Search Results (349)

Natural killer (NK) cells are central to antiviral immunity through a balance of activating and inhibitory receptors, including killer immunoglobulin-like receptors (KIRs). We have previously observed that an increased frequency of the inhibitory receptor KIR2DL2 and its ligand HLA-C1 is associated with heightened susceptibility to human herpesvirus (HHV) infection, supporting a role for KIR-mediated NK cell regulation in host–virus interactions. We investigated whether the co-infection of SARS-CoV-2 and human herpesvirus 6 (HHV-6) might be connected to the expression of KIR2DL2/HLA-C1. We analyzed 110 SARS-CoV-2-positive subjects and 109 SARS-CoV-2-negative subjects for the KIR2DL2 and HLA-C1 genotype and for HHV-6A/B reactivation in plasma samples. SARS-CoV-2-positive subjects showed a significantly higher frequency of the KIR2DL2/HLA-C1 haplotype and increased reactivation of HHV-6A. Among deceased and comorbid patients, the co-occurrence of the KIR2DL2/HLA-C1 haplotype and HHV-6A DNAemia was more frequent, particularly in those with cardiovascular disorders. These findings suggest that the KIR2DL2/HLA-C1 haplotype might promote NK cell inhibition, facilitating HHV-6A persistence and contributing to immune dysregulation during SARS-CoV-2 infection. The combined presence of KIR2DL2/HLA-C1 and HHV-6A may, therefore, represent a molecular signature of COVID-19 outcomes. Full article

Deep-sea hydrothermal vent fauna is often regarded as highly endemic, although exceptions have been reported. We examined genetic connectivity across broad spatial scales within the alvinocaridid genus Rimicaris, which has undergone substantial adaptive radiation worldwide. We analyzed six Rimicaris species using three genetic markers, cytochrome c oxidase subunit I (COI), 16S ribosomal rRNA gene (16S), and histone h3 (H3), and complete mitogenomes, employing newly generated sequences combined with publicly available sequence data. A genetic tree and haplotype networks were constructed, and divergence analyses were performed. Three clades of paired Rimicaris species were identified, each made up of taxa from different oceanic regions but showing relatively low COI divergence (0.35–1.90%). In Clade I, Rimicaris chacei and Rimicaris hybisae are morphologically similar and exhibit bidirectional gene flow, implying a dispersal route between the Mid-Atlantic Ridge (MAR) and the Mid-Cayman Spreading Center (MCSC). In Clade II, Rimicaris exoculata and Rimicaris kairei are morphologically, genetically, and ecologically distinct, reflecting restricted connectivity between the MAR and the Carlsberg Ridge (CR)–Central Indian Ridge (CIR). In Clade III, Rimicaris variabilis and Rimicaris cf. variabilis differ in nutritional strategies, showing a unidirectional dispersal route from the CIR to the southwestern Pacific (SWP), but morphological data to distinguish them are currently lacking. Some Rimicaris lineages maintain connectivity across distinct oceanic regions while others still form unique regional populations. This finding highlights the need for conservation strategies that incorporate both global-scale connectivity and regional endemism, rather than treating individual vent ecosystems as a single homogeneous management unit. Full article

