Brain-derived neurotrophic factor Val⁶⁶Met polymorphism and alcohol-related phenotypes

Abstract

Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients.

In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown–Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence.

The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence.

There are few limitations of the study. The overall study sample size was large (N = 1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied.

In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence.

Introduction

Alcoholism, including alcohol dependence (APA, 2000), is a debilitating disorder which progresses and worsens over time. It is characterized by sensitization, tolerance, withdrawal and alcohol becoming the highest priority in a person's life. Chronic alcoholism affects neural pathways involved in the regulation of motivation, stress, reward and arousal. These neuronal circuits change and adapt to chronic alcohol exposure resulting in the development and maintenance of alcoholism and, after a chronic use, also in neurodegeneration (Gilpin and Koob, 2008). Alcoholism is a worldwide social and economic problem with a higher prevalence in men than in women (Schuckit, 2006). Neurobiology of alcoholism involves the alterations in neurotransmitter and stress systems: dopamine, endogenous opioids, GABA, glutamate, serotonin, corticotrophin releasing factor, neuropeptide-Y and others (Gilpin and Koob, 2008). Both environmental and genetic factors affect the risk of developing alcoholism. Contribution of environmental factors is modified by the genetic factors, a phenomenon called gene × environment interaction (Cloninger et al., 1981, Crabbe, 2002). Alcoholism, depression (Davis et al., 2008) and antisocial personality disorder (ASPD) (Galen et al., 2000) are frequently comorbid in the general population. In addition, alcohol dependence is associated with violent and suicidal behavior, as well as high aggression (Sher, 2006).

Alcoholism is a highly heritable trait, according to twin and adoption studies. A number of genes (Kohnke, 2008), including those regulating the function of brain-derived neurotrophic factor (BDNF), have been studied in the etiology of alcohol dependence. BDNF is a member of the neurotrophin family, with a myriad of different important functions in the regulation of neurogenesis, differentiation, survival, neuroplasticity, repair of neurons (Binder and Scharfman, 2004, Chao et al., 2006), cognition, adaptive processes underlying learning and memory, addiction (Russo et al., 2009), and various mental disorders (Russo-Neustadt, 2003). A single nucleotide polymorphism (SNP) resulting in valine (Val) to methionine (Met) substitution in the BDNF pre-domain coding region (Val66Met or rs6265) has been reported to be associated with different psychiatric disorders including substance abuse (Gratacos et al., 2007). This SNP has been associated with decreased activity-dependent BDNF secretion from the cultured hippocampal neurons (Egan et al., 2003). The Met allele is assumed to affect the abnormal intracellular packaging of the precursor of BDNF (proBDNF) and production of the mature BDNF (Chen et al., 2004).

Significant ethnic and population differences exist in the frequency of the BDNF Val66Met genotypes (Gratacos et al., 2007, Petryshen et al., 2010, Pivac et al., 2009), and the data on the association between BDNF Val66Met and alcoholism are conflicting and inconsistent: more non-replications in European American (Grzywacz et al., 2010, Sery et al., 2011), Taiwanese (Tsai et al., 2005) and Japanese (Matsushita et al., 2004) subjects, than positive associations (Gratacos et al., 2007, Shin et al., 2010) have been reported. As far as the results of the meta-analyses are concerned, different ethnic background of sample populations, methodological issues (diagnostic criteria, inclusion/exclusion criteria, the lack of uniformity in how outcomes are measured, poorly defined phenotypes), population stratification, and other non-genetic factors may contribute to difficulties in detecting significant allelic association with neurobiological phenotype (Walker et al., 2008). The relationship between BDNF Val66Met polymorphism and depression, violent and suicidal behavior is also inconsistent (Hong et al., 2011, Spalletta et al., 2010, Verhagen et al., 2010). To the best of our knowledge, only one study evaluated the association between BDNF Val66Met and alcohol related phenotypes in Japanese subjects (Matsushita et al., 2004), while no study evaluated associations of the BDNF Val66Met with alcohol related depression, aggression, suicidal behavior including prior attempt, delirium tremens, withdrawal syndrome, early/late onset and severity of the disease in the same group of medication-free Caucasian patients, from the same origin. The hypothesis of the study was that the BDNF Met allele will be associated with particular alcohol related phenotypes. Therefore, the aim of this study was to evaluate the association between the gene variants of the BDNF Val66Met polymorphism with alcohol dependence, in ethnically homogenous Caucasian alcoholic patients of the European origin, subdivided according to the presence/absence of alcohol related depression, aggression, suicidal attempt or behavior, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse and mild or severe alcohol dependence.