Shu Qing, Fan Qingqing, Hua Bingzhu, Liu Hang, Wang Shiying, Liu Yunxing, Yao Yao, Xie Han, Ge Weihong
Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People's Republic of China.
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, 210008, People's Republic of China.
Pharmgenomics Pers Med. 2021 Jun 21;14:713-722. doi: 10.2147/PGPM.S295964. eCollection 2021.
Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.
This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 -118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 -106G>A and MPA trough concentration (MPA C), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.
SLCO1B1 521T>C demonstrated a significant association with MPA C/d (p=0.003), in which patients with the CC type showed a higher MPA C/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C/d among the other SNPs. IMPDH1 -106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).
For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C/d and anemia. IMPDH1 -106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.
霉酚酸酯（MMF）是一种新型免疫抑制剂，已成为治疗自身免疫性疾病的一线药物。霉酚酸（MPA）是MMF的活性代谢产物。个体间MPA暴露差异很大，这可能导致药物不良反应，如胃肠道副作用、感染和白细胞减少。遗传因素在MPA水平变化及其副作用中起重要作用。尽管许多已发表的研究聚焦于器官移植患者使用MMF的情况，但仍缺乏针对自身免疫性疾病患者使用MMF的研究。
本研究不仅将探索影响MPA水平和不良反应的遗传因素，还将研究中国自身免疫性疾病患者中尿苷二磷酸葡萄糖醛酸基转移酶1A9（UGT1A9）-118（dT）9/10、UGT1A9 - 1818T>C、尿苷二磷酸葡萄糖醛酸基转移酶2B7（UGT2B7）802C>T、有机阴离子转运多肽1B1（SLCO1B1）521T>C、有机阴离子转运多肽1B3（SLCO1B3）334T>G、肌苷-5'-单磷酸脱氢酶1（IMPDH1）-106G>A与MPA谷浓度（MPA C）以及不良反应之间的关系。共招募了120例自身免疫性疾病患者。采用酶放大免疫测定技术（EMIT）检测MPA谷浓度。使用实时聚合酶链反应（PCR）系统和经过验证的等位基因鉴别分析进行基因分型。收集临床数据以确定副作用。
SLCO1B1 521T>C与MPA C/d显著相关（p=0.003），其中CC型患者的MPA C/d高于TT型患者（p=0.001）或CT型患者（p=0.000）。其他单核苷酸多态性（SNP）之间的MPA C/d未发现显著差异。发现IMPDH1 -106G>A与感染显著相关（p=0.006）。亚组分析显示，UGT2B7 ⑧02C>T与卡氏肺孢子虫肺炎感染显著相关（p=0.036），而SLCO1B1 521T>C与贫血相关（p=0.029）。
对于中国自身免疫性疾病患者，SLCO1B1 521T>C与MPA C/d和贫血相关。IMPDH1 -106G>A与感染显著相关。UGT2B7 802C>T与卡氏肺孢子虫肺炎感染显著相关。
