Anna Grzywacz

Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum

Recent studies provide evidence that anxiety disorders may be linked to malfunction of serotonin neurotransmission or impaired activity of enzymes metabolising the catecholamines. Functional polymorphisms in the MAO-A uVNTR promoter gene, the COMT gene (Val158Met) exon 4, and the 5-HTT promoter gene (44 bp ins/del) were investigated in 101 patients with phobic disorders of the anxiety spectrum and 202 controls matched to the patients for sex, age and ethnicity. There were no significant differences between controls and patients in the allele and genotype frequencies of the 5-HTT and COMT gene polymorphisms. The frequency of >3 repeat alleles of the MAO-A gene polymorphism was significantly higher in female patients suffering from anxiety disorders, specifically panic attacks and generalized anxiety disorder. There was also a trend for the more frequent presence of >3 repeat alleles in female patients with agoraphobia and specific phobia, in contrast to female patients with social phobia, who did not differ from controls. The results support a possible role of the MAO-A gene in anxiety disorders.

Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence

The paper focuses on such candidate gene polymorphisms that alter alcoholism-related intermediate phenotypes including: dopaminergic system polymorphic variants (DRD2 -141C Ins/Del in promoter region, exon 8 and DRD2 TaqI A and DAT 40bp VNTR genes polymorphisms) that cause predisposition to severe alcoholism (haplotype Ins/G/A2); COMT Val158Met gene polymorphism related to differences in executive cognitive function and 5-HTT gene promoter polymorphism, which alters stress response and affects anxiety and dysphoria. The transmission disequilibrium test (TDT) was used in the study. One hundred Polish families with alcohol dependence were recruited. The control subjects for the case-control study were 196 ethnically and gender matched healthy individuals. It was found that DRD2 TaqIA and DAT gene polymorphisms contained statistically significant differences in allele transmission. In the homogenous subgroups of patients with early onset and with withdrawal complications a statistically significant preferential A2 allele transmission was found in DRD2 TaqIA gene polymorphism. The alleles and genotypes distribution of the investigated polymorphisms did not differ significantly between the alcoholics and the controls in the case-control study. The results confirmed the fact that the candidate genes (DRD2 and DAT) are partially responsible for the development of alcohol dependence. The results are also in agreement with the hypothesis that there are various subtypes of alcohol dependence, which differ depending on their genetic background. Meanwhile, the currently available pharmacological therapies for alcoholism treatment are effective in some alcoholics but not for all of them. Some progress has been made in elucidating pharmacogenomic responses to drugs, particularly in the context of Clonninger and Lesch typology classification system for alcoholics.

Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene in alcohol dependence: Family and case control study

AIM Matrix metalloproteinases (MMP) are extracellularly acting endopeptidases, whose substrates are extracellular matrix and adhesion proteins. In the gene polymorphism studies MMP-9 has been suggested to be involved in the pathogenesis of heart disease, cancer, bipolar disorder, and schizophrenia. In animal models MMP-9 has been shown to play a key role in a variety of neuronal plasticity phenomena, including learning and memory as well as drug addiction. METHOD We studied 139 families, Caucasians, with no history of psychiatric disorder of ICD-10 other than alcohol or nicotine dependence. The control subjects were 136 unrelated individuals, matched for ethnicity and gender, with no mental disorder. Alcohol and family history of alcoholism were assessed by means of a structured interview, based on the Polish version of SSAGA (Semi-Structured Assessment on Genetics in Alcoholism). RESULTS We found a statistically significant preferential transmission of the T allele (known to produce higher gene transcriptional activity) from parents to alcoholics (59%, p=0.046). In a case-control study genotype TT and T alleles were significantly more frequent in the alcoholics than in the controls (OR=2.6). CONCLUSION Our results suggest that the MMP-9 gene may play a role in the pathogenesis of alcohol dependence.

The association of catechol-O-methyltransferase genotype with the phenotype of women with eating disorders.

