Genotype distribution of methotrexate and leflunomide related gene polymorphism in patients with rheumatoid arthritis / 中华风湿病学杂志

ABSTRACT

Objective:To study the genotype distribution of drug-related gene polymorphism of methotrexate (MTX) and leflunomide (LEF) in patients with rheumatoid arthritis (RA).Methods:The genotyping results of RA patients' MTX and LEF related genes(MTHFR677C/T, MTHFR1298A/C, ABCB13435T/C, DHODH19C/A and CYP1A2734C/A) detected in Shanghai Guanghua Hospital from December 2018 to May2019 and drug-related adverse effect were statisticallyanalyzed. The independence of allele distribution was tested by Hardy-Weinberg test. Counting data of genotypes and allele frequencies among the groups were analyzed by the chi-square test. Measurement data were showed as Mean±SD deviation. The network between incidence of adverse events and genotypes of patients was analyzed by cytoscape software. Results:Genotype distribution in 151 patients was consistent with Hardy-Weinberg genetic balance ( P>0.05), and genotype and allele distribution of each gene showed no statistical difference in gender ( P>0.05). The results showed that the most common genotype in RA were that genotypes of the good response with moderate resistance to MTX (MTHFR677CC/MTHFR1298AA/ABCB13435CT) (16 cases, 13.5%) and the good response with moderate side effect risk to LEF(DHODH19CC/CYP1A2734AC) (25 cases, 28.4%). According to the distribution frequency of alleles, the incidence of high side effects caused by MTX combined with LEF was predicted to be 2.9%, which was close to 1.8% of the actual genotypes of patients. The types and proportion of clinical adverse reactions in patients were retrospectively analyzed and the correlation network analysis was conducted with the genotype analysis results. It was found that the incidence rates of adverse reactions were liver injury (35.4%, 35/99), leukopenia (14.1%, 14/99), thrombocytopenia (2.0%, 2/99), and skin rash (1.0%, 1/99) from the top to the bottom. The top two genotypes that were related to the occurence of adverse events were MTHFR677CT/MTHFR1298AA/ABCB13435CT and DHODH19CA/CYP1A2734AC, respectively, which verified the consistency between drug-related genotype and clinical manifestations in RA patients. Conclusion:Our results suggested that genotype in RA patients is closely related to drug efficacy and adverse events. 2.9% of RA patients need to stop taking MTX and LEF due to high MTX resistance and poor MTX response and increased toxicity when combined with LEF, in which the proportion of liver injury is the highest.