Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.
Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.
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DOI：
10.1038/tp.2013.26
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发表时间：
2013-06-25
影响因子：
6.8
通讯作者：
Research Units on Pediatric Psychopharmacology Autism Network
中科院分区：
文献类型：
--
作者：
Nurmi EL;Spilman SL;Whelan F;Scahill LL;Aman MG;McDougle CJ;Arnold LE;Handen B;Johnson C;Sukhodolsky DG;Posey DJ;Lecavalier L;Stigler KA;Ritz L;Tierney E;Vitiello B;McCracken JT;Research Units on Pediatric Psychopharmacology Autism Network
无论是儿童还是成人，接触第二代抗精神病药物都会带来体重过度增加的显着风险，这种风险因人而异。我们在 NIMH 儿科精神药理学自闭症网络研究单位的两个试验（N=225）中，对关键能量平衡基因（FTO、MC4R、LEP、CNR1、FAAH）的常见变异与最初 8 周体重增加的关系进行了查询，该试验采用利培酮治疗 4-17 岁患有自闭症谱系障碍的儿童/青少年的烦躁情绪。大麻素受体 (CNR)-1 启动子 (P=1.0 × 10−6)、CNR1 (P=9.6 × 10−5) 和瘦素 (LEP) 启动子 (P=1.4 × 10−4) 的变异赋予了体重增加的稳健独立风险。结合这三种变体的模型非常显着 (P=1.3 × 10−9)，最低和最高风险组之间的效应大小为 0.85。所有结果均经过多次测试校正，且不依赖于剂量、血浆水平或种族。我们没有发现与内源性大麻素代谢酶、脂肪酸酰胺水解酶中报告的功能变异相关的证据，而 FTO 和 MC4R 中与体重指数相关的单核苷酸多态性仅显示出趋势关联。这些数据表明，能量平衡调节基因的常见变异对儿童和青少年个体抗精神病药物相关的体重增加具有显着的遗传贡献，这取代了之前成人研究的结果。效果足够强大，仅 8 周后即可检测到，并且在大部分未接受过治疗的人群中更为突出。这项研究强调了进一步探索多因素不良事件的药物遗传学基础的令人信服的方向。
Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4–17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10−6), CNR1 (P=9.6 × 10−5) and the leptin (LEP) promoter (P=1.4 × 10−4) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10−9) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.
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影响因子：
2.8
作者：
Chowdhury, N. I.;Tiwari, A. K.;Mueller, D. J.
通讯作者：
Mueller, D. J.
影响因子：
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DOI：
10.1016/j.pnpbp.2012.03.001
发表时间：
2012-08-07
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