[Genetic polymorphism of cytokines IL-1ß, IL-4 and TNF-α as a factor modifying the impact of childhood adversity on schizophrenia symptoms]. / Geneticheskii polimorfizm tsitokinov IL-1ß, IL-4 i TNF-α kak faktor, modifitsiruyushchii vliyanie neblagopriyatnogo detskogo opyta na simptomatiku shizofrenii.

OBJECTIVE: Based on the hypothesis that activation of the immune system is one of the mechanisms of influence of early environmental factors on the onset and course of schizophrenia, we investigated the effects of the interaction of childhood adversity and IL-1ß rs16944, IL-4 rs2243250 and TNF-α rs1800629 polymorphisms on schizophrenia symptomatology. MATERIAL AND METHODS: The sample consisted of 546 patients with schizophrenia spectrum disorders. The presence of childhood adversity was determined based on the analysis of medical records and a questionnaire completed by the patient. We used the 5-factor model of the Positive and Negative Syndrome Scale (PANSS) with the nested two-factor negative syndrome model. RESULTS: After adjusting for multiple comparisons, a significant effect of the interaction of childhood adversity and TNF-α on the cognitive/disorganization factor was found, with a difference between genotypes in the group without childhood adversity (pFDR <0.018; η2p=0.03). A significant effect of the interaction of childhood adversity and genotype on the cognitive disorganization syndrome was established (F=5.87; p=0.003; η2p=0.03). Stereotyped thinking and avolition on PANSS had the highest correlations with cognitive disorganization factor (ro=0.84 and ro=0.82, respectively) and the highest significance of differences depending on the interaction of genotype and childhood adversity (Kruskal-Wallis test, H=12.28, p=0.006 and H=12.79, p=0.005, respectively). CONCLUSION: Childhood adversity modifies the relationship between the pathogenesis of schizophrenia and the TNF-α promoter polymorphism rs1800629, which is also an enhancer of another 60 genes located in the major histocompatibility complex.

[Prognosis of the functional outcome of schizophrenia using a multigene panel]. / Otsenka prognoza funktsional'nogo iskhoda shizofrenii s pomoshch'yu mul'tigennogo testa.

OBJECTIVE: To compare the groups of schizophrenic patients with different levels of functional outcome and different frequency of risk variants in polymorphic loci of five candidate genes to create a multigene panel and to test its predictive ability for long-term outcome of the disease. MATERIAL AND METHODS: According to the proposed typology, the patients included in the studies were divided into three groups, which differed in the level of social functioning. Group 1 was characterized by the highest level, in group 2 this indicator was significantly lower, and in group 3 the lowest. The multigenic panel included genes for serotonin receptor type 2a (5-HTR2A T102C), serotonin transporter (5-HTTLPR), C-reactive protein (CRP -717A>G), angiotensin II receptor type 1 (AGTR1 A1166C), and brain neurotrophic factor (BDNF Val66Met). A multi-gene risk score was calculated for each patient by summing the total number all his/her risk alleles. For each polymorphism, a score of 2 was assigned to homozygous high-risk genotypes, a score of 1 to heterozygous genotypes and a score of 0 to homozygous low-risk genotype. Accordingly, the multi-gene risk score for a patient could vary from 0 to 10 risk alleles. RESULTS: A significant effect of the group on the multi-gene risk score was shown (p<0.0001). Between-group differences were significant as well (p<0.01). In group 1, there were no carriers of ≥6 risk alleles, and the number of carriers of less than 5 alleles exceeded 50%. In group 2, the number of carriers of ≥6 risk alleles was 19.4%, and in group 3 - 31.7%. Moreover, in these groups there were no carriers of 0-2 risk alleles, while in group 1 their number was 20.7%. CONCLUSION: The multi-gene risk score predicts the level of functional outcome in patients with schizophrenia. In the case of a smaller number of risk alleles (0-4) in an individual, a favorable functional outcome can be predicted with a high probability in the long-term period of the disease.

