Search Results (1,666)

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is associated with significant renal complications, affecting disease progression and patient outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have emerged as a key therapeutic strategy, offering cardiovascular and renal benefits in these patients. However, interindividual variability in response to dapagliflozin underscores the role of pharmacogenetics in optimizing treatment efficacy. This study investigates the influence of genetic polymorphisms on renal outcomes in HFrEF patients treated with dapagliflozin, focusing on variations in genes such as SLC5A2, UMOD, KCNJ11, and ACE. Methods: This prospective, observational cohort study was conducted at the National Heart Institute, Cairo, Egypt, enrolling 200 patients with HFrEF. Genotyping of selected single nucleotide polymorphisms (SNPs) was performed using TaqMan™ assays. Renal function, including estimated glomerular filtration rate (eGFR), Kidney Injury Molecule-1 (KIM-1), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels, was assessed at baseline and after six months of dapagliflozin therapy. Results: Significant associations were found between genetic variants and renal outcomes. Patients with AA genotype of rs3813008 (SLC5A2) exhibited the greatest improvement in eGFR (+7.2 mL ± 6.5, p = 0.004) and reductions in KIM-1 (−0.13 pg/mL ± 0.49, p < 0.0001) and NGAL (−6.1 pg/mL ± 15.4, p < 0.0001). Similarly, rs12917707 (UMOD) TT genotypes showed improved renal function. However, rs5219 (KCNJ11) showed no significant impact on renal outcomes. Conclusions: Pharmacogenetic variations influenced renal response to dapagliflozin in HFrEF patients, particularly in SLC5A2 and UMOD genes. These findings highlighted the potential of personalized medicine in optimizing therapy for HFrEF patients with renal complications. Full article

Background: Fanconi Anemia (FA) is a rare disorder, characterized by chromosomal instability, congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. FA is caused by pathogenic variants in any of the 23 (FANCA-FANCY) linked genes. Procedure: Retrospective analysis of 13 FA patients with a causative variant was performed. Patients (6 boys and 7 girls) aged from 9 to 26 years old, (mean age of 7.3 years), at diagnosis. Results: Phenotype evaluation demonstrated in 11/13 patients’ congenital anomalies, with pigmentary changes and short stature, present in 90% of cases. Hematological abnormalities were present in 10/11 patients, with thrombocytopenia being the prominent finding. Genetic analysis for the most common complementation group FA-A revealed that 12/13 patients belonged to this group and only one patient was found to be FA-E. Exon deletions, single nucleotide variations, and duplications were identified. Familial patterns, due to consanguinity, were evident in one case. Twelve patients underwent hematopoietic stem cell transplantation (HSCT), with variable pre-HSCT supportive treatments. Post-HSCT data showed that 9 out of 10 patients for whom follow up data was available, survived for a median time of 5.4 years. Complications like acute graft-versus-host disease were noted. Conclusions: Our study highlights the importance of genotype towards tailored monitoring for children and families with FA. Full article

Background/Objectives: Non-syndromic cleft lip with or without palate (NSCL/P) is a common, multifactorial congenital anomaly. As genetic associations can be population-specific, this study aimed to investigate single-nucleotide polymorphisms (SNPs) in the VAX1, MAFB, and WNT3 genes for association with NSCL/P in a Japanese cohort. Methods: A case–control study was conducted with 310 Japanese patients with NSCL/P and 308 ethnically matched healthy controls from Aichi Gakuin Dental Hospital. We genotyped SNPs rs7078160 (VAX1), rs13041247 (MAFB), and rs3809857 (WNT3) using TaqMan assays. Associations were assessed using chi-squared tests, with results stratified by sex and corrected for multiple comparisons using the Bonferroni method. Results: The VAX1 rs7078160 A allele was significantly associated with an increased risk for NSCL/P (OR = 1.67, p < 0.00001). The association was particularly strong in females (OR = 1.93, p < 0.00001) but not significant in males after correction. The MAFB rs13041247 variant showed a nominal protective association with the NSCLO subtype that was not significant after Bonferroni correction. No significant association was found for WNT3. A notable gene–gene interaction was observed, where carrying risk alleles for both VAX1 and MAFB significantly increased overall NSCL/P risk (OR = 2.65, p = 0.00008). Conclusions: VAX1 rs7078160 is a significant risk factor for NSCL/P in the Japanese population, with a pronounced female-specific effect. A synergistic interaction between VAX1 and MAFB elevates disease risk, whereas WNT3 was not implicated in this cohort. These findings underscore the population-specific genetic architecture of NSCL/P. Full article

Background/Objectives: Cardiovascular diseases are a global health issue with an increasing burden and are exacerbated by hypertension. High blood pressure is partly attributed to genetic variants that are generally not well understood or extensively studied in sub-Saharan African populations. Variants linked to blood pressure have been found through genome-wide association studies (GWASs), which were mostly conducted among European ancestry populations; however, limited research has been undertaken in Africa. The current study evaluated single-nucleotide polymorphisms (SNPs) of PCSK9, ABCA1, LPL, and PON1 in relation to blood pressure measurements of 1839 Ghanaian adults. Methods: Genotypes were extracted from data generated by the H3Africa SNP array. After adjusting for sex, age, smoking, and body mass index (BMI), inferential statistics were used to investigate the relationships between SNPs and blood pressure (BP) indices. Additionally, Bonferroni correction was used to adjust for multiple testing. Results: Diastolic blood pressure (DBP) and the minor allele T of the PCSK9 variant (rs17111557) were positively associated at p = 0.006 after covariate adjustments. Although this novel DBP-associated variant is located in the 3′ untranslated region (3′ UTR) of the PCSK9 gene, in silico functional prediction suggests it is an expression quantitative trait locus (eQTL) that may change the binding site of transcription factors, potentially altering the rate of transcription and impacting DBP in this Ghanaian population. Conclusions: Our findings highlight the role of genetics in hypertension risk and the potential of discovering new therapies targeting isolated diastolic blood pressure in this rural African population. Full article

In this study we searched for correlations between polymorphic variants that determine sex hormone-binding globulin concentration (SHBG_con) and uterine fibroids (UFs). The work was performed on a sample of 1542 women (569 with UFs and 973 without UFs [control]), from whom we obtained experimental data on the distribution of nine single-nucleotide polymorphisms (SNPs) affecting the SHBG_con (data confirmed in genome-wide association studies [GWASs]). When searching for associations with UFs, both the independent effects of SNPs and the effects of their SNP–SNP interactions (SNP-SNP_ints) were taken into account during the “deep study” of the functionality of seven important UF loci and 115 strongly linked [r² ≥ 0.80] variants (an in silico methodology was used). As the results show, two SHBG_con-related SNPs correlated with UF risk: rs3779195 [T/A] BAIAP2L1 (OR_AA = 0.38; 95%CI_AA = 0.20–0.91; p_perm(AA) = 0.023) and rs440837 [A/G] ZBTB10 (OR_GG = 1.93; 95%CI_GG = 1.17–3.14; p_perm(GG) = 0.010). At the same time, seven SHBG_con-related SNPs interacting with each other (four models of such SNP-SNP_ints [p_perm ≤ 0.01)] were found to influence UF risk. These SHBG_con-related SNPs, determining susceptibility to UF, showed strong functional relevance and were involved in pathways of gene transcription regulation, interactions with hormone ligand-binding receptors, the content control of SHBG, testosterone, liver enzymes, lipids, etc. This study’s results demonstrate the effect of significant SHBG_con-related genetic determinants of UF risk. Full article

