Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
JAMA Psychiatry. 2013 Oct;70(10):1011-9. doi: 10.1001/jamapsychiatry.2013.187.
There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown.
To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123,865).
Noninterventional studies.
Difference in BMI and/or fat mass between CRTC1 genotype groups.
Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (P(adjusted) = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m² lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m² lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r² = 0.7) was associated with lower BMI (sample 5, n = 123,865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02).
These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry.
精神科患者中肥胖的患病率很高，这可能导致代谢并发症并降低预期寿命。CREB 调节转录共激活因子 1（CRTC1）基因参与动物模型中的能量平衡和肥胖，但它在人类肥胖中的作用尚不清楚。
确定 CRTC1 基因内的多态性是否与精神科患者和普通人群的肥胖标志物相关。
设计、设置和参与者：瑞士洛桑和日内瓦大学医院以及瑞士洛桑的一家私人诊所进行回顾性和前瞻性数据分析以及基于人群的样本。在服用导致体重增加的精神药物的精神科门诊患者的发现队列中（样本 1，n = 152），研究了 3 个 CRTC1 多态性对体重指数（BMI）和/或脂肪量的影响。然后，在 2 个独立的精神科样本（样本 2，n = 174 和样本 3，n = 118）和 2 个白种人基于人群的样本（样本 4，n = 5338 和样本 5，n = 123865）中复制与 BMI 显著相关且经多重比较 Bonferroni 校正后仍具有统计学意义的 CRTC1 变异体。
非干预性研究。
CRTC1 基因型组之间 BMI 和/或脂肪量的差异。
在第一个精神科样本中测试的 CRTC1 变体中，只有 rs3746266A>G 与 BMI 相关（P（调整）=.003）。在 3 个精神科样本中，rs3746266 G 等位基因携带者的 BMI 低于非携带者（AA 基因型）（样本 1，P =.001；样本 2，P =.05；样本 3，P =.0003）。在合并分析中，排除服用其他导致体重增加的药物的患者后，G 等位基因携带者（n = 98）的 BMI 比非携带者（n = 226）低 1.81kg/m²（P <.0001）。在年龄小于 45 岁的女性中观察到最强的关联，G 等位基因携带者（n = 25）的 BMI 比非携带者（n = 48）低 3.87kg/m²（P <.0001），解释了 BMI 变异的 9%。在基于人群的样本中，rs6510997C>T（rs3746266 G 等位基因的替代物；r² = 0.7）的 T 等位基因与 BMI（样本 5，n = 123865；P =.01）和脂肪量（样本 4，n = 5338；P =.03）相关。与脂肪量相关性最强的是绝经前女性（n = 1192；P =.02）。
这些发现表明，CRTC1 有助于精神科患者和普通人群肥胖的遗传。识别高风险患者有助于更好地个体化精神科的药物治疗。
