Allelic Variants Research Articles

The role of SPINK5 mutation distribution in phenotypes of Netherton syndrome

ObjectiveNetherton syndrome (NS) is a rare hereditary dermatosis, and the correlation between genotype and phenotype in this disease warrants further investigation. This study aimed to explore the genotype-phenotype correlation in NS.MethodsWe collect cases from our clinic and relevant literature. After rigorous screening, we included 162 patients with NS-associated symptoms and SPINK5 mutations. We characterized the distribution and mutation types of allele variants. Logistic regression was employed to analyze the correlation between the location of these variants and phenotypes. Additionally, the association between the homozygous condition of variants and death during infancy was analyzed using the Chi-square test.ResultsAmong 162 patients, we identified 324 allele variants, comprising 75 different mutations. Of these, 73 patients carried heterozygous variants, while 89 patients had homozygous variants. We observed that patients with variants or homozygous variants located in the 5′ half of the gene were more likely to experience failure to thrive (P < 0.05). Similarly, variants or homozygous variants located outside DomainR-5 were also associated with an increased risk of failure to thrive (P < 0.05). Furthermore, variants in domain regions were significantly correlated with the presence of ichthyosis linearis circumflexa (P < 0.01). Patients with homozygous fatal variants (c.153delT, c.1431-12G>A, c.1111C>T, c. 1887 + 1G>A, and c. 995delT) had a higher likelihood of mortality during infancy (P < 0.001).ConclusionOur study provides valuable insights into the genotype-phenotype correlation in Netherton syndrome, enhancing our understanding of the disease and potentially informing the development of future therapeutic approaches.

ИЗМЕНЕНИЕ ПОКАЗАТЕЛЕЙ ГЕНЕТИЧЕСКОЙ СТРУКТУРЫ ПОПУЛЯЦИИ СОРТОВ ОВСА, ВОЗДЕЛЫВАЕМЫХ В ТЮМЕНСКОЙ ОБЛАСТИ, ЗА 90-ЛЕТНИЙ ПЕРИОД

The study of indicators of the genetic structure of the population and their changes over time is important for improving the efficiency of the breeding process and competent management of the development of populations of varieties. High efficiency in such studies was shown by prolamin-coding loci. The aim of research was to assess changes over time in the indicators of the genetic structure of the populations of oat varieties included in the State Register of Breeding Achievements in the Tyumen Region from 1929 to 2021 using multiple alleles of avenin-coding loci. The material for the study was 19 varieties of oats. Eight different alleles were identified for the Avn A locus, 7 for the Avn B locus, and 6 for the Avn C locus. C2 and Cnew. Allelic variants A1, A5, Anew, B1, Bnew1, Bnew2 and C1 had a low frequency of occurrence and were eliminated from the population within several decades. The most stable values of intrapopulation diversity and the proportion of rare morphs over time are typical for the Avn A locus. The value of intrapopulation diversity at the Avn B and Avn C loci changed in waves, while periods of a decrease in the value of this indicator for one of the loci were accompanied by its increase for another. The intrapopulation diversity of oat varieties is currently characterized as high. The indicator of the proportion of rare morphs has a low value (0.04–0.09), which indicates the stability of the analyzed population. The alleles of the Avn B and Avn C loci are promising for study as markers of gene associations that determine adaptively significant traits, and the Avn B locus is economically valuable traits in the conditions of the Tyumen Region.

In vitro comparative analysis of metabolic capabilities and inhibitory profiles of selected CYP2D6 alleles on tramadol metabolism.

Tramadol, the 41st most prescribed drug in the United States in 2021 is a prodrug activated by CYP2D6, which is highly polymorphic. Previous studies showed enzyme-inhibitor affinity varied between different CYP2D6 allelic variants with dextromethorphan and atomoxetine metabolism. However, no study has compared tramadol metabolism in different CYP2D6 alleles with different CYP2D6 inhibitors. We hypothesize that the inhibitory effects of CYP2D6 inhibitors on CYP2D6-mediated tramadol metabolism are inhibitor- and CYP2D6-allele-specific. We performed comparative analyses of CYP2D6*1, CYP2D6*2, CYP2D6*10, and CYP2D6*17 using recombinant enzymes to metabolize tramadol to O-desmethyltramadol, measured via UPLC-MS/MS. The Michaelis constant (Km) and maximum velocity (Vmax) for each CYP2D6 allele, and IC50 values for different inhibitors were determined by nonlinear regression analysis. Intrinsic clearance was calculated as Vmax/Km. The intrinsic clearance of tramadol was almost double for CYP2D6*2 (180%) but was much lower for CYP2D6*10 and *17 (20% and 10%, respectively) compared to CYP2D6*1. The inhibitor potencies (defined by Ki) for the various inhibitors for the CYP2D6*1 allele were quinidine > terbinafine > paroxetine ≈ duloxetine >>bupropion. CYP2D6*2 showed the next greatest inhibition, with Ki ratios compared to CYP2D6*1 ranging from 0.96 to 3.87. For each inhibitor tested, CYP2D6*10 and CYP2D6*17 were more resistant to inhibition than CYP2D6*1 or CYP2D6*2, with most Ki ratios in the 3-9 range. Three common CYP2D6 allelic variants showed different metabolic capacities toward tramadol and genotype-dependent inhibition compared to CYP2D6*1. Further studies are warranted to understand the clinical consequences of inhibitor and CYP2D6 genotype-dependent drug-drug interactions on tramadol bioactivation.

P0002 Identification of Infliximab and Adalimumab -derived peptides using MHC class II antibody mediated immunopeptidomics and mass spectrometry: implications for drug re-design

Abstract Background Monoclonal antibodies against tumour necrosis factor (TNF) such as Infliximab (IFX) and Adalimumab (ADA) are used as first line therapy against inflammatory bowel disease (IBD) and have proven efficacy. However, in up to 40% of IBD patients these drugs become ineffective after the first year, principally due to the development of anti-drug immunogenicity. Distinct allelic variants at the HLA DQ1 locus predispose patients to develop immunogenicity to IFX or ADA (1, 2, 3). The aim of this study is to identify peptides derived from IFX and ADA that are presented on class II MHC of antigen presenting cells, in order to determine the epitopes that may play a role in T cell mediated immunogenicity against anti-TNF therapy. This may allow rational drug re-design. Methods Monocyte-derived dendritic cells (MDDCS) from 8 different donors, as well as EBV-transformed B cell lines from 3 different donors of known HLA-type were cultured and pulsed with IFX and ADA. Unpulsed cells were used as a negative control. Cells were processed for sequential immune precipitation with HLA-DQ, HLA-DP and HLA-DR antibodies. Peptides were then purified and analysed by mass spectrometry. These were run against a database of known proteins, including IFX and ADA, using the Peaks analytical software and then mapped to the original protein. Peptides were subjected to a binding prediction algorithm, to determine the likelihood of individual peptides binding to each HLA allele combinations. Peptides were then ranked from highest to lowest binder. Results Analysis of peptides from all three MHC class II antibody fractions showed that the highest number of peptides immunoprecipitated were between 14 to 16 amino acids in length, in line with the predicted length for class II MHC proteins. Additionally, there was an enrichment of peptides predicted to bind to specific class II MHC molecules, with an average of 77% binders versus 23% non-binders for MDDCs, and 84% binders versus 16 % non-binders for B-cells, after immune precipitation. Several overlapping peptides from the variable regions of both the heavy and light chain of IFX and ADA were identified, some of which are predicted to bind to risk alleles for anti-TNF immunogenicity, including DQA1*05:01, DRB1*11:01 and HLA-DQA1*05:05 (Figures 1 and 2). Conclusion We have characterised a series of IFX and ADA derived peptides from MDDCs and B cell lines, that were pulsed with anti-TNF antibody drugs. These peptides represent candidate T cell epitopes that may play a role in eliciting anti-drug antibody responses, and these data will therefore contribute to the understanding of the molecular mechanism of anti-TNF treatment failure. References 1)Doherty R, Liao H, Satsangi J, Ternette N. Extended Analysis Identifies Drug-Specific Association of 2 Distinct HLA Class II Haplotypes for Development of Immunogenicity to Adalimumab and Infliximab. Gastroenterology. 2020, 159: 784-787. 2)Sazonovs A, Kennedy N, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease Gastroenterology. 2020, 158:189-199 3)Ternette N, Liao H., Satsangi J. Association of the HLA DQA1*05 allelic gene variants with immunogenicity to anti-TNF therapeutics - important differences between infliximab and adalimumab. Journal of Crohn's and Colitis. 2024

Associations between IL-33 gene and IL1RL1 gene variants in periodontitis

Background: Periodontitis is initiated by a dysbiosis in the subgingival microbial biofilm and can be related to host genetic factors. This study investigated association between periodontitis and single nucleotide variants (SNVs) in the IL-33 and IL1RL1 genes. Methods: This cross-sectional study involved 359 individuals from a public health service in Brazil. Structured questionnaire was used to collect health status and socioeconomic, demographic and behavioral characteristics. Periodontitis was diagnosed by clinical periodontal examination. Subgingival biofilm was collected at the deepest site of each sextant, and biofilm bacterial DNA was amplified by real time polymerase chain reaction (qPCR) to determine relative quantification of pathogens. Peripheral blood was collected for genomic DNA extraction and SNV genotyping was performed by qPCR. Logistic regression model was used to obtain association measures (95% confidence interval), by ussing the additive model. Results: The C allele variant of IL33 (rs2381416) was inversely associated with periodontitis, even after adjusting for the confounding covariates (p < 0.01 ORadjusted: 0.45; CI: 0.24-0.84), and with the presence of the Aggregatibacter actinomycetemcomitans (Aa) pathogen, adjusting for the same covariates (p < 0.01; ORadjusted: 0.46; CI: 0.27-0.76). Inverse association between this SNV and periodontitis was observed (p = 0.02; ORadjusted: 0.46; CI: 0.28-0.76) using additive genotypic model. Conclusions: Frequency of C allele variant of IL-33 (rs2381416) was lower in individuals with periodontitis and in individuals with relatively higher levels of Aa. Investigations of this variant as a potential predictor of the protective phenotype in the context of periodontitis are needed. This study will contribute to the training of health professionals involved in the treatment of periodontitis.

Are rs1042059 and rs11591377 polymorphisms of BMI1 gene related to leukemia?

Hematologic malignancies, originating from uncontrolled growth of hematopoietic and lymphoid tissues, constitute 6.5% of all cancers worldwide. Various risk factors including genetic disorders and single nucleotide polymorphisms play a role in the pathogenesis of hematologic malignancies. BMI1 is one of the genes involved in regulating the self-renewal and differentiation of hematopoietic stem cells. 69 leukemia patients (45 AML, 18 ALL, and 6 CML) along with 80 control samples were selected. The frequency of rs1042059 and rs11591377 polymorphisms of BMI1 gene was evaluated using the Tetra-ARMS PCR technique. A significant difference in the prevalence of rs1042059 and rs11591377 polymorphisms was observed between the patient and control groups (P = < 0.001). The frequency of GA genotypes for both polymorphisms was higher in patients compared to the control group. Additionally, a significant difference was found in the prevalence of rs11591377 genotypes among the AML, ALL, and CML groups (P = 0.002) however, no significant difference was observed in the prevalence of rs1042059 genotypes among them (P = 0.578). Considering the significant decrease in the prevalence of allelic variants in the control group compared to the leukemia group, the association of BMI1 with leukemias should be considered as a diagnostic and prognostic factor.

Comparison and Classification of LMW-GS Genes at Glu-3 Loci of Common Wheat.

The low molecular weight glutenin subunits (LMW-GS) of wheat have great effects on food processing quality, but the resolution of LMW-GS and the scoring of their alleles by direct analysis of proteins are difficult due to the larger number of expressed subunits and high similarity of DNA sequences. It is important to identify and classify the LMW-GS genes in order to recognize the LMW-GS alleles clearly and develop the functional markers. The LMW-GS genes registered in GenBank were searched at NCBI, and 593 Glu-3 genes with complete coding sequences were obtained, including 146 Glu-A3, 136 Glu-B3, and 311 Glu-D3. Sequence analysis and characterization of DNA and deduced amino acids were performed using the software DNAman. The alignment and classification showed that there were at least 9 genes with 69 allelic variants at the Glu-A3 locus, 11 genes with 64 allelic variants at the Glu-B3 locus, and 10 genes with 96 variants at the Glu-D3 locus, respectively. Furthermore, the specificity of some Glu-3 genes and their variations was analyzed. The results were beneficial to understanding the LMW-GS genes fully and to developing the functional markers and will provide a theoretical reference for the quality improvement of wheat variety.

Chromosome-scale and haplotype-resolved genome assembly of Populus trichocarpa

Abstract Populus trichocarpa, a pivotal model organism for woody transgenic research, not only garners substantial scientific interest but plays an integral role in forestry economics. Previous genomic assemblies of P. trichocarpa predominantly treated its heterozygous genome as homozygous, thereby neglecting crucial haplotypic diversity. Leveraging the high fidelity (HiFi) sequencing capabilities of PacBio sequencing and the chromosome conformation capture insights provided by Illumina's Hi-C technique, this study is the first to achieve a near telomere-to-telomere assembly of both paternal and maternal haplotypes in P. trichocarpa. Comparative genomic analysis between these haplotypes has uncovered several allelic variants and pathways critical for trait determination through allele-specific expression. Furthermore, utilizing RNA-seq data from multiple tissues, this investigation has detailed the tissue-specific expression patterns of the leucine-rich repeat (LRR) gene family, which are essential in mediating plant signal transduction and developmental regulation. Our results not only illuminate the functional genomics landscape of P. trichocarpa but also provide invaluable theoretical underpinnings for the genetic improvement of woody plants and a robust framework for exploring genetic variability and allelic expression disparities in arboreal species.

Genetic Variants and Lifestyle Factors in Androgenetic Alopecia Patients: A Case-Control Study of Single Nucleotide Polymorphisms and Their Contribution to Baldness Risk.

We conducted a study to investigate the role of specific allelic variants in AGA controlling for nutritional and lifestyle factors. Individual patterns of SNPs present in the baldness susceptibility locus at 20p11 (rs1160312 and rs6113491) or close to the androgen receptor (AR) gene in chromosome X (rs1041668) were investigated in 212 male subjects. Information on socio-demographic characteristics, medical history, smoking, and diet was also collected. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). After controlling for age, diet, BMI, family history of AGA, and smoking, an increased risk of AGA was found for subjects with [A] alleles for both rs1160312 (OR: 2.97; 95% CI: 1.34-6.62) and rs6113491 (OR: 2.99; 95% CI: 1.37-6.52), and for subjects with the TT genotype for rs1041668 (OR: 4.47; 95% CI: 1.60-12.5). Multivariate logistic regression indicates that diet, familiarity, and BMI, but not smoking, remain statistically significant despite the different SNP genotypes. To our knowledge, this is the first indication that the rs1160312, rs6113491, and rs1041668 polymorphisms are independent risk factors for AGA that can be modulated by diet.

Genetic Variants Related to Increased CKD Progression-A Systematic Review.

The incidence and prevalence of chronic kidney disease (CKD) are increasing worldwide. CKD is associated with high morbidity, premature mortality, and high healthcare costs. Genetic variants may influence CKD development and progression. This study aimed to identify the associations between allelic variants and CKD progression. We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed, Embase, and Cochrane Central databases were used for data collection. Hereditary causes of CKD were excluded from the analysis. A total of 38 reports were included. The selected studies included cohort studies, case-control studies, and genome-wide association studies (GWASs). The studies involved patients of different ethnicities and with comorbid diseases. Several genetic variants were identified in genes that encode proteins related to metabolic processes, oxidative stress, immune regulation, the renin-angiotensin-aldosterone pathway, and epigenetics, among others. These genetic alterations can affect protein function and lead to renal damage, impacting CKD development and progression. Gene polymorphisms can influence CKD progression. Many of these are population-specific, and their relevance may be influenced by the presence of other diseases and environmental factors. Larger studies are needed to confirm the associations described here.

Involvement of HLADQA1*05 in Patients with Inflammatory Bowel Disease Treated with Anti-TNF Drugs.

Background: Over the past decade, TNF inhibitors such as Infliximab and Adalimumab have become central to Inflammatory Bowel Diseases treatment, greatly enhancing patient outcomes. However, immunogenicity-where anti-drug antibodies diminish effectiveness-remains an issue, often requiring dose changes or combination therapies. Pharmacogenomics is increasingly applied in IBD to personalise treatment, especially since genetic factors like the HLA-DQA1*05 variant heighten the immunogenicity risk with IFX. This study aims to examine the relationship between the HLA-DQA1*05 variant and response loss or antibody development in patients regularly monitored on IFX or ADA. Methods: Sixty-five paediatric IBD patients were enrolled, with therapeutic drug monitoring (TDM) of IFX and ADA, conducted using immunoenzymatic assays. The presence of the HLA-DQA1*05 T>C allele variant was also tested using a Biomole HLA-DQA1 Real-time PCR kit. Results: The HLA-DQA1*05 rs2097432 T>C allele was present in 54% of patients on IFX and 69% of those on ADA. No statistically significant differences were found between HLA carriers and non-carriers across any of the three analysed groups: IFX, ADA and the overall anti-TNFα. Conclusions: Our study suggests that the HLA-DQA1*05 allele does not increase the risk of secondary loss of response to anti-TNF therapy, likely because most patients were on a combination of anti-TNF agents and immunomodulators, which can lower anti-drug antibody production. Testing for HLA-DQA105 can aid in personalising treatment and optimising therapy to minimise immunogenicity risks.

Dissemination of arr-2 and arr-3 is associated with class 1 integrons in Klebsiella pneumoniae clinical isolates from Portugal.

\nKlebsiella pneumoniae is a common pathogen of healthcare-associated infections expressing a plethora of antimicrobial resistance loci, including ADP-ribosyltransferase coding genes (arr), able to mediate rifampicin resistance. The latter has activity against a broad range of microorganisms by inhibiting DNA-dependent RNA polymerases. This study aims to characterise the arr distribution and genetic context in 138 clinical isolates of K. pneumoniae and correlate these with rifampicin resistance. All isolates were subjected to whole-genome sequencing for species identification, typing and AMR genes identification, along with the determination of the minimum inhibitory concentration (MIC) of rifampicin. Molecular detection of arr genes and class 1 integrons was performed for rifampicin-resistant isolates. Efflux activity was investigated as a possible determinant of rifampicin resistance in isolates devoid of known genetic determinants. Twelve isolates exhibited high rifampicin MICs (≥ 64mg/L), 124 showed intermediate MICs (16-32mg/L) and two displayed low (8mg/L) MICs. Two arr allelic variants, arr-2 and arr-3, were found across one and nine K. pneumoniae isolates, respectively, all within class 1 integrons, including a newly described integron, and all associated with high rifampicin MICs (≥ 64mg/L). Elevated resistance levels were additionally linked to increased arr-2/3 expression and closer proximity to the promoter. No arr gene or rpoB mutations were found across the remaining two isolates and no correlation between efflux activity and high-level rifampicin resistance was found for both isolates. In conclusion, this study demonstrates that arr genes confer high levels of rifampicin resistance in K. pneumoniae highlighting its widespread dissemination within class 1 integrons.

An allelic atlas of immunoglobulin heavy chain variable regions reveals antibody binding epitope preference resilient to SARS-CoV-2 mutation escape.

Although immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited. We retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid polymorphism present within germline sequences of IGHV genes. We aassembled the sequences of IgM and IgD repertoire from 130 people to investigate the genetic variations in the population. A dataset comprising 10,643 SARS-CoV-2 spike-specific antibodies, obtained from COV-AbDab, was compiled to assess the impact of SARS-CoV-2 infection on allelic gene utilization. Binding affinity and neutralizing activity were determined using bio-layer interferometry and pseudovirus neutralization assays. Primary docking was performed using ZDOCK (3.0.2) to generate the initial conformation of the antigen-antibody complex, followed by simulations of the complete conformations using Rosetta SnugDock software. The original and simulated structural conformations were visualized and presented using ChimeraX (v1.5). We present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of in the population. Our comprehensive analysis of SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies. We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. We found that antibodies carrying the IGHV1-69*02 allele tended to bind to the RBD E2.2 epitope. The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-5*02 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD. This study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics. These findings underscore the importance of Ig alleles in vaccine design and therapeutic antibody development.

Characterisation of Staphylococcus aureus Strains and Their Prophages That Carry Horse-Specific Leukocidin Genes lukP/Q.

Leukocidins of Staphylococcus (S.) aureus are bicomponent toxins that form polymeric pores in host leukocyte membranes, leading to cell death and/or triggering apoptosis. Some of these toxin genes are located on prophages and are associated with specific hosts. The genes lukP/Q have been described from equine S. aureus isolates. We examined the genomes, including the lukP/Q prophages, of S. aureus strains belonging to clonal complexes CC1, CC350, CC816, and CC8115. In addition to sequencing, phages were characterised by mitomycin C induction and transmission electron microscopy (TEM). All lukP/Q prophages integrated into the lip2=geh gene, and all included also the gene scn-eq encoding an equine staphylococcal complement inhibitor. The lukP/Q prophages clustered, based on gene content and allelic variants, into three groups. One was found in CC1 and CC97 sequences; one was present mainly in CC350 but also in other lineages (CC1, CC97, CC133, CC398); and a third one was exclusively observed in CC816 and CC8115. Prophages of the latter group additionally included a rare enterotoxin A allele (sea320E). Moreover, a prophage from a CC522 goat isolate was found to harbour lukP. Its lukF component could be regarded as chimaera comprising parts of lukQ and of lukF-P83. A putative kinase gene of 1095 basepairs was found to be associated with equine strains of S. aureus. It was also localised on prophages. However, these prophages were different from the ones that carried lukP/Q, and three different integration sites of kinase-carrying phages were identified. These observations confirmed the presence of prophage-located important virulence-associated genes in equine S. aureus and that certain prophages might determine the host specificity of the staphylococcal strains they reside in.