[The study of the association between the C677T polymorphism of the methylenetetrahydrofolate reductase gene and severity of symptoms in patients with schizophrenia]. / Izuchenie assotsiatsii geneticheskogo polimorfizma C677T metilentetragidrofolatreduktazy s vyrazhennost'yu simptomov u bol'nykh shizofreniei.

OBJECTIVE: To study the association of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of schizophrenia in a large sample, including schizophrenic patients and mentally healthy people, and to investigate the relationship of this polymorphism with the severity of schizophrenia symptoms and genotype-environment interaction effects on these symptoms. MATERIAL AND METHODS: The sample for genotyping consisted of 1357 patients with schizophrenia and schizophrenia spectrum disorders and 711 people of the control group. The severity of symptoms was assessed with the PANSS. Obstetrical complications and a traumatic brain injury in medical history were studied as environmental factors. RESULTS AND CONCLUSION: No association was found between MTHFR C677T polymorphism and schizophrenia. There was no genotype effect on the severity of symptoms on the PANSS subscales. The effect of genotype-environment interactions on the severity of schizophrenia symptoms was not detected. The results do not confirm the data of a number of studies on the relationship of MTHFR C677T polymorphism with schizophrenia symptoms.

Effect of VNTR Polymorphism of the AS3MT Gene and Obstetrical Complications on the Severity of Schizophrenia.

The role of the VNTR polymorphism of the AS3MT gene in determining the clinical features of schizophrenia and schizophrenic spectrum disorders was studied. The analysis included 670 individuals. We found no differences in PANSS scores for positive, negative, and common psychopathological symptoms between the carriers of different genotypes. The interaction of the studied polymorphism and obstetrical complications as an environmental factor was found. The genotype-environment interactions were identified for one of the characteristics reflecting the severity of schizophrenia: the level of negative symptoms. Women with the V2/V2 genotype, who have obstetrical complications, showed significantly higher negative symptoms scores, which was associated with a poor prognosis of the disease.

[Genetic variations associated with premorbid personality in patients with schizophrenia]. / Geneticheskie polimorfizmy, assotsiirovannye s razlichnoi stepen'iu vyrazhennosti premorbidnykh lichnostnykh anomalii u bol'nykh shizofreniei.

AIM: To search for genetic variants associated with premorbid personality in patients with schizophrenia. MATERIAL AND METHODS: The sample included 272 men diagnosed with schizophrenia or schizoaffective disorder. Patients were divided into 3 groups based on premorbid personality difficulties: mild (group 1, n=110), moderate (group 2, n=113), marked (group 3, n=49). The following polymorphisms were genotyped: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met), CRP (-717A>G). RESULTS: A significant increase in the frequency of the CC (5-HTR2A T102C), LL (5-HTTLPR) and Met/Met (BDNF Val66Met) genotypes was identified in group 3 compared to group 1. Frequencies of CC and LL genotypes were significantly higher in group 2 compared to group 1 as well. The differences between group 2 and group 3 were found only for the Met/Met genotype. There were no between-group differences in the frequencies of CRP (-717A>G) genotypes. CONCLUSION: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met) polymorphisms previously reported to modify schizophrenia course are also associated with premorbid personality in schizophrenic patients.

[Prevention of progression of cognitive decline in the first-degree relatives of patients with Alzheimer's disease]. / Profilaktika progressirovaniia kognitivnoi nedostatochnosti u rodstvennikov 1-i stepeni rodstva patsientov s bolezn'iu Al'tsgeimera.

