Gamma-glutamyl hydrolase gene polymorphisms – another way to predict methotrexate efficacy in rheumatoid arthritis

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Abstract

The current treatment strategy for rheumatoid arthritis has been formulated within the framework of the European League Against Rheumatism (EULAR) concept “Treatment to achieve the goal”. Methotrexate prescribed as soon as possible after verifying rheumatoid arthritis is recognized as a first-line drug that allows to achieve disease remission and prevent destructive changes in the joints. Long-term clinical experience of using methotrexate allowed to conclude that almost 30% patients with rheumatoid arthritis turn out to be resistant to such treatment, enforcing to change the basal anti-inflammatory therapy, shift to using targeted or genetically engineered biological drugs, so that timeframe to prevent disease progression can be irreversibly lost. In the last decade, genetic testing for drug therapy effectiveness has been gaining momentum based on individual features in functioning of enzyme systems which regulate various stages of drug biotransformation. To date, a personalized approach to treatment of rheumatoid arthritis may be implemented after examining more than a dozen of single nucleotide polymorphisms (SNPs) within the folate cycle genes responsible for metabolizing methotrexate as well as its mechanism of action. In our work, we attempted to test a relationship between therapeutic response (efficacy and resistance) to methotrexate and -401C>T (rs 3758149) SNP in the GGH (gamma-glutamyl hydrolase) gene, which coordinates the processes of extracellular methotrexate transport. A groups patients consisted of 85 basic anti-inflammatory therapy-naïve patients diagnosed with rheumatoid arthritis, who were initially treated with methotrexate at a dose of 10 to 17.5 mg per week, with subsequently assessed therapeutic efficacy 6 months after the treatment onset based on dynamics in DAS28 index that allowed to identify groups of “responders” and “non-responders”. Next, all patients from select groups underwent molecular genetic typing for GGH-401C>T SNP by using real-time polymerase chain reaction. Our study allowed to find that prevalence of the TT homozygous genotype (OR = 5.09; 95% CI 1.11- 23.3; p = 0.037) dominated in “methotrexate non-responders”, whereas “methotrexate responders” tended to have higher C allele frequency (OR = 0.54; 95% CI 0.27-1.01; p = 0.087), which allowed to identify them by genetic predictors of methotrexate therapeutic response in rheumatoid arthritis.

About the authors

I. V. Devald

South Ural State Medical University; Chelyabinsk State University

Email: fake@neicon.ru

PhD (Medicine), Associate Professor, Department of Therapy, Institute of Continuing Professional Education; Associate Professor, Department of Microbiology, Immunology and General Biology

Chelyabinsk

Russian Federation

E. A. Khodus

Chelyabinsk State University

Email: fake@neicon.ru

Senior Laboratory Assistant, Laboratory of Academic Disciplines, Department of Microbiology, Immunology and General Biology

Chelyabinsk

Russian Federation

E. B. Khromova

Chelyabinsk State University

Email: fake@neicon.ru

PhD (Biology), Associate Professor, Department of Microbiology, Immunology and General Biology

Chelyabinsk

Russian Federation

K. Yu. Myslivtsova

Сlinic of Professor Kinsersky

Author for correspondence.
Email: fake@neicon.ru

Myslivtsova Kristina Yu. - Rheumatologist

454092, Chelyabinsk, Blyukher str., 53а 

Phone: 7 (950) 743-09-07

Russian Federation

A. L. Burmistrova

Chelyabinsk State University

Email: fake@neicon.ru

PhD, MD (Medicine), Professor, Head, Department of Microbiology, Immunology and General Biology

Chelyabinsk

Russian Federation

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Copyright (c) 2020 Devald I.V., Khodus E.A., Khromova E.B., Myslivtsova K.Y., Burmistrova A.L.

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This work is licensed under a Creative Commons Attribution 4.0 International License.
Свидетельство о регистрации СМИ ПИ № 77 - 11525 от 04.01.2002 выдано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).


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