P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients Geza Nagy a , Zsolt Ronai b , Aniko Somogyi a , Maria Sasvari-Szekely b , Omar Abdul Rahman b , Attila Mate a , Timea Varga a , Zsofia Nemoda b, ⁎ a Semmelweis University, 2nd Department of Internal Medicine, Budapest, 1088, Szentkiralyi u. 46, Hungary b Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest, 1088, Puskin u. 9, Hungary abstract article info Article history: Received 20 June 2008 Received in revised form 27 August 2008 Accepted 27 August 2008 Available online 4 September 2008 Keywords: Hospital Anxiety and Depression Scale P2RX7 Serotonin transporter TPH2 Aims: Both diabetes mellitus and major depression are public health concerns, and the co-occurrence of these illnesses is highly frequent. Acting as a potential risk factor, hyperglycemia might facilitate the manifestation of depression in patients genetically predisposed to affective disorders. In the present study, candidate polymorphisms of the serotonin transporter, the tryptophan hydroxylase 2 (TPH2) genes, as well as of the brain-derived neurotrophic factor BDNF, and the P2RX7 purinergic receptor genes were analyzed in Hungarian diabetic population. We assumed that genetic influence would be stronger on depressive symptoms in the “poor glycemic control” group (PC: HbA 1C N 7%) compared to the “good glycemic control” group (GC: HbA 1C ≤ 7%). Methods: After excluding patients with current antidepressant medication, 218 diabetic patients' Hospital Anxiety and Depression Scale (HADS) scores were used in multivariate analysis of variance. Based on the HbA 1C levels, 81 patients were in the GC group, and 137 belonged to the PC group. Results: After correcting for multiple testing, only the association of the P2RX7 Gln460Arg (rs2230912) polymorphism with depressive symptoms remained significant. Patients with the G-allele (Arg-variant) had higher scores on the HADS depression scales (p = 0.007). A gene x glycemic control interaction (p = 0.032) was observed on the anxiety scale at the TPH2 promoter polymorphism: the -703T-allele decreased anxiety scores only in the GC group (p = 0.008). Conclusions: Our results support the role of the P2RX7 rs2230912 G-allele in the development of depression and emphasize the importance of good glycemic control, acting as a potential protective factor in diabetic patients. © 2008 Elsevier Inc. All rights reserved. 1. Introduction The prevalence of major depression is two times higher among diabetic patients compared to controls, affecting 11–32% of the diabetic population depending on the method of assessment (Anderson et al., 2001). During depressive episodes, the poor adherence to antidiabetic treatments can cause problems in the management of diabetes mellitus (DM). In turn, poor glycemic control increases the risk for microvascular and macrovascular complications resulting in lower quality of life, as well as higher morbidity and mortality in diabetic patients (Ciechanowski et al., 2000). Even though the relationship between DM and depression has been investigated from many points of view, the explanation of the comorbidity is still unclear. One hypothesis suggests that poor glycemic control may adversely affect mood. In an early study, Lustman and his colleagues demonstrated that hyperglycemia can provoke anxiety symptoms in type 1 diabetic patients using hyperglycemic clamp (Lustman et al., 1981). Another group has shown that depressive symptoms get better by improving metabolic control in type 2 diabetic patients (Testa and Simonson, 1998). Higher glycated hemoglobin (HbA 1C ) levels pre- dicted reduced responsiveness to antidepressant interventions and worse course of depression in a study conducted by Lustman and co- workers over 5 years (Lustman et al., 1997). As hyperglycemia is responsible for the development of micro- and macrovascular complications, poor glycemic control may be a key factor in the development of depression among diabetic patients (Lustman et al., 2000). In the development of depression both genetic susceptibility and environmental factors (e.g. childhood abuse and exposure to stressful life events) play an important role, probably via gene x environment interaction (Caspi et al., 2003). It is not known whether the development of depressive symptoms is augmented by metabolic factors, such as poor glycemic control. To test this possibility, we investigated four depres- sion-related candidate genes in a Hungarian diabetic population. In Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1884–1888 Abbreviations: 5-HTTLPR, serotonin transporter gene-linked polymorphic region; BDNF, brain-derived neurotrophic factor; P2RX7, purinergic receptor P2X, ligand-gated ion channel, 7; TPH2, tryptophan hydroxylase 2; DM, diabetes mellitus; GC, good glycemic control group (HbA 1C ≤ 7%); PC, poor glycemic control group (HbA 1C N 7%). ⁎ Corresponding author. Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, POB 260, H-1444, Hungary. Tel.: +36 1 4591500x4017; fax: +36 1 2662615. E-mail address: nemzso@puskin.sote.hu (Z. Nemoda). 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.08.021 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnpbp