Department of Psychiatry and Behavioral Sciences, Center for Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Mol Psychiatry. 2009 Dec;14(12):1105-18. doi: 10.1038/mp.2009.92. Epub 2009 Oct 20.
We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054 + or - 0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.
我们研究了七个反映抗抑郁药作用的基因，这些基因在四个连续水平上具有相关性：（1）进入大脑，（2）与单胺转运体结合，（3）在转录水平上产生的远距效应，导致（4）神经生长因子和神经肽受体的变化。这些基因是 ABCB1 （ATP 结合盒亚家族 B 成员 1）、去甲肾上腺素、多巴胺和 5-羟色胺转运体（SLC6A2、SLC6A3 和 SLC6A4）、环磷酸腺苷反应元件结合蛋白 1（CREB1）、促肾上腺皮质激素释放激素受体 1（CRHR1）和神经营养酪氨酸激酶 2 受体（NTRK2）。这些基因的序列变异性在外显子和侧翼区域都有发现。我们对来自洛杉矶的 536 名无关墨西哥裔美国人（264 名对照和 272 名重度抑郁症患者）的 5628 万碱基对进行了测序。我们在这些个体中检测到 419 个单核苷酸多态性（SNP）；核苷酸多样性为 0.00054±0.0001。其中，共发现 204 个新的 SNP，占这些基因中所有先前报道的 SNP 的 49%：72 个位于非翻译区，19 个位于编码序列，其中 7 个为非同义突变，86 个位于内含子区，27 个位于上下游区。ABCB1、SLC6A2、SLC6A3、SLC6A4、CREB1 和 NTRK2 中的一些 SNP 或单倍型与 MDD 相关，而在 ABCB1、SLC6A2 和 NTRK2 中与抗抑郁药反应相关。在控制年龄、性别和基线 21 项汉密尔顿抑郁量表（HAM-D21）评分，以及进行多重检验校正后，HAM-D21 评分的相对降低仍与两个 NTRK2 编码 SNP（rs2289657 和 rs56142442）和 rs2289658（剪接位点）、rs2289657 和 rs2289656 处的 CAG 单倍型显著相关。需要在更大的独立样本中进行进一步的研究来证实这些关联。我们的数据表明，对序列变异性的广泛评估可能有助于增加对疾病易感性和药物反应的理解。此外，这些结果强调了在少数民族群体中直接对关键候选基因进行重新测序的重要性，以便发现不能简单地从现有数据库推断出的新遗传变异。
