CES1和SLC6A2基因变异作为自闭症谱系障碍中对哌醋甲酯反应的预测指标
CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders.
作者信息
Hernandez Marta H, Bote Valentin, Serra-LLovich Alexandre, Cendros Marc, Salazar Juliana, Mestres Conxita, Guijarro Silvina, Alvarez Aida, Lamborena Cristina, Mendez Iria, Sanchez Bernardo, Hervas Amaia, Arranz Maria J
机构信息
Research Laboratory Unit, Fundació Docència i Recerca Mútua Terrassa, Terrassa, Spain.
School of Health Sciences Blanquerna, University Ramon Llull, Barcelona, Spain.
出版信息
Pharmgenomics Pers Med. 2022 Nov 8;15:951-957. doi: 10.2147/PGPM.S377210. eCollection 2022.
PURPOSE
Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety.
PATIENTS AND METHODS
A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 () and for its primary metabolic pathway () were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype.
RESULTS
Single marker analyses considering gender, age, and dose as covariates showed association between variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05).
CONCLUSION
CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.
目的
自闭症谱系障碍（ASD）儿童和青少年通常伴有其他疾病，其中40%-70%的患者患有注意力缺陷多动障碍（ADHD）。这些患者药物治疗的首选是哌醋甲酯（MPH）。与ADHD儿童相比，ASD儿童服用MPH时出现的副作用更多，反应也更差。我们研究的目的是确定ASD儿童和青少年对MPH反应的遗传生物标志物，以提高其疗效和安全性。
患者与方法
纳入一项对总共140例接受MPH治疗的ASD儿童和青少年的回顾性研究。对编码MPH靶点NET1（）及其主要代谢途径（）的基因中的15个多态性进行基因分型。对每个多态性和单倍型进行多变量分析，包括反应表型（疗效、副作用、嗜睡、易怒、情绪改变、攻击性、关机、其他副作用）。
结果
将性别、年龄和剂量作为协变量的单标记分析显示，某些变体与MPH引起的副作用之间存在关联（rs2244613-G（p=0.04）、rs2302722-C（p=0.02）、rs2307235-A（p=0.03）和rs8192950-T等位基因（p=0.03）），CES1 rs2302722-C等位基因与嗜睡的存在之间存在边缘关联（p=0.05），SLC6A2 rs36029-G等位基因与关机之间存在边缘关联（p=0.05）。一种CES1单倍型组合与疗效和副作用相关（分别为p=0.02和0.03）。SLC6A2单倍型组合与嗜睡相关（p=0.05）。
结论
CES1基因变体可能会影响合并ADHD的ASD儿童和青少年MPH治疗的临床结果。
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