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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able 2. Allele frequencies in rheumatoid arthritis patients and healthy controls. GGH 16T>C GGH 452C>T FPGS 1994A>G FPGS 114G>A. Allele. RA (n = 352). Controls (n = 360) P-value ‡. T. 0.737. 0.709. 0.32. C. 0.263. 0.291. 0.32. T. 0.088. 0.087. 1.00. C. 0.912. 0.913. 1.00. A. 0.534. 0.572. 0.90. G. 0.466. 0.428. 0.90. A. 0.286. 0.279. 0.23. G. 0.714. 0.721. 0.23. ‡. P-values resulted from two-sided Chi-square test between patients and controls, wild type allele versus variant-type allele. RA = rheumatoid arthritis.. ?I@L:G=@@A@>G>IHERFHKIABLFLBGK:. .

(15) Homozygous GG 110 105. S. E. C. G. T. C. T. G. A. C. T. T. G. Heterozygous GA 110 105. E. S. C. G. T. C. G. T. A. T. C. T. G. Homozygous AA 110 105. E. S. C. G. T. C. G. T. A. T. C. T. G. Figure 1. Representative pyrogram of FPGS 114G>A rs10760502. Different genotypes are shown. Note that this single nucleotide polymorphism is sequenced with antisense primer and therefore the complementary nucleotides are shown. FPGS = folylpoly--glutamate synthase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able 3. Association of polymorphism in GGH gene with methotrexate response at 3 months after starting with methotrexate therapy. OR (95% CI)‡. Adjusted P-value†. GGH 16T>C. Improvement criterion. C-allele. Decrease in DAS of >0.6. 2.1 (1.1–4.1). 0.034. 0.068. C-allele. Decrease in DAS of >1.2. 2.9 (1.5–5.4). 0.001. 0.002. C-allele. Achieving DAS of ≤2.4. 2.1 (1.0–4.7). 0.036. 0.072. P-value. GGH 452C>T, FPGS 114G>A and FPGS 1994A>G were not found to be associated with methotrexate response or safety. GGH 16T>C was not found to be associated with methotrexate safety or efficacy at 6 months. ‡Odds ratios were corrected for age, gender, rheumatoid factor status and DAS at baseline. † Bonferroni correction. CI = confidence interval; DAS = disease activity score; FPGS = folylpoly--glutamate synthase; GGH = -glutamyl hydrolase; OR = odds ratio.. ,>@K>LLBHG:G:ERLBLH?MA>.A:IEHMRI><:KKB>KLLAHP>=MA:MI:MB>GML<:KKRBG@HG> GHKGHG<HIB>LH?MABLA:IEHMRI>P>K> MBF>LFHK>EBD>ERMHK>=N<>MA>-;R FHK>MA:G :MFHGMAL<HFI:K>=PBMAI:MB>GML<:KKRBG@MPH<HIB>LG H?MA> .A:IEHMRI>NG:=CNLM>=* HK:=><K>:L>BG-H?FHK>MA:G :G=:<AB>O. BG@ : - H? HK E>LL :M FHGMAL I:MB>GML <:KKRBG@ HG> HK GH <HIB>L H? MA> . A:IEHMRI>P>K> :G= MBF>LFHK>EBD>ERMHLAHP:K>LIHGL><HFI:K>=PBMAI:MB>GML <:KKRBG@MPH<HIB>LH?MA>.A:IEHMRI>NG:=CNLM>=* :G=* K>LI><. MBO>ER (HHMA>K:LLH<B:MBHGLPBMA>?<:<R:G=MA>.A:IEHMRI>P>K>?HNG= #?MA> HG?>KKHGB:=CNLMF>GML?HKFNEMBIE><HFI:KBLHGL:K>:IIEB>= HGERMA>:LLH<B:MBHGLPBMA: =><K>:L>BG-H?FHK>MA:G :MFHGMALH?MA>K:IRK>F:BGLB@GB<:GM LLH<B:MBHGLH?-(*LBG!!":G= *!-@>G>LPBMA'.2MHQB<BMR ,>@:K=BG@ '.2 L:?>MR H? MA> LMN=R IHINE:MBHG G >QI>KB>G<>= :M E>:LM HG> :=O>KL>=KN@>O>GMPBMABGFHGMALH?MK>:MF>GM PBMAFHLMH?MA>:=O>KL>=KN@>O>GML ;>BG@ FBE= HK FH=>K:M> .A> IK>=HFBG:GM :=O>KL> >O>GML P>K> @:LMKHBGM>LMBG:E <HF. IE:BGML LDBG:G=FN<HL:=BLHK=>KL :G=>E>O:M>=EBO>K>GSRF>L .A> *!- :G= !!" IHERFHKIABLFL :G= A:IEHMRI>L P>K> GHM ?HNG= MH ;> K>E:M>= MH '.2 L:?>MR =NKBG@:G=FHGMALIHLM MK>:MF>GM. ?I@L:G=@@A@>G>IHERFHKIABLFLBGK:. .

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