Dysregulated inflammatory processes contribute to depression, and gene–environment interactions may influence an individual’s risk and resilience. Reduced brain-derived neurotrophic factor (BDNF) expression increases susceptibility for developing depressive symptoms, and the Val66Met (rs6265) single-nucleotide polymorphism (SNP) on the BDNF gene is linked to mood disorders. However, whether Val66Met confers increased vulnerability to inflammation-induced depressive tendencies is unknown. Here, we tested the hypothesis that the Val66Met SNP increases vulnerability to inflammation-induced depressive symptoms in a mouse model of lipopolysaccharide (LPS)-induced depression-like behavior. Behavior and neuroinflammation, following a 24 h LPS challenge, were measured in mice expressing the human BDNF Val66Met gene variant or Val66Val littermates (control). The Val66Met genotype did not affect the peripheral inflammatory response, acute neuroinflammation, or the acute sickness behavior response. Val66Met mice exhibited anhedonia-like behavioral responses following LPS challenge, and we found increased mRNA expression of IL-1β and TNFα in the cerebrum compared to controls. The mRNA expression of IL-1β and TNFα in the hippocampus and the nucleus accumbens of Val66Met mice was increased following LPS, and a significant genotype × LPS interaction was detected for CD68 expression in the nucleus accumbens. In summary, these data suggest that immune activation in Val66Met mice increased susceptibility to anhedonic behavior and dysregulated negative regulation of inflammation. Full article

Periodontitis is a multifactorial disease linked to host immune response and genetic predisposition. The TLR4 Asp299Gly single-nucleotide polymorphism (SNP, rs4986790) has been associated with altered responses to bacterial lipopolysaccharide (LPS) and may influence susceptibility to inflammatory diseases. Given the central role of TLR4 in innate immune recognition of periodontal pathogens, this study investigates the role of rs4986790 in modulating susceptibility to periodontal inflammatory destruction. A total of 1410 individuals from four populations were genotyped, with findings indicating a significant protective effect of the polymorphic allele. Functional assays demonstrated enhanced IL-8 secretion and increased sensitivity to CD14 inhibition in cells expressing the variant receptor. These results suggest that rs4986790 modifies the LPS response via TLR4, potentially offering protection against periodontal breakdown. Full article

The role of G-quadruplexes (G4s) in gene regulation has been widely documented, especially in gene promoters. However, the transcriptional mechanisms involving G4s in other regulatory regions remain largely unexplored. In this study, we integrated the G4-DNA data derived from 22 breast cancer patient-derived tumor xenograft (PDTX) models and MCF7 cell line as potential breast cancer-associated G4s (BC-G4s). Genome-wide analysis showed that BC-G4s are more prevalent in gene promoters and the first introns. The genes accommodating promoter or intronic BC-G4s show significantly higher transcriptional output than their non-G4 counterparts. The biased distribution of BC-G4s in close proximity to the transcription start site (TSS) is associated with an enrichment of transcription factor (TF) interactions. A significant negative correlation was detected between the G4–TF interactions within the first introns and their cognate promoters. These different interactions are complementary rather than redundant. Furthermore, the differentially expressed genes (DEGs) harboring promoter and first intron BC-G4s are significantly enriched in the cell cycle pathway. Notably, promoter BC-G4s of DEGs could be a central hub for TF–TF co-occurrence. Our analysis also revealed that G4-related single nucleotide variants (SNVs) affect the stability of G4 structures and the transcription of disease-related genes. Collectively, our results shed light on how BC-G4s within promoters and first introns regulate gene expression and reinforce the critical role of G4s and G4-related genes in breast cancer-associated processes. Full article

This study identified four new keratin-associated protein genes (KRTAP19-n) in sheep: sKRTAP19-1, sKRTAP19-2, sKRTAP19-4, and sKRTAP19-6. These genes are closely related to the previously identified sheep genes KRTAP19-3 and KRTAP19-5, as well as to human KRTAP19-n genes. However, no clear orthologous relationships were found, suggesting complex evolutionary dynamics for this gene family. Extensive nucleotide sequence variation was observed across the four genes. sKRTAP19-1 had four variants, defined by four synonymous single-nucleotide polymorphisms (SNPs) and a variable number of “GGCTAC” hexanucleotide repeats. sKRTAP19-2 had five variants involving seven SNPs, three of which were non-synonymous. sKRTAP19-4 had five variants with nine SNPs (three being non-synonymous) and a three-nucleotide deletion. sKRTAP19-6 had eight variants, defined by 13 SNPs and a two-nucleotide consecutive substitution, with four of the SNPs being non-synonymous. One distinct variant each of sKRTAP19-4 and sKRTAP19-6 was found exclusively in Yanchi Tan sheep, with seven unique nucleotide differences compared to other variants. These unique variants were identical to the Romanov sheep genome in the region amplified (excluding the primer binding regions), suggesting a shared ancestral origin. The findings highlight considerable genetic diversity in ovine KRTAP19-n and lay a foundation for future research into their role in regulating wool fibre characteristics. Full article

The date palm (Phoenix dactylifera L.) is a key crop in the arid regions of North Africa and the Middle East, with substantial socioeconomic value. Although multiple genome assemblies have been generated using next-generation sequencing (NGS) technologies, they primarily focus on Middle Eastern cultivars, leaving North African varieties unrepresented. This study aims to address this gap by sequencing and assembling the first genome of a North African date palm using Illumina sequencing technology. We present a draft genome assembly of the elite Tunisian variety Deglet Nour. By comparing it with the Barhee BC4 reference genome, we identify key genetic variants, including single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs), potentially associated with ripening processes and fruit quality. This work expands the genomic resources for date palm research, particularly for North African cultivars, and provides new insights into the nucleotide-level variability of the genes linked to key agronomic traits. Full article

Background: Inflammatory bowel disease (IBD) is defined as recurrent inflammatory bowel disorders, the most common of which are Crohn’s disease (CD) and ulcerative colitis (UC). Tumor necrosis factor inhibitors (anti-TNFs), primarily adalimumab (ADA), infliximab (IFX), ustekinumab (UST), and vedolizumab (VLZ), are used to treat moderate-to-severe cases of IBD in patients who either do not tolerate or fail to respond to conventional therapies. However, about one-third of patients are primary non-responders to these treatments, and an additional 30% lose response over time. Several studies have investigated the role of genetic variability in explaining these differences in treatment response among patients. The aim of this study was to design an array of 60 single-nucleotide variants (SNVs) to validate the biomarkers described in the literature in a population of more than 400 IBD patients treated with biological drugs. Method: The primary focus of this study was the most recent reviews published in PubMed, with all relevant SNVs selected for the array design. Subsequently, studies presenting original data on the association between variants and the response to biological treatment were identified. Results: A total of 55.9% of SNVs have been studied in CD, 18.6% have been in UC, and 25.4% have been studied in both pathologies. A total of 44.1% of SNVs have been observed to influence the response to IFX, 16.9% influence the response to ADA, and 37.3% influence the response to both IFX and ADA; however, only one study (1.7%) reported an influence on the response to UST and none reported an influence on the response to VLZ. Conclusions: An array comprising 38 genes and 59 SNVs has been designed to be used to validate biomarkers associated with responses to biologic drug treatments in IBD. Full article

Anticoagulants, including warfarin, are often administered to patients who are exhibiting early symptoms of thromboembolic episodes or who have already experienced such episodes. However, warfarin has a limited therapeutic index and might cause bleeding and other clinical problems. Warfarin inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating vitamin K, in the coagulation cascade. Genetic factors, such as polymorphisms, can change the natural function of VKORC1, causing variations in the medication reaction among individuals. Hence, before prescribing warfarin, the patient’s genetic profile should also be considered. In this study, an electrochemical genosensor capable of detecting the VKORC1 1639 G>A polymorphism was designed and optimized. This analytical approach detects the electric current obtained during the hybridization reaction between two 52 base pair complementary oligonucleotide sequences. Investigating public bioinformatic platforms, two DNA sequences with the A and G single-nucleotide variants were selected and designed. The experimental protocol of the genosensor implied the formation of a bilayer composed of a thiolate DNA and an alkanethiol immobilized onto gold electrodes, as well as the formation of a DNA duplex using a sandwich-format hybridization reaction through a fluorescein labelled DNA signalling probe and the enzymatic amplification of the electrochemical signal, detected by chronoamperometry. A detection limit of 20 pM and a linear range of 0.05–1.00 nM was obtained. A clear differentiation between A/A, G/A and G/G genotypes in biological samples was successfully identified by his novel device. Full article

