Psychiatric Pharmacogenomics Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Pharmacogenomics J. 2013 Jun;13(3):280-5. doi: 10.1038/tpj.2011.62. Epub 2012 Jan 17.
We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P≤0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response.
我们研究了广泛性焦虑症（GAD）患者接受度洛西汀治疗时的遗传相关性。共纳入三项研究，分别是接受度洛西汀 60-120mg/d（N=164）或安慰剂（N=95）治疗的 GAD 患者。采用基于集合的检验（根据每个基因内的 SNP 数量进行调整），检测了 61 个候选基因中 825 个单核苷酸多态性（SNP）与汉密尔顿焦虑量表评分变化之间的关联；对双侧调整后 P≤0.05 的集合使用重复测量分析进行检验。随后的分析探讨了这些 SNP 与接受度洛西汀治疗的伴有抑郁障碍的 GAD 患者（N=241）汉密尔顿抑郁焦虑量表评分变化之间的关联。在 GAD 中，促肾上腺皮质激素释放激素受体 1（CRHR1）、多巴胺受体 D3（DRD3）、核受体亚家族 C 组 1 成员（NR3C1）和磷酸二酯酶 1A（PDE1A）的变体与度洛西汀的反应相关。仅 CRHR1 的 rs4792888 显示出与度洛西汀在 MDD 中的反应有一定程度的关联（GAD 中的 P=0.029，MDD 中的 P=0.054）。总之，CRHR1 的变异值得进一步研究其在焦虑症的发病机制及其治疗反应中的作用。
