Investigation of serotonin-related genes in antidepressant response
Investigation of serotonin-related genes in antidepressant response
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DOI：
10.1038/sj.mp.4001502
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发表时间：
2004-09-01
影响因子：
11
通讯作者：
Hamilton, SP
中科院分区：
文献类型：
--
作者：
Peters, EJ;Slager, SL;Hamilton, SP
在这项研究中，我们试图验证遗传因素可能影响氟西汀抗抑郁反应的假设。该研究集中于参与5-羟色胺合成、转运、识别和降解的7个β-羟色胺能途径的候选基因。我们的临床样本包括96名接受氟西汀治疗的单相抑郁症患者，在12周的试验后评估了反应变量。还收集了患者数据，以研究药物反应模式。使用高通量单核苷酸多态性（SNP）基因分型平台和毛细管电泳，我们在110个SNP和位于7个候选基因（HTR 1A，HTR 2A，HTR 2C，MAOA，SLC 6A 4，TPH 1和TPH 2）的4个重复多态性对患者进行基因分型。进行的统计学检验包括单基因座和单倍型关联检验和连锁不平衡（LD）估计。使用基因组控制程序，在具有20个随机SNP的样本中观察到很少的群体分层证据。我们最有趣的结果涉及TPH 1基因中的三个SNP和SLC 6A 4基因中的一个SNP，当对氟西汀有反应与无反应相比时，显示出显著的单位点关联（P=0.02-0.04）。所有比值比均表明氟西汀无效的风险增加。在特异性应答与非特异性和非应答比较中，TPH 2基因中的3个SNP（P=0.02-0.04）呈正相关，HTR 2A基因中的1个SNP（P=0.02）呈负相关。当比较特异性反应与非特异性反应时，我们发现HTR 2A基因中的三个SNP（P=0.001-0.03）和MAOA基因中的两个SNP（P=0.03-0.05）具有显著的负相关性。我们观察到变量，虽然强LD，在每个基因和意想不到的低数量的估计单倍型，形成标记的SNP。除了HTR 1A和HTR 2C基因外，所有基因均存在显著的单倍型关联。尽管由于样本量小，应谨慎解释这些数据，但这些结果表明TPH 1和SLC 6A 4与氟西汀的一般反应有关，HTR 2A、TPH 2和MAOA与氟西汀的反应特异性有关。有趣的是，我们观察到许多SNP标记的一些频率较低的等位基因与无应答和非特异性表型相关。
In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.