Effects of Xanthine Dehydrogenase and Guanosine Monophosphate Synthetase Gene Polymorphisms on Myelosuppression and Alopecia Induced by Azathioprine in Small Samples

OBJECTIVE To investigate the effects of xanthine dehydrogenase(XDH) and guanosine monophosphate synthetase(GMPS) gene polymorphisms on myelosuppression and alopecia induced by azathioprine(AZA). To explore the value that combined detection of NUDT15 rs116855232 and those genetypes predicted AZA induced myelosuppression. METHODS Patients who have taken or are taking AZA for autoimmune diseases were retrospective analysed. Genotypes of GMPS rs61750368, rs61750369, XDH rs2295475, rs1884725, rs17011368, rs566362 and NUDT15 rs116855232 were determined by direct sequencing. Patients were grouped according to adverse reactions. The association of these genotypes with AZA-induced myelosuppression and alopecia was analyzed, NUDT15 rs116855232 as control gene. RESULTS Eighty patients were included. There were no significant differences in age, daily dose, course of treatment, BMI and 6-thioguanine nucleotide level between two groups. Logistic regression analysis showed that AZA-included myelosuppression was associated with XDH rs2295475 mutation(P=0.003, OR=3.10, 95%CI:1.45-6.25). Sensitivity and specificity of this gene predicted myelosuppression were 69.6%, 63.2% respectively, ROC curve was 0.66. AZA-included myelosuppression was aslo associated with NUDT15 rs116855232 mutation(P=0.008, OR=3.46, 95%CI:1.21-9.93). No other genes were found to be associated with myelosuppression and alopecia. Patients with rs116855232 wild-type and rs2295475 mutant had higher risk of myelosuppression compared to those with two-gene wild-type(OR=6.53, P=0.004), while the patients with both genes mutated at the same time had much higher risk of myelosuppression(OR=51.67, P<0.001). CONCLUSION XDH rs2295475 mutation may be an independent risk factor for AZA-induced myelosuppression in Chinese autoimmune patients. Although the prediction accuracy is low but still has predictive value. Particularly, XDH combine with NUDT15 rs116855232 monitoring may compensate for the risk of inaccurate prediction of myelosuppression in NUDT15 wild-type patients. Combined testing can improve the accuracy of prediction of myelosuppression by NUDT15 mutant type. But these results are further validated by clinical studies.