNF binding. No effect on efficacy ETA [51]; GG associated with inefficacy ETA and INF [63]. TNF/ micro- Linked to TNF a,b,c,d,e satellites 308 polymorphism. May influence TNF levels; increased RA susceptibility risk. No effect on efficacy ETA [51]; TNF 11 and 4 haplotype associated with efficacy INF [79]. Lymphotoxin Mediation of (LTA) inflammatory actions. +177A>G +319C>A +249 +365 +720. Exhibits pro-inflammatory effects. No effect on efficacy ETA [64] No effect on efficacy ETA [51]. HLA DRB1, DRQ1 alleles (SE). Antigen presenting molecules. See references. May affect anti-TNF efficacy; associated with increased susceptibility and severity of RA. No effect on efficacy INF [62,79]; HLA-DBRB1 associated with efficacy ETA [51]; No effect on efficacy ETA [64,66]. Fc receptor polymorphisms. Influence cell activation, apoptosis. Indirect target anti-TNF. 131H/R (FcRIIa) May affect IgG Fc 176F/V (FcRIIIa) binding affinity NA1/NA2 (FcRIIIb) –158V/F (FcIIIa). TNFRSF1. TNF soluble receptor type 1. TNFRSF2. TNF soluble 196G>T receptor type 2. No effect on efficacy ETA [51] No effect on efficacy ETA and INF [67]; FF associated with efficacy all 3 anti-TNF agents [68]. Interleukine-10 Anti-inflamma- –1087G>A GG associated with No effect on efficacy ETA [66] (IL-10) tory cytokine Several microsatel- increased anti-inflam- IL-10 R3 and haplotype lites, see reference matory response IL-10 R3-R9 associated with efficacy ETA [65] Interleukine-1 Pro-inflamma(IL-1) tory cytokine IL-1 receptor antagonist. IL-1 +3954C>T. Inhibits action IL-1-RN +2018T>C of interleukine 1. May affect inflamma- No effect on efficacy INF [62] tory response May affect inflamma- C-allele associated with ineftory response ficacy INF [62]. ETA = etancercept; HLA = human leukocyte antigen; INF = infliximab; TNF = tumor necrosis factor-.. .

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