AIM: To evaluate the efficacy of course neurotrophic therapy with cerebrolysin in a group of first-degree relatives of Alzheimer's disease (AD) patients who had minimal cognitive dysfunction. MATERIAL AND METHODS: Sixty-seven relatives (mean age 57.6±14.2 y.o.) received cerebrolysin in the dose of 20 ml/day in intravenous drips in 100 ml isotonic saline. The duration of treatment was 1 month. RESULTS: The positive effect of course treatment on the CGI was established in 77.6% of the relatives. The scores on the MMSE and MoCA scales were significantly improved in the group with cognitive difficulties objectively confirmed by the clinical/neuropsychological examination (n=27) and in the group without cognitive difficulties (n=40). CONCLUSION: The positive effect of cerebrolysin on the cognitive status of the first-degree relatives of AD patients, regardless of their cognitive deficiency, was demonstrated.

[The interaction effect of ANKK1/DRD2 TaqIA and HTR2C Cys23Ser on approach motivation in schizophrenic patients and normals]. / Éffekt vzaimodeistviia polimorfizmov ANKK1/DRD2 TaqIA i HTR2C Cys23Ser na pobuditel'nuiu motivatsiiu u bol'nykh shizofreniei i zdorovykh.

AIM: To evaluate the association of the DRD2 gene and DRD2 x HTR2C interaction with hedonic and activational aspects of approach motivation in schizophrenia. MATERIAL AND METHODS: Genotypes at polymorphic loci DRD2 rs1800497 and HTR2C rs6318 (Cys23Ser) were identified in a sample that included 174 patients with schizophrenic spectrum disorders and 268 healthy subjects without a family history of psychoses. The participants completed the BIS/BAS and Temporal Experience of Pleasure Scale (TEPS). RESULTS AND CONCLUSION: A MANCOVA with sex and age as covariates revealed the effect of the 'DRD2 x HTR2C x diagnosis' interaction on the BAS scores (p=0.033). The effect was significant for the Fun-Seeking and Drive scales. Among patients, the carriers of the DRD2 TT/CT x HTR2C GG/G genotype showed the highest scores on the both scales, and those with the minor alleles in the two loci had the lowest ones. Differences between these groups were nominally significant for both the Fun-Seeking and Drive, but did not survive the correction for multiple comparisons. Among controls, subjects without minor alleles demonstrated the highest scores on these two scales. They differed significantly from the carriers of the DRD2 TT/CT+HTR2C GG/G genotype on the Fun-Seeking (p=0.008). No effects of DRD2 and HTR2C on TEPS scores were found. In general, the results of the study can be interpreted in favor of the hypothesis about the role of the HTR2C and DRD2 genes interaction in the variability of the activational aspects of approach motivation in schizophrenia and healthy subjects. However, the lack of differences survived correction for multiple comparisons makes it difficult to interpret the revealed effects.

[A study on the association of genes for pro-inflammatory cytokines and depression]. / Sviaz' genov provospalitel'nykh tsitokinov s depressiei.

AIM: To study the association between proinflammatory cytokine genes and depression. MATERIAL AND METHODS: IL-1B С-511T and TNF-a G-308A gene polymorphisms were studied in patients diagnosed with depression and age and sex-matched healthy controls. RESULTS AND CONCLUSION: The IL-1B С-511T and TNF-a G-308A polymorphisms were associated with depression; CC genotype (р=0,001, OR=1.9 CI 1,3-2,7) and GG genotype (р=0,001, OR=3,0 CI 1,8-4,9) were the risk factors. The results suggest that immune factors may play a role in the development of depression. The authors highlight the role of clinical polymorphism of depression that makes it difficult to form homogenous groups of patients and to select phenotypes for biological studies.

[Effect of cytokine genes and season of birth on personality]. / Vliianie genov tsitokinov i sezona rozhdeniia na nekotorye osobennosti lichnosti.

AIM: To evaluate the interaction effects of season of birth and immune system genes on the personality traits 'Novelty seeking' (NS) and 'Self-directedness' (SD). Based on results on an influence of the immune system on the brain processes, the authors hypothesized that the interaction of immune system genes and season of birth, which is relevant for immune phenotype, can contribute to the development of personality traits. MATERIAL AND METHODS: NS and SD were measured in 336 healthy volunteers, aged from 16 to 67 years, using the Temperament and Character Inventory (TCI-125). IL1B C3954T, IL4 C-589T, IL13 C1112T and TNFA G-308A polymorphisms were genotyped. RESULTS: An interaction effect of IL4 C-589T and season of birth on the personality traits was found (F2,322=6.03, pcorr=0.011, η2=0.04). Carriers of the minor allele T, who were born in winter, had lower NS and higher SD. There was a nominal main effect of genotype on SD (F=5.44, p=0.020) as well, with higher SD scores in carriers of the allele T compared to the CC genotype. CONCLUSION: The results suggest that the etiology of personality and immune characteristics can share common genetic elements including IL-4.

[A role of interactions between N-methyl-D-aspartate and dopamine receptors in facial emotion recognition impairment in schizophrenia]. / Rol' vzaimodeistviia genov NMDA- i dofaminovykh retseptorov v narushenii raspoznavaniia émotsional'noi mimiki pri shizofrenii.

AIM: To search for genetic mechanisms of facial emotion recognition (FER) impairment, one of the features of schizophrenia that affects social adaptation of patients. Based on the view implicating the interplay between dopaminergic and glutamatergic systems into the pathogenesis of schizophrenia, authors explored the interaction effects of the C366G polymorphism in the GRIN2B gene encoding NMDA receptor subunit NR2B with ANKK1/DRD2 Taq1A and 48-VNTR DRD4 polymorphisms on FER. MATERIAL AND METHODS: GRIN2B -DRD2 interaction effects were studied in a sample of 237 patients and 235 healthy controls, GRIN2B - DRD4 in 268 patients and 208 controls. RESULTS AND CONCLUSION: Both effects were significant in combined samples of patients and controls (GRIN2B X DRD2, F=4.12, p=0.043; GRIN2B X DRD4, F=6.43, p=0.012). Further analysis confirmed the interaction effect of GRIN2B and DRD2 polymorphisms on FER in patients with schizophrenia. In patients with a less efficient allele of the DRD2 in the absence of the minor allele of the GRIN2B C366G polymorphism, the results were close to normal values while patients with minor alleles of both polymorphisms showed the worst results. This finding is in line with the conceptions on a possible role of NMDA-receptor hypofunction and D2-mediated regulation of NMDA-receptor activity in FER impairments in schizophrenia.

[Association of inflammatory genes with neuroticism, anxiety and depression in male patients with coronary heart disease]. / Sviaz' genov vospalitel'nykh faktorov s nevrotizmom, trevozhnost'iu i depressiei u muzhchin s ishemicheskoi bolezn'iu serdtsa.

AIM: To explore the relationship of depression and its endophenotypes (neuroticism and trait anxiety) with inflammatory genes in patients with coronary heart disease (CHD). MATERIAL AND METHODS: A sample consisted of 78 male CHD patients with depression, 91 CHD patients without depression and 127 healthy men. Polymorphisms of the genes encoding interleukine-4 (IL-4 -589 C/T), interleukine-6 (IL-6 -174 G/C), tumor-necrosis factor alpha (TNF-α -308 G/A) and C-reactive protein (CRP -717A/G) were studied. RESULTS: There was the association between the IL-6 -174 G/C and depression comorbid to CHD (р=0.01; OR=2.3 CI 95% 1.2-4.3). The frequency of the 'high expression' allele G in this group was higher compared to controls. The association between IL-4 -589 C/T and CHD was found. Compared to the control group, the frequency of the IL-4 -589CC genotype was higher in patients regardless of whether they had symptoms of depression (р=0.007; OR=2.1 CI 95% 1.2-3.4). No association between the TNF-α -308G/A and the CRP -717A/G with depression in CHD was observed. There were no differences between neuroticism and anxiety scores in patients with different IL-4 -589 C/T, IL-6 -174 G/C, TNF-α -308 G/A, CRP -717A/G genotypes. CONCLUSION: The finding of the association between the IL-6 -174G/C and depression, comorbid to CHD, is in line with literature on a role of IL-6 in the development of depression in patients with CHD.

[A study of the effect of the genes of inflammatory proteins on basic personality dimensions]. / Issledovanie effekta genov vospalitel'nykh faktorov na bazovye cherty lichnosti.

AIM: The present research examines the association between two basic dimensions of personality and genes of inflammatory cytokines and mediators reported to be elevated in schizophrenia and affective disorders. Genes of interleukin-1B (IL-1B), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) and alpha 1-antitrypsin (A1AT) were studied. MATERIAL AND METHODS: A total of 639 healthy subjects, aged from 17 to 69 years, participated in the study. The following polymorphisms were genotyped: IL-1B С-511Т (rs16944) and С3954Т (rs1143634), IL-6 G-174C (rs1800795), TNF-α G-308A (rs1800629), CRP (rs279452), A1AT 374G/A (rs709932). Basic personality dimensions Extraversion and Neuroticism were assessed using the Eysenck Personality Inventory. RESULTS AND CONCLUSION: The levels of Extraversion and Neuroticism were not associated with IL-1B, IL-6, TNF-α G and CRP polymorphisms. The association between the A1AT 374G/A polymorphism and Extraversion (р=0.036) was shown. There was a trend towards the association between the A1AT 374G/A polymorphism and Neuroticism (p=0,05) in women. Because this is the first study of the effect of IL-1B, IL-6, TNF-α and A1AT on personality dimensions, the results should be considered as preliminary and need to be replicated.

[The association between the GRIN2B gene and verbal fluency and impairment of abstract thinking in schizophrenia].

OBJECTIVE: To search for the association between the GRIN2B gene and signs of thought and speech disorders which may be the result of decreased accessibility to the mental lexicon. MATERIAL AND METHODS: The association between the GRIN2B polymorphism rs7301328 with semantic verbal fluency and five symptoms of thought and speech disorders, as assessed with the PANSS, was studied in 552 patients with schizophrenia-spectrum disorders. RESULTS AND CONCLUSION: There was the association of the GRIN2B gene with verbal fluency and the PANSS item «Difficulty in Abstract Thinking¼. The association was not modified by verbal fluency. The results suggest that the GRIN2B gene may modify the linguistic processes involved in the retrieval of information from the mental lexicon on the basis of semantic traits and, moreover, contribute to the variability of clinical symptoms of impairment of abstract thinking in patients with schizophrenia. The heterozygous genotype may be protective against the development of thought and speech disorders.

[Analysis of the association of interleukin 4 and interleukin 10 gene variants with basic personality traits].

There is growing evidence that serum levels of various inflammation markers are associated with personality traits. However, only few studies investigated the link between genetic variants of cytokine encoding genes and psychological characteristics. In this study, we examined genotypes in 297 individuals to assess the association between common variants of interleukin 4 (IL-4) and interleukin 10 (IL-10) genes and basic personality traits of extraversion and neuroticism, measured using the Eysenck Personality Questionnaire (EPQ). We found that, in homozygous female carriers of high expression alleles Т (IL-4 C-589T) and G (IL-10 G-1082A), neuroticism scores were higher (p = 0.045 and p = 0.08, respectively). In turn, extraversion scores were significantly higher in both male and female carriers of heterozygous variants CT and GA (p = 0.01). Our results are in accordance with the behavioral immune system hypothesis, and the general paradigm on the role of personality traits in health and longevity.

[Polymorphism C366G of gene GRIN2B and verbal episodic memory: No association with schizophrenia].

