Unfavorable Genotypes Research Articles

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival.

T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Potentially functional variants of PARK7 and DDR2 in ferroptosis-related genes predict survival of non-small cell lung cancer patients.

Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (ptrend = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels.

Potentially functional variants of ERRFI1 in hypoxia-related genes predict survival of non-small cell lung cancer patients.

Hypoxia is often involved in tumor microenvironment, and the hypoxia-induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia-related genes play in survival of patients with non-small cell lung cancer (NSCLC). We evaluated the associations between 16,092 single-nucleotide polymorphisms (SNPs) in 182 hypoxia-related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset. An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14-1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) and disease-specific survival (HR = 1.21, 95% CI = 1.04-1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma. Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.

Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.

Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

Additional prognostic value of polymorphisms within the 3'-untranslated region of programmed cell death pathway genes in early-stage breast cancer.

The programmedcell death (PCD) pathway plays an important role in restricting cancer cell survival and proliferation. However, limited studies have investigated the association between genetic variants in the 3'-untranslated region of the PCD pathway genes and breast cancer outcomes. In this study, we genotyped 28 potentially functional single nucleotide polymorphisms (SNPs)in 23 PCD pathwaygenesin 1,177patients withearly-stagebreast cancer(EBC)from a Han Chinese population.The median follow-up period was 174 months. Among all the candidateSNPs, fourindependent SNPs (rs4900321 and rs7150025 in ATG2B, rs6753785 in BCL2L11, and rs2213181 in c-Kit) were associated with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer-specific survival (BCSS)and overall survival (OS), respectively. Further combined genotypes of these four SNPs revealed that the survival decreasedas the number of unfavorable genotypes increased(Ptrend= 1.0 × 10-6, 8.5 × 10-8, 3.6 × 10-4, and 1.3 × 10-4for iDFS, DDFS, BCSS, and OS, respectively). Receiver operating characteristiccurve analysis demonstrated that incorporating unfavorable genotypes and clinicopathological variables improved the ability to predict EBC survival (P= 0.006, 0.004, 0.029, and 0.019 for iDFS, DDFS, BCSS, and OS, respectively).Additionally, rs6753785 and rs2213181 were associated with BCL2L11and c-KitmRNA expression, respectively. Our results suggest that these four SNPs may act as novel biomarkers for EBC survival, possibly by modulating the expression of the corresponding genes.

Genes of Inflammation and Placental Function GWAS Associated with Idiopathic Recurrent Miscarriage in the Kazakh Population.

The loss of two or more pregnancies is considered recurrent miscarriage (RM). One of the causes of this pathology is the occurrence of mutations both in pleiotropic and pathway-specific regulators and in structural genes. The simplest type of such mutations is single nucleotide polymorphisms. The aim of the study is to study the relationship between gene polymorphisms of anti- and pro-inflammatory cytokines - interferon-gamma (T874A), interleukin (IL1B) (C3954T), IL6 (G572C) and IL10 (G1082A); placental function, apoptosis and angiogenesis - apolipoprotein C-III (APOC3) (G5163C), kinase insert domain receptor (A1719T, G1192A), P53 (Arg72Pro) and signal transducer and activator of transcription 3 (STAT3) (C1697G) with the development of idiopathic RM (iRM) in the Kazakh population. This was a case-control study. Molecular genetic studies were performed by TaqMan using a single site-specific amplification and real-time genotyping method in 302 women with iRM and 300 with normal reproduction. DNA isolation from the biomaterial was carried out using kits containing binding magnetic particles. Both samples were analysed for alleles and genotypes for the studied polymorphisms. For statistical data processing, Pearson's criterion, confidence interval (CI) and probability value were taken into account. It was found that the carriage of unfavourable genotypes (G/C, C/C) for the G5163C polymorphism of the APOC3 gene increases the risk of developing iRM by three times (odds ratio = 3.0; 95% CI = 2.24-4.07). Other studied polymorphisms in the genes of ILs, interferon, P53 proapoptotic protein, kinase domain receptor and STAT3 transcription activator were not associated with RM. Significant associations of APOC3 gene genotypes with the development of iRM in the Kazakh population indicate the involvement of the placental system, which is realised by vascularisation defects and defective embryo implantation and leads to early pregnancy termination.

Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival.

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (P trend = 0.0002) and disease-specific survival (DSS, P trend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.

ОСОБЕННОСТИ СИСТЕМНОГО ОТВЕТА НА АДЪЮВАНТНУЮ ЛУЧЕВУЮ ТЕРАПИЮ У НОСИТЕЛЕЙ ПОЛИМОРФИЗМА -308(G/A)TNF БОЛЬНЫХ РАКОМ МОЛОЧНОЙ ЖЕЛЕЗЫ

Background: Adjuvant radiation therapy (ART), an integral part of locoregional breast cance (BC) therapy, acting not only locally, but also systemically and leads to a shift in homeostasis, which is reflected in routine general clinical tests. Tumor necrosis factor (TNF) is a proinflammatory cytokine, the production of which can be influenced by the single-nucleotide substitution -308(G/A)TNF. The minor allele -308A can be included in the stable inherited haplotype AH8.1 of the HLA gene complex. At the same time, the carriage of the -308A without the AH8.1 haplotype is associated with a poor prognosis in patients with BC. The aim of the study was to evaluate the features of the systemic response to the course of ART in carriers of TNF-associated genotypes with BC. Material and methods: The sample is represented by 147 BC patients who underwent a course of ART (2 Gy in 25 fractions). Clinical and morphological characteristics and data of general clinical blood analysis were obtained from medical histories. Venous blood samples for the study were obtained at the beginning and at the end of the ART course. Alleles -308(G/A)TNF and marker alleles of haplotype AH8.1 (HLA-A×01, HLA-B×08 and HLA-DRB1×03) were determined by allele-specific PCR. sTNF concentrations were determined by the ELISA in 102 blood plasma samples. Results: TNF-associated comparison groups were identified based on genotyping: (1) 114 carriers -308GG of the TNF gene, regardless of the AH8.1 haplotype (77,6 %); (2) 23 carrier -308A(AH8.1pos) had at least one AH8.1 marker allele (15.6 %); (3) 10 carriers -308A(AH8.1neg) did not have any AH8.1 marker allele (6.8 %). In the -308A(AH8.1neg) group the average concentration of sTNF both at the beginning and at the end of ART was significantly higher and, unlike other comparison groups, did not significantly decrease at the end of the ART course. A significant decrease in absolute values was revealed during ART in a number of cases for leukocytes, platelets and lymphocytes, however within the reference values. In the group -308A(AH8.1neg) correlation analysis revealed a high strength of positive connections between sTNF and leukocytes (r=0.71; p=0.027), platelets (r=0.67; p=0.04), neutrophils (r=0.70; p=0.027) only at the end of ART, whereas at the beginning ART these correlations were weak (r≤0.3) and statistically unreliable. For other genetic groups, the revealed correlations were not strong enough. Conclusion: The revealed features of the systemic response to ART for carriers of a prognostically unfavorable genotype -308A(AH8.1neg) – a high concentration of sTNF and a positive correlation with the content of leukocytes (probably due to neutrophils) and platelets – can be considered as targets of individualized therapy.

WTAP gene variants and susceptibility to ovarian endometriosis in a Chinese population.

Background: Endometriosis is a common chronic gynecologic disorder with a significant negative impact on women's health. Wilms tumor 1-associated protein (WTAP) is a vital component of the RNA methyltransferase complex for N6-methyladenosine modification and plays a critical role in various human diseases. However, whether single nucleotide polymorphisms (SNPs) of the WTAP gene predispose to endometriosis risk remains to be investigated. Methods: We genotyped three WTAP polymorphisms in 473 ovarian endometriosis patients and 459 control participants using the Agena Bioscience MassArray iPLEX platform. The logistic regression models were utilized to assess the associations between WTAP SNPs and the risk of ovarian endometriosis. Results: In the single-locus analyses, we found that the rs1853259G variant genotypes significantly increased, while the rs7766006T variant genotypes significantly decreased the association with ovarian endometriosis risk. Combined analysis indicated that individuals with two unfavorable genotypes showed significantly higher ovarian endometriosis risk (adjusted OR = 1.71 [1.23-2.37], p = 0.001) than those with zero risk genotypes. In the stratified analysis, the risk effect of the rs1853259 AG/GG and rs7766006 GG genotypes was evident in subgroups of age ≤30, gravidity≤1, parity≤1, rASRM stage I, and the rs7766006GG genotype was associated with worse risk (adjusted OR = 1.64 [1.08-2.48], p = 0.021) in the patients with rASRM stage II + III + IV. The haplotype analysis indicated that individuals with GGG haplotypes had a higher risk of ovarian endometriosis than wild-type AGG haplotype carriers. Moreover, false positive report probability and Bayesian false discovery probability analysis validated the reliability of the significant results. The quantitative expression trait loci analysis revealed that rs1853259 and rs7766006 were correlated with the expression levels of WTAP. Conclusion: Our findings demonstrated that WTAP polymorphisms were associated with susceptibility to ovarian endometriosis among Chinese women.

Candidate genes related to acute cerebral circulatory disorders in Preeclampsia in the Kazakh Population

BackgroundThe purpose of this study is to conduct a comparative analysis of the population frequencies of alleles and genotypes of polymorphic variants of coagulation and fibrinolysis genes SERPINE1 rs1799889, ITGA2 rs1126643, THBD rs1042580, FII rs1799963, FV rs6025, FVII rs6046, angiogenesis and endothelial dysfunction PGF rs12411, FLT1 rs4769612, KDR rs2071559, ACE rs4340, GWAS associated with the development of acute cerebral circulatory disorders in preeclampsia, in an ethnically homogeneous population of Kazakhs with previously studied populations of the world. MethodsThe genomic database was analysed based on the results of genotyping of 1800 conditionally healthy individuals of Kazakh nationality ∼2.5 million SNPs using OmniChip 2.5 M Illumina chips at the DECODE Iceland Genomic Center as part of the joint implementation of the project “Genetic Studies of Preeclampsia in Populations of Central Asia and Europe” (InterPregGen) within the 7th Framework Programme of the European Commission under Grant Agreement No. 282540. ResultThe study discovered a significantly higher population frequency of carrying the unfavorable rs1126643 allele of the ITGA2 gene polymorphism when compared with European populations. The population frequencies of carrying minor alleles of the SERPINE1 (rs179988) and KDR (rs2071559) genes in the Kazakh population were significantly lower when compared with the previously studied populations of Europe and Asia. An intermediate frequency of unfavorable minor alleles between European and Asian populations was found in Kazakhs for gene polymorphisms: FV rs6025, PGF rs12411, and ACE rs4340. The genomic analysis determined the choice of polymorphisms for their further replicative genotyping in patients with ACCD in PE in the Kazakh population. ConclusionThe obtained results will serve as a basis for the development of effective methods of early diagnosis and treatment of PE in pregnant women, carriers of unfavorable genotypes.

Metabolic activity of bone tissue osteoblasts in patients with chronic pancreatitis

Objective — to investigate the level and role of osteocalcin in patients with chronic pancreatitis, to determine the dependence of changes in this indicator on the vitamin D receptor gene. Materials and methods. Examinations involved 70 patients with chronic pancreatitis (CP), who formed the main group. Women (46 or 66.4%) prevailed in this group. The age of the patients was from 29 to 43 years, the mean age 33.2±2.1 years. Control group consisted of 78 practically healthy subjects. The groups were comparable in terms of age and gender ratio. The diagnostic search included the study of the polymorphism of vitamin D receptor (VDR) gene and the biochemical marker of bone tissue, osteocalcin. Their possible effects on the course of the disease and the formation of complications have been investigated. Results. In the process of determining the VDR gene polymorphism, the significant difference was found in the distribution of gene alleles (χ2=30.08, df=4; p &lt;0.01). According to the results of genetic testing, both groups of patients were divided into three subgroups: 1st subgroup (bb‑genotype carriers), 2nd subgroup (Bb‑genotype carriers), 3rd subgroup (BB‑genotype carriers). In the control group, the distribution was as follows: 27 (38.6%), 34 (48.6%) and 9 (12.8%) patients, in the main group — 13 (18.5%), 30 (42.8%) and 27 (38.7%) patients. With the presence of CP, there was a change in the distribution of alleles towards the BB genotype of the VDR gene, which was associated with a higher risk of osteoporosis. 35 (50.0%) patients with CP and 3 (3.8%) individuals from the control group had a history of bone fractures (p &lt;0.01). In CP, the average osteocalcin level was 22.20±2.53 ng/ml, 27 (38.6%) patients had normal levels, 15 (55.6%) of them had the Bb genotype, 7 (25.9%) — genotype BB, in 5 (18.5%) — genotype bb. A decrease in the level of osteocalcin below the norm (to 12.7±1.87 ng/ml) was registered in 4 (5.7%) patients, of which 2 (50.0%) had the BB genotype, 1 (25.0%) — Bb genotype, another 1 (25.0%) — bb genotype. A higher than normal level of osteocalcin (45.1±23.24 ng/ml) was recorded in 39 (55.7%) patients of the main group, of which 18 (43.6%) had the BB genotype, 14 (35.9%) — Bb genotype, 7 (20.5%) — bb genotype. Conclusions. The course of CP in most cases is accompanied by an increase in osteocalcin levels, which can be considered as an indicator of a violation of the mineral density of bone tissue. Changes in the ratio of genotypes of the VDR gene are registered in patients with CP, which gives reason to assume a violation of the absorption of vitamin D due to genetic aberrations. In the majority of patients with CP, in the presence of an unfavorable genotype (BB) of the VDR gene, an increase in the content of osteocalcin is observed, which can be explained by one of the ways of the formation of osteoporotic conditions — a violation of the differentiation of osteoblasts. Chronic pancreatitis can be considered as an unfavorable nosology that provokes interference in bone metabolism with a high probability of formation of osteoporotic conditions, which requires early diagnosis and prevention of complications.

Comparison of the severity of metabolic, liver and cardiovascular damage in NAFLD patients attending the hepatology clinic over the last three decades

Background and aimsNAFLD prevalence is increasing worldwide. Aim: to assess whether severity of hepatic, metabolic and cardiovascular (CV) disease changed over time. Methods422 NAFLD patients (388 biopsy proven and 34 clinical cirrhosis) diagnosed between 1990 and 2021 and subdivided according to decade of presentation. Metabolic parameters, early atherosclerosis (carotid plaques at Doppler ultrasound), severity of liver damage (NAS score, NASH, significant fibrosis (≥2) and cirrhosis) and PNPLA3 genotyping were assessed. ResultsNo difference in age, sex and prevalence of dyslipidemia and hypertension was found across decades (p for trend), whereas a higher prevalence of diabetes (p = 0.02), obesity (p<0.001), histological severe steatosis (p<0.001), NASH (p<0.001), fibrosis ≥2 (p<0.001), cirrhosis (p<0.001) and carotid plaques (p = 0.05) was observed in the last decade compared to the others. A higher prevalence of PNPLA3 GG polymorphism was found over time (p = 0.02). In the whole cohort, age, metabolic alterations and PNPLA3 G homozygosity were independent risk factors for hepatic fibrosis and carotid plaques, independently of the decade considered. ConclusionOver the past 10 years compared to previous decades, NAFLD patients presented to observation with more severe liver disease and subclinical atherosclerosis, paralleling the spread of diabetes and obesity. PNPLA3 unfavorable genotype became more prevalent over time.

Influence of polymorphic variations of IFNL, HLA, and IL-6 genes in severe cases of COVID-19.

