title: Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients.
abstract: OBJECTIVE
  Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs).
  
  
  METHODS
  The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX.
  
  
  RESULTS
  According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed.
  
  
  CONCLUSIONS
  The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.
authors: Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia. jekic.b@gmail.com
authors: Biljana
authors: B
authors: Jekic
authors: Ljiljana
authors: L
authors: Lukovic
authors: Vera
authors: V
authors: Bunjevacki
authors: Vera
authors: V
authors: Milic
authors: Ivana
authors: I
authors: Novakovic
authors: Tatjana
authors: T
authors: Damnjanovic
authors: Jelena
authors: J
authors: Milasin
authors: Branka
authors: B
authors: Popovic
authors: Nela
authors: N
authors: Maksimovic
authors: Nemanja
authors: N
authors: Damjanov
authors: Goran
authors: G
authors: Radunovic
authors: Ljiljana
authors: L
authors: Kovacevic
authors: Maja
authors: M
authors: Krajinovic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D001853:Bone Marrow / Q000187:drug effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D016009:Chi-Square Distribution; D019938:Cyclin D1 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000493:pharmacokinetics; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012720:Severity of Illness Index; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics* / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; C530104:CCND1 protein, human; D019938:Cyclin D1; D013940:Thymidylate Synthase; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate