Manuscrit VI: Influence of CRTC1 polymorphisms on body mass index in patients with psychotropic treatments. Manuscrit en préparation

Le CRTC1 a récemment été montré comme faisant partie du cycle de la leptine et jouant un rôle dans la régulation de la satiété et de l’homéostasie de l’énergie dans des modèles animaux. Cette étude décrit l’influence de trois SNPs du CRTC1, sélectionnés de façon exploratoire, sur l’IMC et la prise de poids dans deux populations différentes provenant de l’Etude prise de poids Genève (N=152) et de l’Etude Suivi métabolique Lausanne (N=174).

Le SNP rs3746266A>G du gène CRTC1, amenant à un changement d’acide aminé, a été associé à une différence de l’IMC. Les porteurs de l’allèle G ont un IMC significativement plus bas que les individus AA, le génotype GG étant donc associé à un effet protecteur.

Cet effet est plus marqué chez les femmes pré-ménopausées que chez les femmes post-ménopausées et n’est pas visible chez les hommes. Une différence allant jusqu’à 2.9 kg/m² entre les deux génotypes a ainsi été observée chez les femmes pré-ménopausées. Ce résultat positif trouvé dans la première cohorte a été répliqué dans la deuxième. Les deux autres SNPs sélectionnés (rs10402536 et rs8104411) n’ont pas montré d’associations significatives avec l’IMC. Cette étude est, à notre connaissance, la première à démontrer l’influence d’un polymorphisme du CRTC1 sur l’IMC des patients sous psychotropes.

Chapitre IV 112

Influence of CRTC1 polymorphisms on body mass index in patients with psychotropic treatments.

Eva Choong (1), Quteineh Lina (1), Mehdi Gholam-Rezaee (4), Jean-René Cardinaux (2), Maria Dobrinas (1), Guido Bondolfi (6), Manuela Etter (6), Laurent Holzer (5), Pierre Magistretti (3,9), Michel Gaillard (5), Armin von Gunten (5), Martin Preisig (5), Peter Vollenweider (8), Philippe Conus (5), Murielle Bochud (7), Chin B Eap (1,10)

List and positions of co-authors is not definite.

1Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Hospital of Cery, Prilly, Switzerland.

2Centre for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.

3Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.

4Centre of Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Hospital of Cery, Prilly, Switzerland.

5Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.

6Department of Mental Health and Psychiatry, University Hospital of Geneva, Geneva, Switzerland.

7Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

8Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

9Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

10School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

Manuscrit en préparation

Chapitre IV 114 Abstract

Weight gain is one of the most frequent side-effect associated with the use of atypical antipsychotics and/or mood stabilisers, with an important interindividual variability. The CREB-regulated transcription coactivator (CRTC1) gene was recently reported to be involved in energy balance and satiety in animal models. The present study investigates the role of CRTC1 polymorphisms (rs10402536, rs8104411 and the non-synonymous rs3746266) on body mass index (BMI) in patients treated with psychotropic drugs. Two independent Caucasian psychiatric populations were included (n1=152 and n2=174 patients) and mixed-model analysis controlling for age, gender, type of drug, dose, and comedication causing weight-gain was performed. In the first cohort, lower BMIs were measured in carriers of the rs3746266G allele than in AA genotypes (p1=0.008), a finding confirmed in the second group (p2=0.048) and in the combined cohort (p<0.001), with an increased BMI of 1.6, 1.0 and 1.3 kg/m², respectively. When combining both cohorts, lower BMI (1.5 kg/m², p=0.020) were measured in women carriers of the rs3746266G allele (n=40) than in AA genotypes (n=78), but not in men (p=0.17). The strongest effect was observed in the premenopausal women group with 2.9 kg/m² higher BMI in AA genotype (n=38) compared to G carriers (n=23, p=0.005), while no differences between genotypes were measured in the postmenopausal women group (p=0.30). In conclusion, CRTC1 rs3746266 polymorphism was associated with differences in BMIs in patients receiving psychotropic drugs, an effect which seems to be restricted to premenopausal women.

1. Introduction

Several studies have demonstrated an increased mortality in psychiatric populations (1-3), due in part to the high cardiovascular risk factors linked to the illness and to several comorbidities including obesity, metabolic syndrome, lifestyle factors (smoking status) and also to the pharmacological treatment (Choong et al, submitted)(4-8). The strong effect on weight of atypical antipsychotics (AP) and of other drugs such as the mood stabilizers (MS) lithium and valproate (9-11) has been of growing concern for the health care management of patients. Thus, weight gain and obesity in the long term can lead to several metabolic complications such as dyslipidemia, insulin resistance, type 2 diabetes and cardiovascular diseases, which can ultimately reduce life expectancy by several years (12-15).This led to the establishments of guidelines to monitor the potential metabolic complications during AP treatment (16;17).

The cyclic AMP response element-binding protein (CREB)-regulated transcription coactivators (CRTCs, also called TORCs) comprise three members, namely CRTC1, CRTC2, and CRTC3 that are expressed in different tissues (18). They are localised in the cytoplasm in a phosphorylated form (19).

Following the activation by calcium or by cyclic AMP, CRTCs are dephosphorylated, shuttle to the nucleus, bind to CREB, and thereby enhance the transcription of CREB-dependent transcription genes (19-21). CRTC1 gene is of particular interest since it was recently associated with energy balance in mice models (22). CRTC1 knock-out mice were observed eating more and expending less energy, thus developing an obese feature under a normal diet (21;22). In the long term, the mutant mice presented a hypertriglyceridemia, a hyperglycemia and 2 to 3 times more white adipose tissue than their littermates (22). Because no difference was observed in other tissues, the authors concluded on a specific impact of CRTC1 on body weight, which might be specific to white adipose tissue.

Although the role of CRTC1 in obesity has not yet been elucidated, it was suggested that it might alter the expression of anorexigen neuropeptides and be involved in satiety (22). The CRTC1 is mainly expressed in the brain (22-24) and is a putative target for leptin in the hypothalamus, where it may transduce its anorexic effect by promoting the expression of neuropeptides mediating satiety (i.e.

the cocaine- and amphetamine-regulated transcript CART and the brain derived neurotrophic factor BDNF (22;25). Interestingly, CRTC1 has been associated with the regulation of CARTPT (CART prepropeptide) gene expression in vitro and CART was reported to inhibit food intake in response to leptin in arcuate neurons (22). In addition, a role in reproduction was also reported for CRTC1 even if this point is more controversial (21;22). The CRTC1 knockout mice were reported to be infertile and presented low luteinizing hormone (LH) levels (22) although this was not confirmed in another study

Chapitre IV 116 (21). The mechanism underlying infertility was supposed to be linked to the absence of CRTC1 stimulation on kisspeptin-1 (KISS1) expression (22).

The risk of obesity has a heritable component suggesting that it might be caused by genetic variations. In addition, significant inter-individual variability in weight gain was reported during psychotropic treatment, which might be due, among others, to genetic factors. Thus, a certain number of genes that showed consistent associations with antipsychotic-induced weight gain are already known (26-28). Given the strong effect of CRTC1 in mice, this gene might also play a role in obesity in humans. The present work analyses the association of human CRTC1 polymorphisms with BMI, weight gain during psychotropic treatment in two independent psychiatric populations treated with APs and/or with MS.

2 Materiel and Methods