Gene expression in visceral and subcutaneous adipose tissue in overweight women.

Excess weight and obesity are common health problems with multifactorial and polygenic causes. Abdominal or visceral obesity is associated with a higher risk of obesity related complications. The aim of the study was to evaluate differentially expressed genes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 overweight women undergoing elective laparoscopic cholecystectomy. Following expression profiling using microarrays, a set of 294 genes that exhibited differential expression between VAT and SAT was further analyzed to test the functional correlation of gene sets using the Gene Set Enrichment Analysis method. To confirm the functional pathways involved in differential expression between SAT and VAT, additional pathway analysis was done using the GeneGo MetaCore software and the Ingenuity Pathway Analysis. Ten differentially expressed genes were selected according to the microarray data, with seven exhibiting significant differential expression in the RT-PCR experiments. The data from this preliminary study suggest enrichment of inflammation and oxidative stress related pathways in VAT, while insulin homeostasis pathways as well as pathways pertaining to several growth factors are enriched in SAT.

Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents.

Obesity in children and adolescents is a worldwide health problem, characterized by various somatic, psychosocial and psychiatric complications, and is often associated with adult obesity and related complications. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with important roles in feeding behavior, food intake regulation, energy metabolism and weight control. A common polymorphism of the BDNF genotype (Val66Met) has been associated with various forms of eating disorders, alterations in body mass index (BMI) values and obesity in adult populations. The aim of this study was to determine the association between the gene variants of the BDNF Val66Met polymorphism and obesity in 300 healthy Caucasian children and adolescents of the same ethnic background of Croatian origin, subdivided according to the BMI percentile, but without any form of eating disorders. The frequency of the Met/Met, Met/Val and Val/Val genotypes, Met and Val alleles, and Met carriers (the combined Met/Met and Met/Val genotypes versus the homozygous Val/Val genotype) differed significantly between underweight, normal weight, overweight and obese children, and the presence of one or two Met alleles contributed to this significant effect. These results showed for the first time the significant association between the presence of one or two Met alleles and obesity in ethnically homogenous groups of healthy Caucasian children and adolescents. These data confirmed the major role of BDNF in energy metabolism, food regulation and BMI.

The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder.

OBJECTIVES: Psychotic symptoms frequently occur in veterans with combat-related posttraumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) plays a major role in neurodevelopment, neuro-regeneration, neurotransmission, learning, regulation of mood and stress responses. The Met allele of the functional polymorphism, BDNF Val66Met, is associated with psychotic disorders. This study intended to assess whether the Met allele is overrepresented in unrelated Caucasian male veterans with psychotic PTSD compared to veteran controls. METHODS: The BDNF Val66Met variants were genotyped in 576 veterans: 206 veterans without PTSD and 370 veterans with PTSD subdivided into groups with or without psychotic features. RESULTS: Veterans with psychotic PTSD were more frequently carriers of one or two Met alleles of the BDNF Val66Met polymorphism than veterans with PTSD without psychotic features and veterans without PTSD. CONCLUSIONS: The study shows that veterans with psychotic PTSD carried more Met alleles of the BDNF Val66Met than non-psychotic veterans with PTSD or veterans without PTSD. The results might add further support to the hypothesis that psychotic PTSD is a more severe subtype of PTSD.

Insomnia, platelet serotonin and platelet monoamine oxidase in chronic alcoholism.

Insomnia is a common sleep disorder frequently occurring in chronic alcoholic patients. Neurobiological basis of insomnia, as well as of alcoholism, is associated with disrupted functions of the main neurotransmitter systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Blood platelets are considered a limited peripheral model for the central 5-HT neurons, since both platelets and central 5-HT synaptosomes have similar dynamics of 5-HT. Platelet 5-HT concentration and platelet monoamine oxidase type B (MAO-B) are assumed to represent biomarkers for particular symptoms and behaviors in psychiatric disorders. The hypothesis of this study was that platelet 5-HT concentration and platelet MAO-B activity will be altered in chronic alcoholic patients with insomnia compared to comparable values in patients without insomnia. The study included 498 subjects: 395 male and 103 female medication-free patients with alcohol dependence and 502 healthy control subjects: 325 men and 177 women. The effects of early, middle and late insomnia (evaluated using the Hamilton Depression Rating Scale), as well as sex, age and smoking on platelet 5-HT concentration and platelet MAO-B activity were evaluated using one-way ANOVA and multiple regression analysis by the stepwise method. Platelet 5-HT concentration, but not platelet MAO-B activity, was significantly reduced in alcoholic patients with insomnia compared to patients without insomnia. Multiple regression analysis revealed that platelet 5-HT concentration was affected by middle insomnia, smoking and sex, while platelet MAO activity was affected only by sex and age. The present and previous data suggest that platelet 5-HT concentration might be used, after controlling for sex and smoking, as a biomarker for insomnia in alcoholism, PTSD and in rotating shift workers.

Association study of a functional catechol-o-methyltransferase polymorphism and cognitive function in patients with dementia.

A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions.

Suicide attempt, smoking, comorbid depression, and platelet serotonin in alcohol dependence.

The risk of suicide in patients with alcoholism increases if alcoholism is related to comorbid depression. Both alcoholism and suicidal behavior are associated with reduced serotonin (5-hydroxytryptamine [5-HT]) function. Because suicide is enormous public health problem worldwide, to prevent suicide attempts, it is important to find peripheral marker of suicidal behavior. The aim of this study was to assess whether platelet 5-HT concentration is altered in alcoholic patients with or without suicide attempt. Platelet 5-HT concentration was evaluated in 397 male and 108 female ethnically homogenous medication-free patients with alcoholism, subdivided according to smoking status, comorbid depression, and a history of suicide attempt and in 450 male and 139 female healthy control (nonsuicidal) subjects. Suicide attempt was assessed by two measures: according to the score 4 on the item 3 from the Hamilton Rating Scale for Depression and according to the Structured Clinical Interview regarding suicidal attempt during lifetime. Both male and female patients with alcoholism who were nonsmokers had significantly lower platelet 5-HT concentration than the corresponding healthy subjects. Multifactor analyses of variance revealed the significant effects of alcoholism and smoking, but the lack of significant effects of suicide attempt, sex, or comorbid depression, and no interactions between variables, on platelet 5-HT concentration. Platelet 5-HT concentration did not differ significantly between suicidal patients compared with nonsuicidal patients with alcoholism. Because the results from the present study showed similar platelet 5-HT values between patients with or without a history of suicide attempt, our data did not support the hypothesis that platelet 5-HT concentration might be used as a peripheral marker of the pronounced suicidal behavior in alcoholism.

Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders.

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.

The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNF polymorphism (BDNF Val66Met) was reported to influence the effects of stressful life events or childhood adversity on depression and suicidal behaviour in various psychopathologies. The study evaluated the association between BDNF Val66Met variants and suicide, committed with violent or non-violent methods, in victims with or without stressful childhood experience. METHODS: BDNF Val66Met polymorphism was genotyped on 560DNA samples from 359 suicide victims and 201 control subjects collected on autopsy from unrelated Caucasian subjects and subdivided according to gender, method of suicide, and influence of childhood adversity. RESULTS: A similar frequency of BDNF Val66Met variants was found between all included suicide victims and the control groups, and also between the male groups. The frequency of the combined Met/Met and Met/Val genotypes and the homozygous Val/Val genotype was significantly different between the female suicide victims and female controls, between the female suicide victims who used violent suicide methods and female controls, and between all included suicide victims with or without stressful life events. The combined Met/Met and Met/Val genotypes contributed to this significance. LIMITATION: A small group of suicide victims with available data on childhood adversity was studied. CONCLUSIONS: The combined Met/Met and Met/Val genotypes of the BDNF Val66Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. These results confirm a major role of BDNF in increased vulnerability to suicide.

Association study of a functional catechol-O-methyltransferase (COMT) Val108/158Met polymorphism and suicide attempts in patients with alcohol dependence.

Alcohol dependence is frequently associated with aggressive and suicidal behaviour. Genetic factors contribute to both behaviours. Candidate genes, related to suicide and aggression, include genes involved in serotonin, norepinephrine and dopamine pathways. The enzyme catechol-O-methyl transferase (COMT) degrades dopamine, epinephrine and norepinephrine. The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lower COMT activity. This polymorphism is associated with aggressive and suicidal behaviour, but the literature data on this relationship is contradictory and inconsistent. The hypothesis of this study was that Met allele carriers with alcohol dependence will have a higher frequency of suicide attempts compared to other genotypes. Participants were 312 male and 81 female medication-free patients with alcohol dependence and 487 male and 122 female unrelated, non-suicidal medication-free Caucasian healthy subjects. Our results showed significant (χ2 test with standardized residuals) differences in the frequencies of COMT variants in all alcoholics, alcoholics with different comorbid diagnoses, and in male but not in female alcoholics, with or without suicide attempts. Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.

Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD. METHOD: BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A χ(2) test, with Bonferroni correction and standardized residuals were used to evaluate the data. RESULTS: Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD. CONCLUSION: Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD.

Association study of a functional catechol-O-methyltransferase polymorphism and smoking in healthy Caucasian subjects.

Tobacco smoking is a global health problem. The association of a functional common polymorphism in the catechol-o-methyltransferase gene (COMT Val158Met) with smoking behavior has been extensively studied, but with divergent findings. In the present study the frequency of COMT genotypes and alleles was evaluated in 578 male and a smaller group of 79 female unrelated, medication-free Caucasian healthy subjects of Croatian origin. Smokers were classified as subjects smoking