OBJECTIVE The modern brain imaging studies in patients with eating disorders have shown that neurotransmitting regulation differs distinctly from control groups. These disturbances have involved serotonin and dopamine system can be inherited and conditioned by genes. The aim of this work has been the analysis of association between eating disorders of anorexia or bulimia type and two polymorphisms of COMT gene. The additional goal has been the analysis of correlation among chosen personality and psychological features of ED women with the research gene variations. METHODS The group taken as research sample consisted of adult 103 women (mean age=22.45+/-3.8 years) suffered from serious ED with illness lasting minimum 12 months. According to ICD-10 criteria, 61 women were diagnosed as anorexia nervosa while as 42 bulimia nervosa. The control group consisted of 108 ethnically and age-matched women with excluded major psychiatric disorders. The study groups were filling up the Eating Disorders Inventory and the Temperament and Character Inventory. The genotype of catechol-O-methyltransferase in two polymorphisms rs4633 (his102his) and rs4680 (val158met) was determined. RESULTS The joined GGCT genotype increased the risk of having ED over fivefold and over sevenfold the risk of having bulimia. Also haplotype CT was found three times more often in ED women than in controls. Besides the homozygous genotypes, AACC and GGCC reduced substantially the relative risk of ED. The patients with the low activity COMT genotype scored higher in EDI scales ineffectiveness, drive for thinness and perfectionism. The high activity genotype was connected with underdeveloped features of character marked in the poor cooperativeness and the poor self-directedness. These connections among genotypes and character scales were more expressed in bulimia group.

Family-based study of brain-derived neurotrophic factor ( ΒDNF) gene polymorphism in alcohol dependence

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to the nerve growth factor family, which are responsible for the proliferation, survival and differentiation of neurons. BDNF is thought to be involved in the pathogenesis of bipolar disorder, schizophrenia, eating disorders and addiction. We hypothesize that a functionally relevant polymorphism of the BDNF gene promoter may be associated with the pathogenesis of alcohol dependence. We performed an association study of 141 families with alcohol dependence. One hundred and thirty-eight healthy control subjects were matched based on ethnicity and gender. An association between the BDNF Val66Met gene polymorphism and alcoholism was not found.

Genetics of Lesch's typology of alcoholism

It is widely accepted that dopamine and serotonin (5-HT) neurotransmission can be critically involved in the development of alcohol abuse and alcohol dependence. Leschs typology of alcoholism has been gaining increasing popularity as it qualitatively differentiates patients into different treatment response subgroups. The aim of the present study was to evaluate a possible genetic background of Leschs typology with special emphasis placed on dopamine- and serotonin-related genes. 122 alcoholics (the mean age: 35+/-9 years) were investigated. According to Leschs typology, 58 patients were of type I, 36 patients of type II, 11 patients of type III, and 17 patients of type IV. Alcohol drinking and family history was assessed by means of a structured interview, based on the Semi-Structured Assessment for the Genetics of Alcoholism. 150 control subjects without psychiatric disorders were also recruited. The control group was ethnically-, age- and gender-matched to the patients. The DRD2 TaqIA, exon 8, and promoter -141C ins/del polymorphisms as well as COMT Val158Met, 5HTT 44 bp del in promoter, and DAT 40 bp VNTR polymorphisms were detected by means of PCR. No significant differences were observed when the whole group of alcoholics and the controls were compared. Similarly, there were no differences between either the Lesch type I or type II alcoholics and the control subjects. No significant differences were observed between type I and type II alcoholics. Alleles frequencies were not calculated for the Lesch type III and type IV alcoholics since the number of patients was too small. The present results argue against any major role of the investigated polymorphisms in either Lesch type I or type II alcoholism. More comprehensive studies are needed to define the role of the investigated polymorphisms in Lesch type III and type IV alcoholism.

Association of Eating Disorders with Catechol-O-Methyltransferase Gene Functional Polymorphism

Aim: The aim of this study was to evaluate functional catechol-O-methyltransferase (COMT) genetic variation as a risk factor for eating disorders (ED). Method: Eighty women receiving treatment for serious ED (52 for anorexia nervosa, 28 for bulimia nervosa) and 116 age-matched females in the control group underwent COMT genotyping for polymorphism in exon 4 (codon 158). Both the low-activity allele and the high-activity allele (H) were determined. Results: The H/H genotype was twice as frequent in the ED group as in the control group (52.5% in the ED group and 25% in controls, χ2 = 15.5, d.f. = 2, p < 0.001, odds ratio = 3.343). The H/H genotype was found in 57.7% of anorexia nervosa patients (χ2 = 16.860, p < 0.001, Hardy-Weinberg equilibrium = 0.003, odds ratio = 4.202). The H allele (val) was discovered in 66.9% of ED patients in comparison to 47.8% of patients from the control group (χ2 = 13.89, p < 0.001, odds ratio = 6.088). In the anorexia group, H allele frequency was enhanced even higher (70.2 vs. 47.8%, χ2 = 14.48, p < 0.001, odds ratio = 8.175). The genotype associations in the subgroup of bulimia patients were not significant, but a trend for a higher frequency of the H allele was found (p = 0.084, odds ratio = 5.309). Conclusions: These findings seem to suggest that a turnover of catecholamines, connected with polymorphism determining high activity of COMT enzyme, is connected with the risk of ED occurrence, particularly anorexia nervosa. The risk is significantly higher for women with an allele of higher activity.

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients

BACKGROUND D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail. METHODS Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12. RESULTS Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects. CONCLUSION This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.

Psychosocial characteristics of benzodiazepine addicts compared to not addicted benzodiazepine users.

OBJECTIVE Although the addictive potential of benzodiazepine drugs has been known for a long time, new cases of benzodiazepine addictions keep emerging in clinical practice. The etiology of benzodiazepine addiction seems to be multifactorial. The objective of this study was to investigate and measure psychological and situational factors differentiating benzodiazepine addicts from not addicted users. METHODS A psychological profile and situational factors of patients with the diagnosis of benzodiazepine addiction and a carefully matched control group of not addicted former benzodiazepine users were defined and investigated. RESULTS The investigated benzodiazepine addicts differed significantly from the control group in particular psychological dimensions, such as higher neuroticism and introversion, prevalence of emotional rather than task based coping mechanisms. There were also significant correlations between the addiction and situational factors such as BZD - treatment circumstances and adverse life events previous to the treatment. CONCLUSIONS The results show psychological and situational factors which differentiate benzodiazepine addicts from not addicted benzodiazepine users. This data suggest that benzodiazepine addiction might be associated with higher neuroticism, introversion and less effective coping mechanisms as well as with previous accumulation of adverse life events and/or inadequate BZD treatment. The psychological and situational factors mentioned above might be considered as potential risk factors for benzodiazepine addiction.

Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: results from a larger multicenter association study

Genetic variants of the alcohol‐metabolizing enzyme ADH4, located on chromosome 4q22–4q23, have been related to alcohol dependence (AD) risk in previous research. The aim of this association study in a large multicenter sample of alcohol‐dependent individuals and controls is to confirm ADH4 single nucleotide polymorphism (SNP) and haplotype association with AD and relevant related phenotypes. One thousand, six hundred and twenty‐two (1622) inpatient subjects and 1469 control subjects with DSM‐IV. AD from four addiction treatment centres were included. Characteristics of AD and related phenotypes including alcohol withdrawal, Cloningers type I and II and first ages of drinking, regular drinking and AD onset were obtained using standardized structured interviews. After subjects were genotyped for 2 ADH4 polymorphisms, single SNP case‐control and haplotype analyses were conducted. Both variants—rs1800759 and rs1042364—and the A‐A and C‐G haplotypes were significantly related to AD across samples. Furthermore, associations with AD‐related phenotypes and subtypes revealed a potential protective influence of this haplotype. This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. While the rs1800759 and rs1042364 A‐A haplotype had a potential protective influence on the risk for several AD‐related phenotypes, this effect is rather small compared to functional variants of other alcohol or acetaldehyde‐metabolizing enzymes like ALDH2*2 or ADH1B*2.