Background: HM is a rare, severe form of migraine with aura, characterised by motor weakness and strongly influenced by genetic factors affecting the brain. While pathogenic variants in CACNA1A, ATP1A2, and SCN1A genes have been implicated in familial HM, approximately 75% of cases lack known pathogenic variants in these genes, suggesting a more complex genetic basis. Methods: To advance our understanding of HM, we applied a variant prioritisation approach using whole-exome sequencing (WES) data from patients referred for HM diagnosis (n = 184) and utilised PathVar, a bioinformatics pipeline designed to identify pathogenic variants. Our analysis incorporated two strategies for association testing: (1) PathVar-identified single nucleotide variants (SNVs) and (2) PathVar SNVs combined with missense and rare variants. Principal component analysis (PCA) was performed to adjust for ancestral and other unknown differences between cases and controls. Results: Our results reveal a sequential reduction in the number of genes significantly associated with HM, from 20 in the first strategy to 11 in the second, which highlights the unique contribution of PathVar SNVs to the genetic architecture of HM. PathVar SNVs were more distinctive in the case cohort, suggesting a closer link to the functional changes underlying HM compared to controls. Notably, novel genes, such as SLC38A10, GCOM1, and NXPH2, which were previously not implicated in HM, are now associated with the disorder, advancing our understanding of its genetic basis. Conclusions: By prioritising PathVar SNVs, we identified a broader set of genes potentially contributing to HM. Given that HM is a rare condition, our findings, utilising a sample size of 184, represent a unique contribution to the field. This iterative analysis demonstrates that integrating diverse variant schemes provides a more comprehensive view of the genetic factors driving HM. Full article

Background/Objectives: Cxbladder^® Triage Plus is a multimodal urinary biomarker assay that combines reverse transcription-quantitative analysis of five mRNA targets and droplet-digital polymerase chain reaction (ddPCR) analysis of six DNA single-nucleotide variants (SNVs) from two genes (fibroblast growth factor receptor 3 (FGFR3) and telomerase reverse transcriptase (TERT)) to provide risk stratification for urothelial carcinoma (UC) in patients with hematuria. This study evaluated the analytical validity of Triage Plus. Methods: The development dataset used urine samples from patients with microhematuria or gross hematuria that were previously stabilized with Cxbladder solution. Triage Plus was evaluated for predicted performance, analytical criteria (linearity, sensitivity, specificity, accuracy, and precision), extraction efficiency, and inter-laboratory reproducibility. Results: The development dataset included 987 hematuria samples. Compared with cystoscopy (standard of care), Triage Plus had a predicted sensitivity of 93.6%, specificity of 90.8%, positive predictive value (PPV) of 46.5%, negative predictive value of 99.4%, and test-negative rate of 84.1% (score threshold 0.15); the PPV increased to 74.6% for the 0.54 score threshold. For the individual FGFR3 and TERT SNVs, the limit of detection (analytical sensitivity) was a mutant-to-wild type DNA ratio of 1:440–1:1250 copies/mL. Intra- and inter-assay variance was low, while extraction efficiency was high. All other pre-specified analytical criteria (linearity, specificity, and accuracy) were met. Triage Plus showed good reproducibility (87.9% concordance between laboratories). Conclusions: Cxbladder Triage Plus accurately and reproducibly detected FGFR3 and TERT SNVs and, in combination with mRNA expression, provides a non-invasive, highly sensitive, and reproducible tool that aids in risk stratification of patients with hematuria. Full article

Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical and genetic data from nine unrelated subjects with arterial aneurysms who were identified to harbor rare variants in the TNXB gene, mainly affecting fibronectin type III (FNIII) domains. The cohort included three female and six male subjects with a mean age of 53.5 years (SD = 14.4). The most frequently affected vascular territory was the thoracic ascending aorta (n = 7). A range of pathogenic impacts was predicted via multiple in silico tools that analyze evolutionary conservation and biochemical properties. Computational protein structure modeling with AlphaFold 3 predicted domain-specific alterations across multiple FNIII regions for four unique missense variants and one in-frame deletion, and premature protein truncation resulting from two frameshift variants. To our knowledge, this study is one of the first and largest to associate TNXB variants with arterial aneurysmal disease. Our findings demonstrate the potential of computational genomics and structural modeling to advance the understanding of extracellular matrix gene alterations in aneurysm pathogenesis. Full article