Molecular characterization of a novel photoperiod-insensitive allele Ppd-B1a.3 and its effect on heading date in Chinese wheat (Triticum aestivum) cultivar Qingchun 37.

Breeders adjust wheat heading dates to improve regional adaptability and reduce or mitigate yield losses caused by meteorological disasters, pests and diseases. The Ppd-1 genes play a crucial role in determining wheat sensitivity to changes in day-length and serve as key regulators of heading dates once the vernalization requirement is satisfied. In this study, we identified a new allelic variant of the promoter region, Ppd-B1a.3, in the Chinese wheat cultivar Qingchun 37. Compared to the Ppd-B1b.1 (carried by Chihokukomugi), the main mutation sites in Ppd-B1a.3 include a substitution of C with G at the -505-bp, a T base insertion at the -625-bp, a mutation of TCG to GGT at the -632 to -634-bp, and a 163-bp insertion at the -691bp. Analysis of F2 populations indicated that Ppd-B1a.3 promotes heading and flowering (approximately 6days earlier in population 1 and 17days in population 2) under short-day conditions in a greenhouse. However, the evaluation of Ppd-B1a.3's effect under field conditions may be influenced by the copy number of the Ppd-B1 locus inherited from the other parent in the F2 populations. Ppd-B1a.3 disrupts circadian rhythm expression and exhibits a stronger effect on heading and flowering than the three-copy Ppd-B1 allele carried by Jing 411. Origin analysis suggests that Ppd-B1a.3 may have derived from non-native germplasm. These results deepen our understanding of wheat photoperiod genes and provide useful genetic resources for fine-tuning wheat heading dates during breeding.

ALLELIC VARIANTS OF MATRIX METALLOPROTEINASE TIPES 1 AND 3 GENES IN PRESCHOOL CHILDREN SUFFERING FROM RECURRENT RESPIRATORY

Matrix metalloproteinases (MMPs) have numerous physiological and pathological effects. In particular, they are involved in extracellular matrix degradation and remodeling, cell differentiation and apoptosis, immune and inflammatory mechanisms, embryogenesis, etc. Aim. To determine the state of interdependence between the allelic variants of the genes MMP-1-1607 (1G/2G) and MMP-3-1171 (5A/6A), on the one hand, and the different frequency of acute respiratory infections (ARI) in preschool children, on the other hand. Materials and methods. A total of 33 children (15 boys and 18 girls), aged 1-6 years, undergoing inpatient treatment for ARI were included in the clinical trial. The number of ARI episodes during the previous year of life was regarded. The distribution of allelic variants was also studied, specifically: 1) 1G/2G of the MMP-1 gene at position 1607 (rs 1799750) and 2) 5A/6A of the MMP-3 gene at position 1171 (rs 35068180). Statistical processing of the obtained digital data was performed using IBM SPSS Statistics 28 licensed software (No. 3922/01/2021). Results. The association between preschool children belonging to the subgroup with more frequent ARI episodes and the 2G/2G genotype for the rs 1799750 polymorphism locus of the MMP-1-1607 gene was demonstrated (OR=7.778; p1=0.008; p2=0.025; CI: 1.561 - 38.756). On the contrary, the 1G/2G genotype was significantly more frequent in patients forming a subgroup with fewer ARI episodes (OR=0.127; p1=0.014; p2=0.039; CI: 0.022 - 0.739). Furthermore, the 1G allele was more frequent in children with fewer ARI episodes, and the 2G allele was more frequent in those with a greater number of such episodes in their history (OR=2.778; p1=0.044; p2=0.080; CI: 1.016 - 7.639). At the same time, there was no association between alleles 5A and 6A and their corresponding genotypes, determined for the rs 35068180 polymorphism locus of the MMP-3 gene at position 1171, and subgroups of children with less frequent and more frequent ARI episodes. Conclusions. The results obtained suggest a significant dependence of the frequency of ARI episodes in preschool children on the studied genotypes (2G/2G and 1G/2G) of the MMP-1 gene (rs 1799750). They should be considered in predicting whether such children are at risk for recurrent course of ARI. The study was conducted within the framework of the initiative research work of the Department of Pediatrics with Childhood Infections of Luhansk State Medical University (Rubizhne, Ukraine) - "Current aspects of the influence of perinatal factors on the development of somatic pathology in children aged 1-14 years" (2017-2021, state registration number 0117U003041). No external funding was received for this study. The study was conducted in accordance with the tenets of the Declaration of Helsinki. The study protocol was approved by the local ethics committees of Bogomolets National Medical University and Luhansk State Medical University. Informed parental consent was obtained for the study in children. No conflict of interests was declared by the authors.

