Department of Psychiatry & Psychotherapy, Charité University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany.
Pharmacogenomics. 2010 Jun;11(6):773-80. doi: 10.2217/pgs.10.50.
Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy.
We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP).
PATIENTS & METHODS: We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests.
We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs.
The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism.
药物引起的体重增加（BWG）是第二代抗精神病药物治疗中的一个严重问题。个体间的差异可能受遗传因素的调节。过去，药物遗传学研究得出了相互矛盾的结果，没有一种确定的遗传改变对这种精神药物治疗的严重副作用具有足够的预测价值。
我们旨在复制和扩展先前的关联发现，并研究编码 5-羟色胺 2C 受体（HTR2C）、胰岛素诱导基因 2（INSIG2）和瘦素（LEP）的基因。
我们调查了 128 名德国精神分裂症患者中 HTR2C、LEP 和 INSIG2 SNP 与抗精神病药物引起的 BWG 的关联。对 9 个 SNP（HTR2C：rs498207、rs3813928、rs6318 和 rs3813929；INSIG2：rs17587100、rs10490624、rs17047764 和 rs7566605；LEP：rs7799039）进行了基因分型。关联分析包括逻辑回归分析和 Pearson χ2 检验。
我们报告了三个 HTR2C SNP（rs498207、rs3813928 和 rs3813929）和相应的单倍型与抗精神病药物引起的 BWG 显著相关。关于 X 染色体 SNP rs498207，AA/A 基因型的个体比 GG/G 基因型的个体体重增加更多。在进行多重检验校正后，观察到 SNP rs498207 的关联仍然显著（p=0.0196）。未发现 INSIG2 和 LEP SNP 的关联。
这些结果为 X 染色体 HTR2C 基因与抗精神病药物引起的 BWG 相关的累积证据做出了贡献。提出的潜在机制包括 5-HT 调节的下丘脑前阿黑皮素原神经元激活减少导致 HTR2C 基因表达降低，以及 D2 受体拮抗作用下的 5-HT2C 反向激动作用。
