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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
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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
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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
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Journal Article
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
2013
Overview
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.
Publisher
Springer-Verlag,Springer,Springer Nature B.V
Subject
/ Aged
/ Antirheumatic Agents - adverse effects
/ Antirheumatic Agents - pharmacokinetics
/ Arthritis, Rheumatoid - diagnosis
/ Arthritis, Rheumatoid - drug therapy
/ Arthritis, Rheumatoid - enzymology
/ Arthritis, Rheumatoid - genetics
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Bone Marrow Diseases - chemically induced
/ Bone Marrow Diseases - enzymology
/ Bone Marrow Diseases - genetics
/ Diseases of the osteoarticular system
/ Female
/ gamma-Glutamyl Hydrolase - genetics
/ gamma-Glutamyl Hydrolase - metabolism
/ Genetic Predisposition to Disease
/ Humans
/ Male
/ Methotrexate - adverse effects
/ Methotrexate - pharmacokinetics
/ Patients
/ Pharmacology. Drug treatments
/ Thymidylate Synthase - genetics
/ Thymidylate Synthase - metabolism
/ Toxicity