Association of GUCY1A3 (rs7692387), CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893) gene polymorphism with antiplatelet drug metabolism and prognosis of cardiovascular complications

Introduction: The identification of predictors for resistance to antiplatelet drugs including the search for new gene polymorphisms responsible for the development of the pathological process is an important direction to reduce the risk of complications after cardiac surgery and improve postoperative prognosis. Objective: The study was aimed at investigating the available data on the molecular genetic markers GUCY1A3 (rs7692387), CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893) and their association with antiplatelet drug metabolism and adverse outcome after cardiac surgery.Methods: The systematic review was conducted in accordance with the PRISMA criteria. The search was performed in databases Medline (PubMed), Google Scholar and the Russian Science Citation Index using queries and keywords. During the first selection, 3,210 results were obtained. The final analysis included 21 studies conducted between 2004 and 2024.Results: Since 2017 a number of studies have revealed the association of GUCY1A3 gene polymorphism with a high risk of cardiovascular diseases, as well as with an abnormal reaction to acetylsalicylic acid. The mechanism of the pathological process was related to the impact of gene polymorphism on vasoreactivity, platelet aggregation and, as a consequence, on the risk of thrombotic complications.Polymorphisms of CYP2C19*2 and CYP2C19*3 were the most common variants of alleles that reduced clopidogrel metabolism and increased the risk of cardiovascular events. However, therapy based on CYP2C19 genotyping requires a more detailed investigation with the inclusion of ethnic, demographic and socio-economic factors in the analysis.Conclusion: Resistance to acetylsalicylic acid, clopidogrel and other antiplatelet drugs depends on many genetic factors. Further investigation of the GUCY1A3 and CYP2C19 gene polymorphisms is promising for the development of algorithms for genotype-oriented antiplatelet therapy, the introduction of which into medical practice will reduce the number of complications after cardiac surgery and improve the quality of medical care. Received 16 September 2024. Revised 2 November 2024. Accepted 5 November 2024. FundingThe study did not have sponsorship. Conflict of interestThe authors declare no conflict of interest. Contribution of the authorsConception and study design: A.V. Kurguzov, O.V. KamenskayaData collection and analysis: I.Yu. Loginova, A.S. Isaev, D.V. DoroninDrafting the article: I.Yu. Loginova, A.S. KlinkovaCritical revision of the article: O.V. Kamenskaya, A.M. ChernyavskiyFinal approval of the version to be published: I.Yu. Loginova, A.V. Kurguzov, A.S. Isaev, O.V. Kamenskaya, D.V. Doronin, A.S. Klinkova, A.M. Chernyavskiy

Gene variability of natriuretic peptides in patients with rheumatic heart disease and atrial fibrillation

Introduction: Atrial fibrillation (AF) is one of the most common arrhythmias in rheumatic heart disease (RHD) patients. The pathophysiological mechanisms of AF development against the background of RHD are still understudied. Similarly to most cardiovascular pathologies, AF is a multifactorial disease with a significant genetic predeterminacy.Objective: The study was aimed at searching for associations of polymorphic gene variants of the natriuretic peptides (NPPA, NPPB and NPPC) with the AF risk in RHD patients. Methods: The study included 251 patients diagnosed with RHD, who were divided into 2 groups: patients with RHD and AF (n = 191) and patients with RHD without AF (n = 60). Genotyping of 7 allelic variants of genes encoding natriuretic peptides was performed using real-time polymerase chain reaction.Results: Polymorphic variants rs198388 and rs198389 of the NPPB gene were found to have a protective effect against the AF in RHD patients on the model of a codominant inheritance. The rs198358 allelic variant of the NPPA-AS1 gene was associated with the two-fold increased AF risk in RHD patients (OR 1.96, 95% CI 1.02-3.75, p = 0.037). Two models of gene-gene interactions characterized by the high efficacy and sensitivity have been identified in this study. The most significant combinations of genotypes associated with an increased AF risk in RHD patients were rs198388 C/T × rs198389 A/G × rs198358 T/C × rs5063 C/C × rs632793 A/G and rs198388 C/T × rs198358 T/ C × rs5063 C/C.Conclusion: Polymorphic gene variants of the natriuretic peptides (NPPB rs198388, rs198389 and NPPA-AS1 rs198358), associated with AF risk, were identified in RHD patients. Three-locus (NPPB rs198388, NPPA-AS1 rs198358 and NPPA rs5063) and five-locus (NPPB rs198388, NPPB rs198389, NPPA-AS1 rs198358, NPPA rs5063 and NPPA rs632793) models of gene-gene interactions were associated with the studied phenotype. Received 16 April 2024. Revised 10 October 2024. Accepted 2 November 2024. FundingThis research was supported by the Complex Program of Fundamental Research of the Siberian Branch of the Russian Academy of Sciences within the framework of the fundamental research project of the Research Institute for Complex Issues of Cardiovascular Diseases No. 0419-2022-0001. Conflict of interestThe authors declare no conflict of interest. Contribution of the authorsConception and study design: A.V. Sinitskaya, M.V. KhutornayaData collection and analysis: O.N. Hryachkova, A.O. Poddubnyak, M.V. Khutornaya, M.A. Asanov Statistical analysis: A.V. SinitskayaDrafting the article: A.V. SinitskayaCritical revision of the article: M.Yu. SinitskyFinal approval of the version to be published: A.V. Sinitskaya, M.V. Khutornaya, O.N. Hryachkova, A.O. Poddubnyak, M.A. Asanov, M.Yu. Sinitsky

