Hongkaew Yaowaluck, Gaedigk Andrea, Wilffert Bob, Gaedigk Roger, Kittitharaphan Wiranpat, Ngamsamut Nattawat, Limsila Penkhae, Puangpetch Apichaya, Sukprasong Rattanaporn, Sukasem Chonlaphat
Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
Front Pharmacol. 2021 Oct 6;12:743494. doi: 10.3389/fphar.2021.743494. eCollection 2021.
We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor () gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of /ankyrin repeat and kinase domain containing 1 () 1A, -141C indel, and -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.
我们研究了药效学基因的遗传变异与利培酮诱导的自闭症谱系障碍（ASD）儿童及青少年催乳素水平升高之间的关联。在一项回顾性研究中，对124例接受利培酮治疗至少3个月的ASD患者的药效学基因变异进行了分析。为简化基因型解读，我们创建了一种算法来计算多巴胺D2受体（）基因遗传风险评分。催乳素水平与单个单核苷酸多态性（SNP）之间没有关系。然而，ankyrin重复序列和含激酶结构域1（）1A的H1/H3双倍型（A2/A2-Cin/Cin-A/G）、-141C插入缺失以及-141A>G，其遗传风险评分为5.5，与最高的催乳素中位数水平（23 ng/ml）相关。随着利培酮、9-羟基利培酮和活性部分的剂量校正血浆水平升高，携带H1/H3双倍型患者的催乳素水平显著高于其他双倍型患者。随着血浆利培酮水平升高，双倍型患者的催乳素水平显著升高。对利培酮有反应的患者检测到较低水平的催乳素。这是首个基于其蛋白质表达使用遗传风险评分来描述单倍型的系统。临床医生在临床实践中应考虑采用基于药物遗传学的决策方法来预防催乳素升高。
