[CLINICAL AND PHARMACOLOGICAL FACTORS INFLUENCING RESISTANCE TO CLOPIDOGREL IN PATIENTS WITH CARDIOVASCULAR DISEASES].

We analysed clinical and pharmacological factors influencing resistance to clopidogrel in 250 patients with cardiovascular diseases during 18 months. It was shown that the risk ofresistance depends on the form of coronary heart disease, carbohydrate metabolism, the AA genotype of CYP2C19*2 and TBS1 genes. The cardiovascular events significantly morefrequently occurred during 12 and 18 months in resistant diabetics and in the patients with an allele lacking the *2/*3 CYP2C9 gene function and AT/TT polymorphism of the thromboxane synthase gene TBS1.

[Positive effect of low-activity thromboxane A synthase gene on prognosis in coronary heart disease].

AIM: To analyze the influence of pharmacogenetic factors on the risk of clopidogrel resistance and cardiovascular events during 18-months follow-up. SUBJECTS AND METHODS: Two hundred and fifty patients taking clopidogrel were examined. Platelet function was determined by optical aggregometry. Thromboxane A synthase 1 (TBS1) gene polymorphism was investigated in all the patients. The impact of TBS1 gene polymorphism on the risk of clopidogrel resistance and cardiovascular events was analyzed during 18 months of follow-up. RESULTS: The carriage of TBS1 gene polymorphism AA was shown to affect the risk of clopidogrel resistance. Cardiovascular complications significantly less frequently occurred in TBSI gene polymorphism AA carriers during 18 months. CONCLUSION: The carriage of a slow AA allele of the'TBS1 gene is suggested to be a clinically significant protective factor in the secondary prevention of coronary heart disease

[Modern approaches to the primary prevention of the development of psychoactive substance dependence on the base of accounting of environmental and genetic risk factors].

In the work there was performed an assessment of the interaction of microsocial and genetic factors of the development of psychoactive substance (PS) dependence. The objects of the psycho-hygienic and molecular-genetic studies were 538 male patients from the specialized diagnostic and treatment center at the age from 17 to 65 years with a diagnosis of "PS dependence" according to F10-F09 in the ICD-10. There were determined personality predictors of early (before 25 years) manifestation of systematic abuse, such as low self-control, individualisticity, authoritarianism, unjustified optimism and reduced capacity for social adaptation. Manifestation of the PS dependence at an early age (25 years) is determined by the contribution of genotype 9R+ DAT gene in the combination with other predisposing genotypes A1 + DRD2/ANKK1, SS SERT and 7R+ DRD. The risk of development of PS dependence at a more younger age increases with the superimposition of individual predisposing genotypes ranging from 1,2 (7R+ gene DRD4) to 1,9 (A1 + gene DRD2/ANKK10 on a destructive milieu. Pairwise combinations of genotypes 7R+ DRD4 x A1+ DRD2, 7R+ DRD4 x 9R+ DAT, 9R+ DAT x A1+ DRD2, 9R+ DAT x SS SERT significantly increase the risk by 2 or more times (2.5-2.8). There was suggested an algorithm for the prenosological forecast of the development of PS dependence in adolescents and young men.

[Clinical and genetic markers of chronic cerebral ischemia].

OBJECTIVE: To study the effectiveness of common neuropsychological tests for the verification of the diagnosis of cerebral ischemia (CE) and a role of polymorphisms in SERT, ApoE and BDNF genes in its development. MATERIAL AND METHODS: We studied 272 inpatients, aged from 37 to 70 years, with CE of the first stage (58 patients), CE of the second stage (121 patients) and CE of the third stage (93 patients). A set of neuropsychological tests, as well as biochemical and molecular-genetic studies were performed. RESULTS AND CONCLUSION: Reitan test was the most effective test for the diagnosis of cognitive impairment. The results of the Clock Drawing Test and MMSE were correlated with the disease severity but did not distinguish between the first and second stages of CE. Arterial hypertension and stenosing atherosclerosis of brain vessels were significant predictors of CE. SERT gene was a marker of the CE risk in men. The genotype SS was associated with the risk of CE with early age-at-onset. No association of ApoE and BDNF genes with CE was found.

[CARD15 and TLR4 genes polymorphisms in atopic bronchial asthma].

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene contribute to atopic bronchial asthma we performed a comparative analysis of alleles and genotypes frequencies of these polymorphisms in Russian patients from Moscow. DNA samples from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. There were associations neither of G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene with asthma nor of markers of CARD15 gene with asthma severity. Haplotype frequency analysis of CARD15 gene polymorphisms did not reveal significant difference between groups. However, a strong association was found between Asp299Gly and asthma severity. Allele Asp of this marker showed association with mild atopic bronchial asthma and allele Gl--with moderate/severe asthma = 0.47, 95% CI [0.24-0.93] i OR = 2.12, 95% CI [1.08-4.18] respectively).

[Molecular genetic mechanisms of individual sensitivity to synthetic fatty acids in case of valproic acid].

Individual sensitivity to structural analogues of free fatty acids (FFA), some of which are endocrine destructors, resulting in hormonal metabolic disturbances, was studied using valproic acid (VA) as an example. The individual sensitivity was considered by the example of polymorphism in the PPAR@g2 gene. The homozygous genotype Pro12Pro of this gene was proved to be responsible for weight gain and development of insulin resistance during VA administration, which should be kept in mind when developing the safe levels of exposure to FFA-like substances.

[Association of interleukin-13 gene polymorphisms with atopic bronchial asthma].

A comparative analysis of allele and genotype distribution of C(-1055)T and R130Q IL13 gene polymorphisms has been performed in Russian patients from the Moscow region. In the study, 283 DNA specimens of atopic bronchial asthma (BA) patients and 227 DNA specimens of healthy donors were used. No association of these markers with ABA development as well as with total IgE concentration has been found. Haplotype frequency analysis did not reveal significant difference between samples. However, significant association ofC(-1055)Tpolymorphism with the disease severity has been revealed (OR = 2.39, 95% confidence interval 1.44-3.98, p = 0.001). Therefore, C(-1055)T polymorphism was shown to be associated with atopic BA progression.

[Association between dopamine (DRD2) and serotonin (5HTR2A) gene polymorphisms with the indicators of adolescent behavior adaptiveness].

The paper gives the results of a study of the impact of dopamine (DRD2) and serotonin (5HTR2A) genes on the development of personality characteristics in adolescents, by applying the Cattell (16PF) questionnaire. The study was performed in a group of 360 Moscow teenagers (185 girls and 175 boys) aged 14-17 years. The boys carrying the A1 allelle of the DRD2 gene were found to have a lower self-control, indiscipline, and impulsiveness. An association between the indicators of unconscientiousness, social introversion, and group independence was established in the girls with the G/G genotype of the 5HTR2A gene. Thus, gender differences have been revealed from the impact of dopamine and serotonin gene polymorphisms on the teenagers' personality characteristics that characterize the forms of disadaptive behavior, such as unconscientiousness, indiscipline, low self-control, and impulsiveness.

[An association between the FABP2 gene polymorphism and efficacy of valproates].

To search for association between the 163G>A polymorphism of the fatty acid binding protein 2 (FABP2) gene and intracellular transport of the valproic acid in the small intestines, 168 patients with different forms of epilepsy, aged from 1 to 89 years, and different illness duration have been studied. The patients received valproates (127 patients) and topiramate (41 patients) as a monotherapy. It has been shown that the 163G>A (Ala54Thr) polymorphism exerts an influence on effective dose of the valproic acid but not of topiramate.

[D3 dopamine receptor gene Ser9Gly polymorphism in Russian patients with schizophrenia]. / Izuchenie polimorfizma Ser9Gly gena dofaminovogo retseptora D3 u bol'nykh shizofreniei iz russkoi populiatsii.

Polymorphic marker Ser9Gly of dopamine receptor D3 gene is considered perspective for associative studies of schizophrenia. Allele and genotype frequency of this polymorphism were studied in different ethnic groups of schizophrenic patients as well as the attempts have been made to reveal an association with clinical presentations of the disease. However, the results are inconsistent. The present study aimed at investigating Ser9Gly DRD3 gene polymorphism in Russian sample of schizophrenic patients. One hundred and fifty patients with ICD-10 diagnosis of schizophrenia (broad definition), 69 male and 81 female, aged 34.8+/-13.87 years, age at disease onset 24.3+/-9 years, have been examined. Control group consisted of 150 healthy subjects without family history of schizophrenia, 60 male and 90 female, aged 32.7+/-13.5 years. No between-group differences have been found for Ser9Gly DRD3 allele and genotype frequencies. However, a frequency of homozygous genotype Gly/Gly was significantly higher in female patients, comparing to female controls (p=0.038 Yate's corrected, OR 9. CI 0.95% 1.0-79.5). A role of sex-dependent association between Ser9Gly DRD3 polymorphism and schizophrenia is discussed.

Analysis of the linkage of the Taq1A and Taq1B loci of the dopamine D2 receptor gene with schizophrenia in patients and their siblings.

The linkage of the polymorphous markers Taq1A and Taq1B of the DRD2 dopamine receptor gene, located in region 11q22-11q23 of chromosome 11, with schizophrenia was studied. The investigation involved 29 complete families containing concordant and discordant sibling pairs. Common alleles at locus Taq1A were found significantly more frequently in concordant pairs (p = 0.04), and there was a tendency to a higher frequency of transmission of the maternal allele as compared with the paternal allele (p = 0.06). No such relationships were seen in the case of the Taq1B locus. Neither locus showed any significant difference in the frequency of common alleles in discordant pairs or in the predominance of allele transmission from one of the parents. These data demonstrate a possible linkage with schizophrenia for the Taq1A marker but not for the Taq1B marker.

[Molecular genetic polymorphism of the genes of neurotransmitter systems in schizophrenics with early manifestation of the disease]. / Molekuliarno-geneticheskii polimorfizm genov neirotransmitternykh sistem u bol'nykh shizofreniei s rannei manifestatsiei zabolevaniia.

Molecular-genetic polymorphism of genes-candidates was investigated: the genes of serotonin receptor--type 2a (HTR2A), dopamine receptor gene--type 2, serotonin transporter (5HTTLPR). Thirty one schizophrenic patients whose age was 12.6 +/- 3.6 years at the onset of the disease and 208 patients whose age was 23.5 +/- 6.7 years at the onset of the disease were examined. The frequencies of HTTLPR and DRD2 genotypes differed insignificantly in both groups. The distribution of 5HTR2A genotypes in the schizophrenic group with an early manifestation of the disease differed from that with a later manifestation significantly (chi 2 = 6.27; df = 2; p = 0.044). The relative risk (odds ratios) was 7.9 with 95% significance interval 1.008-61.94; p = 0.045. The severity of the disease and a positive family history were also examined in A2A2 genotype carriers. A positive family history was found in 9 (52.9%) of the 17 schizophrenics with an early manifestation and only in 15 (21.1%) of 71 patients of the similar group with a later one. Assessment of the clinical symptoms revealed that the total scores by the negative symptomatology subscale (PANSS) was higher in the patients with an early manifestation than in those with later one; but these differences did not achieve the significance level. These and earlier findings lead to the conclusion that A2A2 genotype was more frequently observed in the patients with more pronounced negative symptoms and high hereditary burden, which suggests that the A2A2 genotype is associated with an early onset.

[Dopamine receptor gene (DRD2) polymorphism in patients with endogenous psychoses with regard to their clinical heterogeneity]. / Polimorfizm gena dofaminovogo retseptora vtorogo tipa u bol'nykh s éndogennymi psikhozami s uchetom ikh klinicheskoi geterogennosti.

Recently an association between genetic dopamine receptor gene (DRD2) polymorphism and schizophrenia was observed in several studies. In the current investigation we attempted to undertake further study of such association using an extended sample which comprised patients with schizophrenia (n = 184), schizoaffective psychosis (n = 63), affective disorders (n = 121)); healthy control subjects (n = 117) and first-degree relatives of the patients with psychoses who show no signs of mental diseases (n = 111). The genotypes A1A1, A1A2 and A2A2 and the relationship between Taq1DRD2 variants and some clinical symptoms and pathogenetic features of the patients with schizophrenia were studied. The results did not confirm the association between DRD2 genotype and any of disorders studied. But the A2A2 genotype frequency in the schizophrenic patient's group, with illness duration above 20 years and highly expressed positive, negative and psychopathological symptoms, increased significantly as compared to control group (73.7% vs 52.9%) and patients with less illness duration (73.7% vs 42.5%). In the latter case odds ratio was calculated as 4.12. In the light of this finding, A2A2 DRD2 genotype appears to be related to chronicity of schizophrenia.

[Association of allele polymorphism of dopamine d2 receptors with schizophrenic and affective disorders]. / Assotsiatsiia allel'nogo polimorfizma dofaminovogo retseptora DRD2 s psikhicheskimi zabolevaniiami shizofrenicheskogo spektra i affektivnymi rasstroistvami.

DRD2 Taq polymorphism has been studied in the samples from 214 patients (119 males, 95 females, mean age 37.8 +/- 13.6) and of 96 controls (50 males, 46 females, mean age 40.7 +/- 20.0). The latter group comprised 75 unrelated controls and 21 healthy first degree relatives of schizophrenic patients. All the patients were diagnosed according to ICD-10 and have been divided into 4 groups: paranoid schizophrenics (n = 102), schizotypic patients (n = 25), patients with schizoaffective psychoses (n = 40) and affective disorders (n = 47). Taq1A DRD2 polymorphism was represented by 3 genotypes: A1A1, A1A2, A2A2 (allele A2 was a result of nucleotide substitution). The frequencies of genotypes in affected group didn't significantly differ from a control one. However, a frequency of A2A2 genotype (0.45) in a group of paranoid schizophrenics was significantly higher, than in the patients with schizoaffective psychoses (0.22) or in a control group (0.26), but was similar to that of the patients with schizotypic or affective disorders (0.4). A2A2 DRD2 genotype seems to be a potential genetic factor of susceptibility to schizophrenia.