Soybean is the world’s foremost oilseed crop, and leaf morphology significantly influences yield potential by affecting light interception, canopy structure, and photosynthetic efficiency. In this study, leaf length, leaf width, maximum leaf width, leaf apex opening angle, and leaf area were measured in 216 soybean accessions, and genome-wide association studies (GWAS) were conducted using genomic resequencing data to identify genetic variants associated with leaf morphological traits. A total of 824 SNP loci were found to be significantly associated with leaf shape, and 130 candidate genes were identified in the genomic regions flanking these significant loci. KEGG enrichment analysis revealed that the above candidate genes were significantly enriched in arginine biosynthesis (ko00220), nitrogen metabolism (ko00910), carbon metabolism (ko01200), pyruvate metabolism (ko00620), glycolysis/glycogenolysis (ko00010), starch and sucrose metabolism (ko00500), plant–pathogen interaction (ko04626), and amino acid biosynthesis (ko01230). By combining KEGG and GO enrichment analysis as well as expression level analysis, four candidate genes related to leaf shape (Glyma.10G141600, Glyma.13G062700, Glyma.16G041200 and Glyma.20G115500) were identified. Further, through candidate gene association analysis, it was found that the Glyma.10G141600 gene was divided into two major haplotypes. The leaf area of haplotype 1 was significantly smaller than that of haplotype 2. Subsequently, the cutting amplification polymorphism sequence (CAPS) molecular marker was developed. The marker Chr.10:37502955 can effectively distinguish the differences in leaf size through enzymatic digestion technology, and has excellent typing ability and application potential. The above results can provide a theoretical basis for molecular-assisted selection (MAS) of soybean leaf morphology. Full article

Background: Identifying causal genes underlying quantitative trait loci (QTLs) remains challenging due to small effect sizes and the prevalence of non-coding variants. Although multi-omics integration frameworks such as eQTL- and epigenomic-based approaches and TWAS have advanced gene prioritization, their application in poultry and livestock is often constrained by limited reference panels and tissue resources. This review introduces a cost-effective F₂-based integrative framework and compares it with existing multi-omics strategies. Methods: The proposed framework combines QTL remapping, transcriptome analysis, haplotype frequency comparison, association analysis, and conditional correlation analysis within a single workflow. Causal analysis and quantitative complementation tests using knockout birds are incorporated to identify causal genes. Results: By reusing the original F₂ population employed for QTL mapping, this approach enables hypothesis-independent gene prioritization without requiring additional fine-mapping crosses. Its effectiveness is demonstrated through comparison with conventional multi-omics methods, and the integration of causal analysis and quantitative complementation testing provides robust genetic evidence for pinpointing causal genes. Conclusions: This F₂-based framework efficiently prioritizes and verifies causal gene candidates directly within the mapping population, offering a cost-effective alternative to multi-omics approaches that require large-scale resources. It is broadly applicable to diverse chicken crosses and readily transferable to other small livestock species and model organisms. Full article

Background/Objectives: Identifying candidate genes underlying quantitative trait loci (QTL) in poultry has traditionally required labor-intensive positional cloning. Previous studies using an F₂ population derived from native Japanese Nagoya (NAG) and White Plymouth Rock (WPR) breeds revealed a major QTL on chromosome 2 affecting 3-week body weight and 4-week pectoralis muscle weight. This study aimed to identify candidate genes for this QTL using a hypothesis-free integrative genetic approach. Methods: We employed a multi-step analytical framework combining QTL remapping, transcriptome analysis, gene enrichment analysis, haplotype frequency comparison, and correlation analysis. QTL remapping was performed using individual traits and their first principal component (PC1) in 239 F₂ chickens. RNA-sequencing (RNA-seq) of liver tissue was conducted for F₂ individuals with extreme PC1 scores, followed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation. Results: QTL remapping refined the 95% confidence interval to a chromosome 2 region containing 329 genes. RNA-seq analysis identified 23 differentially expressed genes (DEGs) within this interval. Although gene enrichment analysis initially highlighted GATA binding protein 6 (GATA6) as a potential candidate, RT-qPCR in NAG, WPR, and F₁ chickens showed no significant expression differences, excluding GATA6. Haplotype frequency and correlation analyses prioritized cadherin-17 (CDH17) as the strongest candidate gene and ring finger protein 151 (RNF151) as a secondary candidate. Conclusions: Our hypothesis-free integrative approach effectively refined candidate genes for a chromosome 2 QTL influencing early growth and pectoralis muscle weight. CDH17 and RNF151 represent promising targets for functional validation and may support marker-assisted selection to improve muscle-related traits in chickens. Full article