Polymorphism of allelic variants of genes in dairy cow’s breed in the conditions of mountain and plain dagestan

In the Republic of Dagestan, where livestock farming is a key area, dairy cattle breeds such as Red Steppe and Caucasian Brown have not been studied in terms of genetic identification. Variations in the PIT1, PRL and GH genes associated with milk productivity can provide important insights into the adaptation of these breeds to various environmental conditions of Dagestan - from plains to mountains and foothills. This can also reveal the unique allelic characteristics of these genes, which is the central focus of our study. The DNA used for the study was extracted from the blood of Caucasian Brown cows bred in mountain (n=74) and foothill (n=52) vertical zonality, as well as the Red Steppe breed bred in the conditions of lowland Dagestan (n=52). The studied cattle populations were genotyped by the polymerase chain reaction method – restriction fragment length polymorphism (PCR-RFLP) on a programmable fourchannel thermal cycler "Tercik" of the company "DNA-technology" (Russia). The polymerase chain reaction (PCR) was carried out using synthesized specific primers. The study of the Caucasian brown cattle breed showed differences in the genetic profiles of individuals living in different ecosystems. In mountainous areas, the allele of the pituitary transcription factor PIT-1A occurs with a frequency of 0.10, while the allele PIT-1B - with a frequency of 0.90. On the contrary, in lowland areas, the proportion of the allele PIT-1A increases to 0.18, and PIT-1B decreases to 0.82. In the mountain zone, the genotypes PIT-1AA, PIT-1BB and PIT-1AB are 2.0%, 82.0% and 16.0%, respectively. In the plain zone, the genotype PIT-1AA is not observed. Cattle raised in certain natural conditions demonstrate unique allelic combinations that are the result of adaptation to the local environment. The data obtained allow us to take these features into account and use them in further breeding work.

Genetic Association Study of Acetylcholinesterase (ACHE) and Butyrylcholinesterase (BCHE) Variants in Sudden Infant Death Syndrome (SIDS).

Sudden infant death syndrome (SIDS) is the leading cause of death among infants aged between one month and one year. Altered enzyme activities or expression of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have been observed in SIDS patients that might lead to disturbed autonomic function and, together with other risk factors, might trigger SIDS. To explore the contribution of AChE and BChE from a genomic viewpoint, we sought to investigate the association between SIDS and selected single nucleotide polymorphisms (SNPs) in the ACHE and BCHE genes. In this case-control study, 13 potentially regulatory SNPs were selected from ACHE and BCHE and were genotyped in 201 SIDS cases and 338 controls. The association of SIDS with the 11 successfully genotyped candidate variants was examined using statistical analyses of overall or stratified cases and haplotype analyses. No significant overall associations were observed between SIDS and ACHE and BCHE variants in allele, genotype, and haplotype analyses. In subgroup analyses, eight variants were found to be nominally associated with SIDS, though these associations did not remain statistically significant after correction for multiple comparisons. One haplotype (T-C-G-C-C in rs3495-rs1803274-rs1355538-rs2048493-rs1126680) of BCHE was associated with the female SIDS subgroup (57.3% in controls vs. 46.3% in female SIDS cases, p = 0.010). The selected variants in ACHE and BCHE were not overall associated with SIDS in this study, and thus cannot generally explain the previously reported dysregulation of enzyme activities in SIDS. However, some evidence of association in subgroups and a possible contribution of variants other than those tested here would need to be explored in larger studies.