CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders.

IF 1.8 4区医学 Q3 PHARMACOLOGY & PHARMACY Pharmacogenomics & Personalized Medicine Pub Date : 2022-11-08 eCollection Date: 2022-01-01 DOI:10.2147/PGPM.S377210

Marta H Hernandez, Valentin Bote, Alexandre Serra-LLovich, Marc Cendros, Juliana Salazar, Conxita Mestres, Silvina Guijarro, Aida Alvarez, Cristina Lamborena, Iria Mendez, Bernardo Sanchez, Amaia Hervas, Maria J Arranz

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Abstract

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 (SLC6A2) and for its primary metabolic pathway (CES1) 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 CES1 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.

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CES1和SLC6A2基因变异是自闭症谱系障碍患者对哌甲酯反应的预测因子。

目的:自闭症谱系障碍(ASD)儿童和青少年通常存在合并症，其中40-70%的儿童和青少年伴有注意缺陷多动障碍(ADHD)。这些患者的首选药物治疗是哌甲酯(MPH)。ASD儿童比ADHD儿童表现出更多的副作用和更差的反应。我们的研究目的是确定自闭症儿童和青少年对MPH反应的遗传生物标志物，以提高其疗效和安全性。患者和方法:对140例接受MPH治疗的ASD儿童和青少年进行回顾性研究。对MPH靶基因NET1 (SLC6A2)及其主要代谢途径(CES1)的15个基因多态性进行了基因分型。对每种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、关闭、其他副作用)。结果:以性别、年龄和剂量为协变量的单标记分析显示，CES1等位基因与mph诱导的副作用(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)存在关联，CES1 rs2302722-C等位基因与嗜睡存在(p=0.05)、SLC6A2 rs36029-G等位基因与关闭存在边际关联(p=0.05)。CES1单倍型组合与疗效和副作用相关(p分别=0.02和0.03)。SLC6A2单倍型组合与嗜睡相关(p=0.05)。结论:CES1基因变异可能影响儿童和青少年ASD合并ADHD患者MPH治疗的临床结果。

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来源期刊

Pharmacogenomics & Personalized Medicine Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

3.30

自引率

5.30%

发文量

110

审稿时长

16 weeks

期刊介绍： Pharmacogenomics and Personalized Medicine is an international, peer-reviewed, open-access journal characterizing the influence of genotype on pharmacology leading to the development of personalized treatment programs and individualized drug selection for improved safety, efficacy and sustainability. In particular, emphasis will be given to: Genomic and proteomic profiling Genetics and drug metabolism Targeted drug identification and discovery Optimizing drug selection & dosage based on patient''s genetic profile Drug related morbidity & mortality intervention Advanced disease screening and targeted therapeutic intervention Genetic based vaccine development Patient satisfaction and preference Health economic evaluations Practical and organizational issues in the development and implementation of personalized medicine programs.