Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects

Behavioral and Brain Functions Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects Jian-Xin Zhou 0 1 3 He-Chao Li 0 1 3 Xue-Jun Bai 2 3 Bao-Cheng Chang 0 1 3 Chun-Jun Li 0 1 3 Pei Sun 0 1 3 Li-Ming Chen 0 1 3 0 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin , China 1 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health) , Metabolic 2 Center of Psychology and Behavior, Tianjin Normal University , Tianjin , China 3 Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin , China Background: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM. Methods: A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit. Results: In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 5.19 pg/ml) and Val/Val (83.83 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 5.35 vs. 79.84 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = 0.346, p < 0.01), depression scores (r = 0.486, p < 0.01) and HbA1c (r = 0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM. Conclusions: The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects. Type 2 diabetes (T2DM); Depression; Brain-derived neurotrophic factor (BDNF); Polymorphism - Introduction Depression and type 2 diabetes (T2DM) are two of the most prevalent and devastating diseases. There is a strong association between T2DM and depression [1,2]. Epidemiological data indicates that approximately 26-30% of diabetic patients suffer from differential severity of depression, excessive above that of the normal population [3,4]. Moreover, the mortality rate is significantly higher among patients with T2DM and depression than among patients with diabetes without depression [5]. Therefore, it is important to study the etiology of depression with T2DM. Brain-derived neurotrophic factor (BDNF) is a member of the neurothophic factor family, which plays a key role in regulating survival, growth and maintenance of neurons [6]. It has been suggested that reduction in BDNF expression is a pathogenic factor common to Alzheimers disease and major depression [7,8]. For example, a study by Karege et al. have reported that major depressive patients exhibited significantly lower levels of serum BDNF compared with normal controls [9,10], whereas the use of antidepressants led to an up regulation of BDNF in the hippocampus of subjects with major depression [8]. The association between BDNF and depression is also supported by animal studies in which infusion of recombinant BDNF exerted antidepressant effect [11]. The human BDNF gene has been mapped to chromosome 11p13 and a common single nucleotide polymorphism (SNP) consisting of a missense change (G196A), which produces a valine (Val) to methionine (Met) change, has been identified in the coding exon of the BDNF gene at position 66 (Val66Met) [12]. The Val66Met polymorphism in the BDNF gene has been shown to impact intracellular trafficking and activity-dependent secretion of BDNF [13]. Clinical studies demonstrate that the Met allele is associated with decreased hippocampal volume in both normal and depressed patients and with decreased executive function and cognition [13,14] Hong et al. first reported that BDNF Val66Met polymorphism was associated with major depressive disorders in a Caucasian population [15]. Subsequently, increasing clinical studies have confirmed that the Met allele was more commonly found among individuals with mood disorders [16-18]. In line with these clinical findings, animal study showed that a variant BDNF mouse (BDNF Met/Met) reproduced the phenotypic hallmarks of humans with this variant allele, and exhibited increased anxiety-related behaviors [19]. Paradoxically, Tsai SJ et al. reported a higher incidence of depression in Val, not Met carriers [20]. Currently, it is still unclear what the consequences of the Val66Met polymorphism are on the brain function, as both alleles have been associated with different disease processes, including emotion response [21], esoghageal hypersensitivity [22], individual's sexual activities [23] and depression [15,24,25]. Of interest, several studies have shown that the degree of therapeutic response to antidepressants is associated with the BDNF Val66Met polymorphism, suggesting that BDNF gene may be a good candidate gene for the pharmacogenetic study of antidepressants [7]. Furthermore, a decrease in BDNF concentration has been strongly linked to T2DM. BDNF was reported to improve glucose metabolism insulin sensitivity, and reduce food consumption [26]. The direct role of BDNF in metabolism is supported by studies on BDNF-deficient mice, which developed diabetes and obesity in early adulthood [27]. Animals studies have also shown that BDNF has important effects on the regulation of eating behavior [28] and modulation of the secretion and activities of insulin, leptin, ghrelin and pro-inflammatory cytokines associated with energy homeostasis[29]. These findings sug (...truncated)