The administration of vaccination doses to the global population has led to a decrease in the incidence of COVID-19. However, the clinical picture developed by infected individuals remains extremely concerning due to the great variability in the severity of cases even in vaccinated individuals. The clinical progression of the pathology is characterized by various influential factors such as sex, age group, comorbidities, and the genetics of the individual. The immune response to viral infections can be strongly influenced by the genetics of individuals; nucleotide variations called single-nucleotide polymorphisms (SNPs) in structures involved in the innate and adaptive immune response such as interferon (IFN)-λ, human leukocyte antigen (HLA), and interleukin (IL)-6 are frequently associated with pathological progression. In this study, we conducted a review of the main SNPs of these structures that are associated with severity in COVID-19. Searches were conducted on some platforms of the National Center for Biotechnology and Information (NCBI), and 102 studies were selected for full reading according to the inclusion criteria. IFNs showed a strong association with antiviral function, specifically, IFN-λ3 (IL-28B) demonstrated genetic variants commonly related to clinical progression in various pathologies. For COVID-19, rs12979860 and rs1298275 presented frequently described unfavorable genotypes for pathological conditions of hepatitis C and hepatocellular carcinoma. The high genetic variability of HLA was reported in the studies as a crucial factor relevant to the late immune response, mainly due to its ability to recognize antigens, with the HLA-B*46:01 SNP being associated with susceptibility to COVID-19. For IL-6, rs1554606 showed a strong relationship with the clinical progression of COVID-19. In addition, rs2069837 was identified with possible host protection relationships when linked to this infection.

Genetic variants of SOS2, MAP2K1 and RASGRF2 in the RAS pathway genes predict survival of HBV-related hepatocellular carcinoma patients.

The RAS pathway participates in the cascade of proliferation and cell division process, and the activated RAS pathway can lead to tumorigenesis including hepatocellular carcinoma (HCC). However, few studies have explored the effects of genetic variants in the RAS pathway-related genes on the survival of patients with HBV-related HCC. In the present study, we assessed the associations between 11,658 single-nucleotide polymorphisms (SNPs) in 62 RAS pathway genes and the overall survival (OS) of 866 HBV-related HCC individuals, which were randomly split (1:1) into discovery and validation datasets. As a result, three potentially functional SNPs were identified, based on multivariable cox proportional hazards regression analyses, in SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2, rs4632055 A > G), Ras protein-specific guanine nucleotide releasing factor 2 (RASGRF2, rs26418A > G) and mitogen-activated protein kinase 1 (MAP2K1,rs57120695 C > T), which were significantly and independently associated with OS of HBV-related HCC patients [adjusted hazards ratios (HRs) of 1.42, 1.32 and 1.50, respectively; 95% confidence intervals (CI), 1.14 to 1.76, 1.15 to 1.53 and 1.15 to 1.97, respectively; P = 0.001, < 0.001 and 0.003, respectively]. Additionally, the joint effects as the unfavorable genotypes of these three SNPs showed a significant association with the poor survival of HCC (trend test P < 0.001). The expression quantitative trait loci (eQTL) analysis further revealed that the rs4632055 G allele and the rs26418 A allele were associated with lower mRNA expression levels of SOS2 and RASGRF2, respectively. Collectively, these potentially functional SNPs of RASGRF2, SOS2 and M2PAK1 may become potential prognostic biomarkers for HBV-related HCC after hepatectomy.

Genetic variants of IFIH1 and DHX58 affect the chronicity of hepatitis C in the Chinese Han population.

Hepatitis C remains a major public health problem in the world. The host immune system plays a key role in viral clearance. This study aimed to investigate the connection between retinoic acid-inducible gene I-like (RIG-I-like) receptor gene polymorphism and hepatitis C chronicity in the Chinese Han population. The current study genotyped three SNPs (IFIH1 rs10930046 and DHX58 rs2074158, rs2074160) to assess their association with the chronicity of hepatitis C virus (HCV) infection among 1,590 participants (590 spontaneous HCV clearance cases and 1,000 persistent infection patients). Our research shows that DHX58 rs2074158-G allele (dominant model: adjusted OR = 1.53, 95% CI [1.20-1.95], P=0.001; additive model: adjusted OR = 1.50, 95% CI [1.27-1.78], P<0.001) and IFIH1 rs10930046-C allele (additive model: adjusted OR = 1.26, 95% CI [1.07-1.49], P=0.005) were associated with chronic hepatitis C (CHC). And the risk of CHC increased in people carrying more unfavorable genotypes (rs2074158-AG/GG or rs10930046-CC), with the chronic rates for genotypes number from zero to two in 60.69%, 57.33%, and 85.93%, respectively (adjusted OR = 3.64, 95% CI [2.18-6.08]; P<0.001). Genetic polymorphism of IFIH1 and DHX58 may be related to CHC in the Chinese Han population. Furthermore, the risk of CHC increases as the number of unfavorable genotypes carried by the HCV-infected person increases. IFIH1 rs10930046, DHX58 rs2074158, age, ALT, and AST levels were all independent predictors of CHC.

