НИИ
медицинской
генетики

Purpose: The purpose of this study was to identify genes in the placenta of monosomy X embryos whose methylation abnormalities may be associated with embryonic death. Methods: Methylation levels were assessed via reduced representation bisulfite sequencing of the chorionic villi of embryos from 8 spontaneous abortions during the first trimester of pregnancy with the 45,X karyotype and 7 embryos from medical abortions with the 46,XX and 46,XY karyotypes. The methylation levels of several identified differentially methylated genes were analyzed in 22 embryos from spontaneous abortions with monosomy X compared with 11 embryos from medical abortions using targeted bisulfite massive parallel sequencing. Results: Compared with embryos with 46,XX and 46,XY karyotypes, respectively, differentially methylated CpG sites in embryos with monosomy X were located in 831 and 254 differentially methylated genes (DMGs). However, only 74 DMGs were unique for 45,X embryos after subtraction of the DMG of spontaneously aborted embryos with a normal karyotype (n = 4). Compared with embryos of both sexes, 48 genes in embryos with monosomy X were differentially methylated, 21 of which are important in normal placental and embryonic development and whose dysregulation is linked to preeclampsia and embryonic death. Targeted analysis confirmed that the ALCAM gene is hypermethylated and that the BDH1 gene is hypomethylated in embryos with monosomy X. Conclusion: Aberrant methylation of genes involved in placentation, proliferation, and cell differentiation has been detected in spontaneously aborted embryos with monosomy X. These disorders may be associated with the high lethality of embryos with monosomy X.

Dopamine receptor inhibition underlies both the therapeutic and adverse effects of antipsychotics, but the mechanisms modulating these effects in patients with schizophrenia remain incompletely understood. Hyperprolactinemia (HPRL), a direct consequence of D2 dopamine receptor blockade, provides a unique clinical model to investigate how genetic variation in glutamatergic signaling influences the downstream effects of dopaminergic disruption. We hypothesized that polymorphisms in GRIN2A and GRIN2B, encoding NMDA glutamate receptor subunits, modify the neuroendocrine consequences of dopamine receptor inhibition. By studying antipsychotic-induced HPRL, we aimed to demonstrate that NMDA receptor genetic variants shape the functional outcomes of dopaminergic perturbation.
In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels—a sensitive biomarker of D2 receptor inhibition—and genotyped 23 GRIN2A/GRIN2B variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates.
NMDA receptor genetic variation significantly influenced susceptibility to HPRL, with distinct effects observed between antipsychotic classes with the highest effect for the typical antipsychotics, which are D2 dopamine receptor antagonists. This demonstrates that glutamatergic genotypes predict interindividual variability in the neuroendocrine response to dopamine receptor blockade.
These results provide the first clinical evidence in support of the hypothesis that NMDA receptor polymorphisms modulate the effects of dopaminergic inhibition in schizophrenia. Beyond HPRL, this dopamine-glutamate relationships paradigm may extend to other clinical outcomes of antipsychotic treatment, including therapeutic response and neurological side effects. Our findings underscore the importance of glutamatergic pathways in determining the functional consequences of dopamine receptor targeting.

The role of the genetic component in the development of schizophrenia and the formation of its clinical heterogeneity has been proven. To conduct a pilot associative analysis between positive and negative schizophrenia symptoms and polymorphic variants of the Transcription Factor 4 (TCF4) gene. The study included 373 patients with schizophrenia of Caucasian ethnicity, who underwent a comprehensive clinical examination, and a control group consisted of 194 mentally and somatically healthy individuals. Genotyping of three polymorphic variants of the TCF4 gene was carried out in the studied samples (rs2958182, rs8766, and rs9636107). Statistical analysis of the results was performed using Statistica for Windows V.12.0. Association analysis in SNPs was conducted using the chi-square criterion and Bonferroni correction. Groups of schizophrenia patients and healthy individuals were compared for selected TCF4 gene polymorphisms. No statistically significant differences in genotype and allele frequencies were found. The AA genotype and the A allele of the rs2958182 polymorphic variant, as well as the A allele of the rs9636107 polymorphic variant, had an effect predisposing to the predominance of negative symptoms. The TT genotype and the T allele of the rs2958182 polymorphic variant, as well as the G allele of the rs9636107 polymorphic variant, were statistically significantly more common among patients with leading positive symptoms. As a result of the study, associations of the polymorphic variant TCF4 rs2958182 and TCF4 rs9636107 with the leading symptoms of schizophrenia were discovered for the first time in Caucasian populations of the Siberian region. The obtained data confirm the contribution of the genetic component to the formation of clinical heterogeneity of schizophrenia and open up prospects for further search for genetic markers in order to prevent an unfavorable outcome of the disease.

Цель исследования. Изучить клинико-анамнестические особенности у пациенток с различными формами недостаточно гороста плода для определения факторов риска развития этого осложнения беременности.
Материал и методы. В исследование включены 329 пациенток, которые в зависимости от исходов беременности были разделены на 3 группы: в 1-ю (основную) группу вошли 165 женщин, беременность которых осложнилась недостаточным ростом плода. Основная группа была разделена на 2 подгруппы: 1a — 72 пациентки, беременность которых осложнилась
развитием маловесного для гестационного возраста (МГВ) плода, 1b — 93 пациентки, беременность которых осложнилась задержкой роста плода (ЗРП). Во 2-ю (сравнения) группу включили 164 пациентки, беременность которых закончилась рождением живого доношенного ребенка без признаков недостаточного роста. У всех пациенток изучены соматический
и акушерский анамнез, течение беременности.
Результаты. Показано, что пациентки моложе 20 лет чаще встречались в подгруппах МГВ и ЗРП (отношение шансов (ОШ) 5,8; 95% доверительный интервал (ДИ) 1,450—23,039; p=0,010 и ОШ 4,4; 95% ДИ 1,102—17,322; p=0,039 соответственно). Анализ акушерского анамнеза показал, что преждевременные роды в группе МГВ встречались чаще, чем в группе сравнения
(ОШ 2,8; 95% ДИ 1,077—7,165; p=0,038). Недостаточный рост плода в предыдущую беременность чаще встречался у женщин основной группы и увеличивал шанс данного осложнения беременности в настоящую беременность: в 4,3 раза (ОШ 4,3; 95% ДИ 1,282—14,330; p=0,016) для ЗРП и в 3,7 раза (ОШ 3,7; 95% ДИ 0,994—13,306; p=0,072) для МГВ плода. Рубец на матке у пациенток группы МГВ встречался чаще, чем в группе сравнения (ОШ 2,4; 95% ДИ 1,143—4,867; p=0,029). Ранний токсикоз и гестационный сахарный диабет у пациенток группы ЗРП встречался чаще, чем в группе сравнения (ОШ 3,1; 95% ДИ 1,622—6,011; p<0,001 и ОШ 2,1; 95% ДИ 1,181—3,829; p=0,014).
Заключение. В исследовании выявлены новые факторы риска недостаточного роста плода. Необходимо учитывать возраст пациентки, наличие рубца на матке, преждевременных родов, недостаточного роста плода в предыдущую беременность, раннего токсикоза, гестационного сахарного диабета с целью своевременной оценки риска недостаточного роста плода.