The present study searched for associations between gene GRIN2B (glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2B) and component processes of verbal episodic memory in schizophrenic patients. The Rey Auditory Verbal Learning Test (RAVLT) as a part of a large neuropsychological battery was administered to 302 patients with schizophrenic spectrum disorders (sample PI). Also, 285 patients (sample P2) and 243 healthy controls (sample C2) performed the "10 words" test that measures short-term memory. The GRIN2B rs7301328 (C366G) polymorphism was genotyped for each subject. There were no associations between the polymorphism and any measure of the RAVLT either in the whole PI sample or in a subsample of patients with a severe cognitive deficit. The GRIN2B influenced immediate recall and proactive interference in the "10 words" test in the control group: homozygotes CC recalled fewer words and showed a lower effect of proactive interference than carriers of other genotypes. The results suggest that the C366G polymorphism could influence verbal episodic memory in the general population, but this influence is absent in schizophrenic patients.

[The Association of Brain-Derived Neurotrophic Factor and Serotonin Transporter Genes with the Parameters of Early Event-Related Potentials During the Passive Perception of Words].

We explored the association of brain-derived neurotrophic factor (BDNF) and serotonin transporter genes with neurophysiological characteristics of the early stages of verbal information processing in the brain in the groups of patients with schizophrenia and schizophrenia spectrum disorders and healthy people. It has been shown that Val66Met and 5-HTTLPR polymorphisms are associated with P100 and N170 during the passive reading of single words written in Russian presented with different occurrence frequency. The healthy carriers of the ValVal genotype (BDN F Val66Met) allele or the SS (5-HTTLPR) genotype performed the task better compared to those with an Met or an L allele. The differences were significant in healthy people and observed as a trend in thepatients.

[Depression comorbid to ischemic heart disease: a psychometric and molecular-genetic study].

OBJECTIVE: To compare psychometric and molecular-genetic characteristics of depression caused by ischemic heart disease (IHD) and depression in patients with IHD caused by other psychogenic factors. MATERIAL AND METHODS: One hundred and thirty-five patients with depression comorbid to ischemic heart disease (IHD) were examined. Depression was associated with IHD in 71 patients (group 1). In 64 patients, depression was caused by other psychogenic factors (group 2). The HAMD-21 scale was used to measure depressive symptoms. RESULTS AND CONCLUSION: The comparative analysis of the core symptoms of depression demonstrated that group 1 had a peculiar psychometric profile with marked apathy, which was not accompanied by marked hypothymia, guilt feelings or anxiety, compared to group 2. The molecular-genetic correlate of this profile was found. It included a combination of an allele S (5-HTTLPR) of the serotonin transporter gene, an allele G (A-1438G) of the serotonin receptor type 2A gene and the genotype ValVal (Val66Met) of the brain-derived neurotrophic factor gene.

[Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

[Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals].

The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism.

[No effect of the BDNF Val66Met polymorphism on cognitive deficit in patients with schizophrenia and on the risk of the disease in their relatives].

OBJECTIVE: The brain-derived neurotrophic factor (BDNF) gene is thought to be a candidate gene for schizophrenia. At the same time, many studies failed to find the association between BDNF and the disease though the contribution of the BDNF Val66Met polymorphism to the variance of characteristics of schizophrenia has been confirmed. Authors suggested that this contribution was the consequence of the involvement of this gene in the formation of "cognitive reserve" that had a protective effect on the different aspects of the disease. This protective effect should emerge in relatively intact cognitive function in patients with the protective Val66Met genotype as well as in the accumulation of the protective genotypes in unaffected relatives. MATERIAL AND METHODS: We examined 169 patients with schizophrenia spectrum disorders, 320 their first-degree relatives and control groups using molecular-genetic and experimental psychological methods. RESULTS: No effect of the Val66Met polymorphism on verbal memory, executive functions and total index of cognitive functioning was found. Besides, we did not find any differences in Val66Met genotype frequencies in first-degree relatives of patients with schizophrenia and healthy people without family history of schizophrenia. CONCLUSION: The results do not support our hypothesis that BDNF is a gene of "cognitive reserve".