Association Study of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor Gene with Clozapine-Induced Metabolic Syndrome: Preliminary Results

Abstract

The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR = 2.39; 95% CI: 1.05–5.41; p = 0.039; corrected p = 0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p = 0.005; corrected p = 0.03), but not in females (p = 0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p = 0.007; corrected p = 0.042 and p = 0.002; corrected p = 0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings.

rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor Is Associated with Diabetes Mellitus Type 2 in Caucasian Females with Obesity

“…However, fasting and postprandial plasma glucose were the only significant factors after adjusting for BMI. In another study [26], Val66Met polymorphism of BDNF gene (rs6265) was genotyped, and the serum levels of fasting glucose, triglyceride, and high density lipoprotein cholesterol were measured. There was a trend indicating a significant association between the homozygous Met/Met genotype and prevalence of metabolic syndrome in male patients (OR   2.39, 95% CI 1.05-5.41).…”

Effect of the rs10767664 Variant of the Brain-Derived Neurotrophic Factor Gene on Weight Change and Cardiovascular Risk Factors in Morbidly Obese Patients after Biliopancreatic Diversion Surgery

“…For example, an association between the rs4074134- BDNF minor allele and diabetes mellitus type 2 were reported [26], and this variant was associated with BMI, waist circumference, fasting and postprandial plasma glucose, insulin and HOMA-IR in subjects without diabetes mellitus. In another study, the rs6265 variant showed a significant association between the homozygous Met/Met genotype and prevalence of metabolic syndrome in male patients [27]. …”

Interplay of Brain-Derived Neurotrophic Factor and Cytokines in Schizophrenia

“…In schizophrenia, as in obesity, there is an imbalance between adiponectin and the proinflammatory cytokines TNF-α and IL-6 (70). Also, BDNF deficiency has been reported in increased food intake, hyperphagia and obesity (71). Obesity itself does not affect the value of BDNF in the serum in adults (72), but BDNF levels in plasma were decreased in patients with Metabolic Syndrome (MetS) compared with control subjects (73) (Figure 1D).…”

“…Obesity itself does not affect the value of BDNF in the serum in adults (72), but BDNF levels in plasma were decreased in patients with Metabolic Syndrome (MetS) compared with control subjects (73) (Figure 1D). For the first time, Zhang et al (2013) tested the relationship between the BDNF Val66Met polymorphism and MetS in patients with schizophrenia under long-term clozapine treatment. BDNF serum levels appeared to be associated with clozapine-induced MetS, and that effect is only evident in male patients (71).…”

“…For the first time, Zhang et al (2013) tested the relationship between the BDNF Val66Met polymorphism and MetS in patients with schizophrenia under long-term clozapine treatment. BDNF serum levels appeared to be associated with clozapine-induced MetS, and that effect is only evident in male patients (71).…”