Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver · 2025
Response to azathioprine treatment in autoimmune hepatitis is dependent on glutathione transferase genotypes.
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Appell Malin Lindqvist, Hindorf Ulf, Almer Sven, Haglund Sofie
Аннотация
BACKGROUND: Azathioprine (AZA) is part of the standard treatment for autoimmune hepatitis (AIH). The first step in the complex bioconversion of AZA to active metabolites is mediated by glutathione transferases (GSTs).
AIMS: Elucidate the association between GSTM1 and GSTT1 copy number variation (CNV), genetic variation in GSTA2, GSTP1, and inosine-triphosphate-pyrophosphatase, and the response to AZA in AIH.
METHODS: Genotyping was performed in AIH patients (n = 131) on AZA, and in a Swedish background population (n = 283). Thiopurine metabolites in blood erythrocytes were determined by high performance liquid chromatography.
RESULTS: GSTM1 and GSTT1 CNV were associated with treatment response to AZA. Gene deletion of GSTM1-but not of GSTT1-was associated with the liver transaminase levels. None of the studied genetic variants were associated with the thiopurine metabolite concentrations, suggesting non-enzymatic mechanisms of GSTM1 and GSTT1 in the context of AZA efficacy in AIH. The prevalence of GSTM1 and GSTT1 CNV genotypes was similar in AIH and in the background population.
CONCLUSION: This study shows the effects of GSTM1 and GSTT1 CNV on AZA efficacy in AIH, not previously described. It also elaborates on the impact of the definition of treatment response, on the importance of the various GSTs studied. Furthermore, the GSTM1 and GSTT1 CNV frequencies previously reported in European populations were confirmed.
AIMS: Elucidate the association between GSTM1 and GSTT1 copy number variation (CNV), genetic variation in GSTA2, GSTP1, and inosine-triphosphate-pyrophosphatase, and the response to AZA in AIH.
METHODS: Genotyping was performed in AIH patients (n = 131) on AZA, and in a Swedish background population (n = 283). Thiopurine metabolites in blood erythrocytes were determined by high performance liquid chromatography.
RESULTS: GSTM1 and GSTT1 CNV were associated with treatment response to AZA. Gene deletion of GSTM1-but not of GSTT1-was associated with the liver transaminase levels. None of the studied genetic variants were associated with the thiopurine metabolite concentrations, suggesting non-enzymatic mechanisms of GSTM1 and GSTT1 in the context of AZA efficacy in AIH. The prevalence of GSTM1 and GSTT1 CNV genotypes was similar in AIH and in the background population.
CONCLUSION: This study shows the effects of GSTM1 and GSTT1 CNV on AZA efficacy in AIH, not previously described. It also elaborates on the impact of the definition of treatment response, on the importance of the various GSTs studied. Furthermore, the GSTM1 and GSTT1 CNV frequencies previously reported in European populations were confirmed.