Эндотелиальная дисфункция при привычном невынашивании беременности: генетические факторы и факторы внешней среды

Objective. To examine the association between the carriage of endothelial dysfunction-related gene polymorphisms and recurrent pregnancy loss (RPL). Patients and methods. This case-control study included 87 patients who were divided into two groups. The study group consisted of 65 patients with a history of two or more consecutive pregnancy losses (2 to 11 losses). Primary RPL was detected in 20 patients, secondary in 26, and tertiary in 19. The control group consisted of 22 women with a history of three or more full-term births without episodes of miscarriage. The frequency of polymorphisms of the VEGFA -634G&gt;C and IL6 -174G&gt;C genes was determined by a ready-to-use real-time polymerase chain reaction (RT-PCR) test kits. Results. Carrying the VEGFA -634G&gt;C GC genotype increases the risk of RPL 4-fold (p = 0.0072) and the IL6 -174G&gt;C GC genotype – 3-fold (p = 0.028). Analysis of the impact of combinations of unfavorable genotypes showed that 65.0% of patients with primary RPL, 61.5% with secondary RPL, 63.2% with tertiary RPL, and 9% of healthy controls had a combination of GC VEGFA -634G&gt;C and CC IL6 -174G&gt;C. One of the key environmental factors determining the realization of susceptibility genes is age: the maximum age at the time of the first intended pregnancy was observed in patients with primary RPL (32.6 years vs. 25.5 years in the control group; p &lt; 0.05), with 9% of healthy controls having a combination of two genotypes associated with pregnancy loss. That is, successful pregnancy at a younger age is possible even when carrying multiple risk alleles. The birth interval length is also important for successful pregnancy: a short inter-pregnancy interval allows to carry out the reproductive function during the most favorable period of the reproductive system before the influence of genotypes predisposing to RPL begins. Other environmental factors leading to the realization of carriage of RPL risk alleles include a history of intrauterine interventions and sexually transmitted infections. Conclusion. Study of the VEGFA -634G&gt;C and IL6 -174G&gt;C gene polymorphisms may serve as an effective method to predict RPL. For patients carrying these unfavorable gene polymorphisms, it is especially important to perform the reproductive function in time, i.e., before the realization of environmental factors. Key words: recurrent pregnancy loss, VEGF, endothelial dysfunction, susceptibility genes

Genetic predisposition to gestational diabetes mellitus in the Kazakh population

Background and aimsThe purpose of the study was to conduct a comparative analysis of population frequencies of alleles and genotypes of polymorphic variants of genes for impaired insulin synthesis and associated with insulin signal transduction. MethodsThis investigation uses a genomic database of 1800 conditionally healthy individuals of Kazakh ethnicity, who underwent full genome genotyping using OmniChip 2.5–8 Illumina chips of ∼2.5 million Single Nucleotide Polymorphism at deCODE Iceland Genomic Centre. ResultsThe highest frequency of carriage of minor A allele – 17.6% rs4607517 polymorphism of Glucokinase gene, unfavorable genotypes A/G – 29.5% and A/A – 3.0% in comparison with European and Asian populations, indicates a contribution of hereditary family forms of Maturity-onset diabetes of the young type 2 to gestational diabetes mellitus in Kazakh population. ConclusionsThe study of the associations of genetic markers of gestational diabetes mellitus will allow timely identification of high-risk groups before and at an early stage of pregnancy, carrying out the necessary effective preventive measures and, in the case of gestational diabetes mellitus development, optimizing the correction of carbohydrate metabolism disorders and predicting outcomes for the mother and the fetus.

Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy?

Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma with heterogeneous clinical presentation. As there are no randomised trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed-duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavourable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-haematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Giving fixed-duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still our preferred choice in WM. However, BTKi remain a valuable option in frail patients unsuitable for CIT.

Polymorphism of genes that characterize the functional state of the vascular wall in newborns born to mothers with preeclampsia

The features of polymorphism of genes characterizing the functional state of the vascular wall in newborns born to mothers with preeclampsia were studied. 150 children were examined, the main group consisted of 100 newborns born to mothers with preeclampsia (PE), the control group included 50 children born to women without preeclampsia. Single-nucleotide polymorphisms were determined in the blood of newborns: ADD1 G1378T (rs4961), AGT T704C (rs699), AGT C521T (rs4762), AGTR1 A1166C (rs5186), AGTR2 G1675A (rs1403543), CYP11B2 –344 C/T (rs1799998), GNB3 C825T (rs5443), NOS3 –786 T/C (rs2070744), NOS3 G894T (rs1799983) using the real-time polymerase chain reaction method with the DTprime 5 device (DNA-Technology, Russia) and the Cardiogenetics kit (DNA-Technology, Russia). The genetic analysis revealed that newborns born to mothers with PE were significantly more likely to have unfavorable genotypes АDD1 1378 G/T, AGT 704 T/C, AGT 704 C/C, AGTR2 1675 A/A, NOS3 (-786) C/C, NOS3 894T/T and alleles АDD1 1378T, AGT 704 C, AGTR2 1675A, NOS3 (-786) C, NOS3 894T. In newborns from mothers without PE, genotypes homozygous for the “wild type” alleles were significantly more common: АDD1 1378 G/G, AGT 704 T/T, CYP11B2 (-344) C/C, NOS3 (-786) T/T, NOS3 894 G/G and the NOS3 (-786) T allele. The revealed changes in newborns born to mothers with PE indicate an increased risk of developing disorders of the cardiovascular system.

Gene Polymorphism and Total Genetic Score in Martial Arts Athletes with Different Athletic Qualifications.

The personalized approach in sports genetics implies considering the allelic variants of genes in polymorphic loci when adjusting the training process of athletes. The personalized approach is used both in sports genetics and in medicine to identify the influence of genotype on the manifestations of human physical qualities that allow to achieve high sports results or to assess the impact of genotype on the development and course of diseases. The impact of genes of the renin-angiotensin and kinin-bradykinin systems in the development of cardiovascular disease in athletes has not been defined. This study aims to determine the polymorphisms of four genes (ACE, BDKRB2, PPARGC1A and NOS3) and the total genetic score to reveal the predisposition to the formation of physical qualities in martial arts athletes with different athletic abilities. The products of these four genes are involved in the control of blood pressure. The allelic variants of these genes are associated with the development of the physical quality “endurance” and have an indirect influence on the formation of speed and power qualities. The total genetic score (TGS: from 0 to 100 arbitrary units) was calculated from the genotype score in each polymorphism. The athletes were divided into Group I with high and Group II with low qualifications depending on their sports success. Single nucleotide polymorphisms (SNPs) are identified through restriction endonucleases cleavage for PCR amplicons for discriminating between alleles of the target genes ACE (rs4646994), BDKRB2 (rs5810761), PPARGC1A (rs8192673) and NOS3 (rs1799983). Significant differences between the allelic variants of target genes and athletic ability were found between Group I and Group II for genotype G/G of NOS3 gene and genotypes Gly/Gly and Gly/Ser of PPARGC1A gene. The data obtained confirm that athletes with unfavourable genotypes are excluded in the screening phase because their endurance is not fully developed to the required level in martial arts. Martial arts athletes with the highest TGS have the highest skill level. Polymorphic loci of four genes whose products are involved in blood pressure control (ACE, BDKRB2, NOS3 and PPARGC1A) can be used in martial arts not only to determine predisposition to cardiovascular disease but also to predispose to the development of speed and power qualities and endurance. The total genetic score can serve as a tool for predicting athletic success.