Abstract：
OBJECTIVE: Glucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC.
METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype.
RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases.
CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.
METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype.
RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases.
CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.
摘要：
目的：糖皮质激素（GC）给药与影响多器官系统的药物不良反应（ADR）有关。虽然长期使用被广泛认为是ADR的重要独立预测因子，值得注意的是，即使是短期使用也会导致严重的不良反应。ADR发生的相当大的个体间差异可能受遗传因素的影响。这项研究,我们介绍了一个孩子的例子，他经历了显著的体重增加和骨质疏松症，在GC的简短管理之后。
方法：为了全面研究潜在的机制，我们利用全外显子组测序(WES)技术进行了基因组分析.该分析包括对I期和II期代谢的检查，涌入运输，外排运输，和药物靶向。此外,对52,119名儿童进行了综合分析，以确定他们的ABCB1rs1045642基因型，另外37,884名儿童接受了CYP3A5rs776746基因型检测。
结果：药物遗传学分析揭示了ABCB1rs1045642中存在高风险变异体和CYP3A5rs776746中存在缓慢代谢变异体，这两种变异体都有可能导致ADR。这项研究的结果表明，患者中ABCB1rs1045642CT类型的患病率为47.58％，TT型占15.69%，CC型占36.73%。此外，CYP3A5rs776746CC基因型分布在50.54%的个体中，而CT和TT基因型分别存在于41.15%和8.31%的人群中。ABCB1和CYP3A5基因型在中国儿科人群中的分布具有显著特点。具体来说,对于ABCB1rs1045642基因型，不到50%的儿童表现出中间型。相反，在CYP3A5rs776746基因型的儿童中，酶活性的主要原因是缓慢的代谢类型，占病例的90%。
结论：因此，必须全面评估等位基因突变对糖皮质激素药物或ABCB1和CYP3A5代谢的其他药物的有效性和安全性的影响,特别是在中国儿科患者中.
方法：为了全面研究潜在的机制，我们利用全外显子组测序(WES)技术进行了基因组分析.该分析包括对I期和II期代谢的检查，涌入运输，外排运输，和药物靶向。此外,对52,119名儿童进行了综合分析，以确定他们的ABCB1rs1045642基因型，另外37,884名儿童接受了CYP3A5rs776746基因型检测。
结果：药物遗传学分析揭示了ABCB1rs1045642中存在高风险变异体和CYP3A5rs776746中存在缓慢代谢变异体，这两种变异体都有可能导致ADR。这项研究的结果表明，患者中ABCB1rs1045642CT类型的患病率为47.58％，TT型占15.69%，CC型占36.73%。此外，CYP3A5rs776746CC基因型分布在50.54%的个体中，而CT和TT基因型分别存在于41.15%和8.31%的人群中。ABCB1和CYP3A5基因型在中国儿科人群中的分布具有显著特点。具体来说,对于ABCB1rs1045642基因型，不到50%的儿童表现出中间型。相反，在CYP3A5rs776746基因型的儿童中，酶活性的主要原因是缓慢的代谢类型，占病例的90%。
结论：因此，必须全面评估等位基因突变对糖皮质激素药物或ABCB1和CYP3A5代谢的其他药物的有效性和安全性的影响,特别是在中国儿科患者中.
