Kraft Jeffrey B, Peters Eric J, Slager Susan L, Jenkins Greg D, Reinalda Megan S, McGrath Patrick J, Hamilton Steven P
Department of Psychiatry and Center for Human Genetics, University of California, San Francisco, California 94143-0984, USA.
Biol Psychiatry. 2007 Mar 15;61(6):734-42. doi: 10.1016/j.biopsych.2006.07.017. Epub 2006 Nov 21.
SLC6A4 encodes the serotonin transporter, the protein primarily responsible for the termination of serotonin neurotransmission. Because many antidepressants inhibit the transporter, it has been the focus of intense pharmacogenetic analysis. We sought to replicate our previous findings that SLC6A4 is associated with response to a selective serotonin reuptake inhibitor (SSRI) in a large case-control study.
Genotypes at the SLC6A4 locus were obtained for 1,914 subjects in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and then tested for association to treatment response of the SSRI citalopram.
Nine tagging single nucleotide polymorphisms and two variants previously associated with antidepressant response, including a promoter repeat polymorphism, were genotyped. Single marker and haplotypic analyses failed to detect association with antidepressant response in the largest clinical sample studied to date.
The lack of association between response to an SSRI and variation at the SLC6A4 locus in this large sample, carefully characterized for response to citalopram, strongly suggests that SSRI response in major depression is not determined by DNA variation at this locus. These findings do not replicate findings of a number of studies with considerably smaller sample sizes. Other genetic determinants of SSRI response in depression should be sought.
SLC6A4编码5-羟色胺转运体，该蛋白主要负责5-羟色胺神经传递的终止。由于许多抗抑郁药会抑制该转运体，因此它一直是深入药物遗传学分析的重点。我们试图在一项大型病例对照研究中重复我们之前的发现，即SLC6A4与对选择性5-羟色胺再摄取抑制剂（SSRI）的反应有关。
在缓解抑郁症的序贯治疗替代方案（STAR*D）研究中，获取了1914名受试者SLC6A4基因座的基因型，然后测试其与SSRI西酞普兰治疗反应的相关性。
对9个标签单核苷酸多态性以及之前与抗抑郁反应相关的两个变体进行了基因分型，其中包括一个启动子重复多态性。单标记和单倍型分析未能在迄今为止研究的最大临床样本中检测到与抗抑郁反应的相关性。
在这个对西酞普兰反应进行了仔细特征分析的大样本中，SSRI反应与SLC6A4基因座变异之间缺乏相关性，这强烈表明重度抑郁症中SSRI反应并非由该基因座的DNA变异决定。这些发现未能重复许多样本量小得多的研究结果。应该寻找抑郁症中SSRI反应的其他遗传决定因素。
