Publikationsdatum:
2012-07-07
Beschreibung:
Purpose 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. Conclusion 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. Content Type Journal Article Category Pharmacogenetics Pages 1-7 DOI 10.1007/s00228-012-1341-3 Authors Biljana Jekic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Ljiljana Lukovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Vera Bunjevacki, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Vera Milic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Ivana Novakovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Tatjana Damnjanovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Jelena Milasin, Institute of Biology and Human Genetics, Faculty of Dentistry, University of Belgrade, 1 Dr Subotica Str, 11000 Belgrade, Serbia Branka Popovic, Institute of Biology and Human Genetics, Faculty of Dentistry, University of Belgrade, 1 Dr Subotica Str, 11000 Belgrade, Serbia Nela Maksimovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Nemanja Damjanov, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Goran Radunovic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Ljiljana Kovacevic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Maja Krajinovic, Centre de Recherche, CHU Sainte-Justine, Departments of Pediatrics and Pharmacology, University of Montréal, 3175 Chemin de la Côte-Ste-Catherine, Montreal, QC H3T 1C5, Canada Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970
Print ISSN:
0031-6970
Digitale ISSN:
1432-1041
Thema:
Chemie und Pharmazie
,
Medizin
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