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Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study.

ABSTRACT: The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280-508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.

SUBMITTER: Chen ZY

PROVIDER: S-EPMC8167793 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeSerum uric acid (UA) not only affects the development of obesity but also alters the metabolic status in obese subjects; thus we investigated the relationship between serum UA and the overweight/obese metabolic phenotypes.MethodsThe demographic, biochemical, and hematological data were collected for 12,876 patients undergoing routine physical examination, and 6,912 participants were enrolled in our study. Participants were classified into four obesity metabolic phenotypes according to their BMI and the presence of metabolic syndrome: metabolically healthy overweight/obese (MHOO), metabolically healthy and normal weighted (MHNW), metabolically abnormal and overweight/obese (MAOO), and metabolically abnormal but normal weighted (MANW). Univariate and multivariate logistic regression analysis, stratified analysis, and also interaction analysis were conducted to analyze the relationship between serum UA and obesity metabolic phenotypes.ResultsMultivariable logistic regression analysis showed that hyperuricemia was positively associated with MHOO, MANW, and MAOO phenotypes relative to MHNW. After adjusting for the confounding factors, the odds ratios (OR) for individuals with hyperuricemia to be MHOO, MANW, and MAOO phenotypes were 1.86 (1.42-2.45), 2.30 (1.44-3.66), and 3.15 (2.34-4.24), respectively. The ORs for having MHOO, MANW, and MAOO increased 6% [OR: 1.06 (1.05-1.07), P < 0.0001], 5% [OR: 1.05 (1.03-1.07), P < 0.0001], and 11% [OR: 1.11 (1.10-1.13), P < 0.0001] for each 10 unit (μmol/L) of increase in serum UA level. Stratification analysis as well as an interaction test showed that sex and age did not interfere with the association of hyperuricemia with each metabolic phenotype. In terms of the components of the metabolic syndrome, after adjusting for other confounding factors including all of the metabolic indicators except itself, hyperuricemia was positively associated with increased BMI [OR: 1.66 (1.32-2.09), P < 0.0001], hypertriglyceridemia [OR: 1.56 (1.21-2.02), P = 0.0006], and hypertension [OR: 1.22 (1.03-1.46), P = 0.0233], while it had no significant association with hyperglycemia and low HDL-C (all P > 0.05).ConclusionIn our study, we discovered that hyperuricemia was positively associated with MHOO, MANW, and MAOO phenotypes, and this relationship was independent of sex and age.

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Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study.

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