Background/Objectives: Changes in the physiological activity of transforming growth factor-beta (TGF-β) family caused by genetic variability may significantly affect the phenotype of the musculoskeletal system and, consequently, the risk of sports injuries. This study aimed to investigate whether the TGFBI (rs1442), TGFBR3 (rs1805113 and rs1805117), and MSTN (rs11333758) polymorphisms, either individually or in combination, were associated with susceptibility to muscle injury, anterior cruciate ligament (ACL) rupture, and other injuries. Methods: The study group included 202 physically active Caucasians with reported sport injuries and 133 healthy controls. All the samples were genotyped using real-time polymerase chain reaction (real-time PCR). Results: The results revealed that (1) the TGFBR3 rs1805117 TC genotype was nominally associated with increased ACL injury risk; (2) the MSTN rs11333758 heterozygotes was more frequent in the one injury group (vs controls) and in the ACL group, whereas in the multiple vs. one comparison the over-dominant model suggested lower odds for heterozygotes; and (3) the TGFBI rs1442 CG genotype was nominally associated with lower odds of fractures, dislocations or sprains. In addition, simultaneous analysis of chosen SNPs revealed interactions between TGFBR3 rs1805117 and rs1805113, with a nominal association of the rs1805113 G allele with increased injury risk, as did rs11333758 and rs1805113, with a potential effect of rs11333758 on injury status. However, haplotype analysis of the TGFBR3 SNPs revealed no significant associations. After Bonferroni correction, none of the associations remained statistically significant. Conclusions: The results suggested that carrying specific TGFBI, TGFBR3, and MSTN genotypes may be potentially associated with susceptibility to musculoskeletal injuries in a physically active Caucasians. Full article

The morphology of rice grains represents one of the most vital agronomic characteristics, significantly impacting both grain productivity and the subsequent milling and nutritional quality of the crop. A comprehensive understanding of the genetic basis and molecular drivers of grain shape is vital for the targeted breeding of high-performance rice lines with consistent yield stability. To pinpoint the genomic regions influencing grain dimensions, we conducted a genome-wide association analysis across a panel of 231 distinct rice accessions, focusing on the discovery of loci associated with length and width. Our analysis revealed four consistent quantitative trait loci (QTLs) distributed across chromosomes 3, 4, and 11. Notably, grain length was associated with qGL3.1, qGL3.2, and qGL11. The first two were co-localized with GS3 and SMG3, respectively, whereas qGL11 likely constitutes a novel locus. One QTL, qGW4, which governs grain width, was found to co-localize with the gene OsOFP14. Haplotype analysis further revealed that the characteristic haplotypes of the candidate genes for qGL3.1, qGL3.2, and qGW4 were enriched in eight germplasm accessions (including Newbonnet, Skybonnet, and Lemont), all of which exhibit a slender-grain phenotype. This finding suggests that the specific combination of these characteristic haplotypes is a common genetic signature of slender-grain rice, serving as a potential gene combination for the targeted improvement of rice grain shape. Our results reveal valuable QTLs and candidate genes and highlight specific germplasm resources that can be readily applied in marker-assisted breeding to improve rice grain shape. Full article

Background: Hypoadiponectinemia, a metabolic hallmark of obesity, is common in polycystic ovary syndrome (PCOS) yet the association of variants in the ADIPOQ gene with obesity in PCOS remains uncertain. To investigate whether ADIPOQ variants are associated with obesity in PCOS in relation to circulating adiponectin levels, and whether integrating genotypes, adiponectin, and a polygenic risk score (PRS) improves risk stratification. Methodology: In 324 Tunisian women with PCOS, classified as obese or non-obese by WHO criteria, serum adiponectin was measured, and nine ADIPOQ variants were genotyped using TaqMan assays. Associations with obesity were assessed using logistic regression, gene phenotype interaction analysis, and models incorporating a PRS; epistasis, QTL, and diplotypes were also evaluated. Results: Adiponectin levels were significantly lower in obese women and modestly predicted obesity (AUC = 0.605). Variants rs1501299 and rs3774261 were significantly associated with obesity under recessive models (OR up to 5.18, 95% CI [2.32–11.56], p = 7.14 × 10⁻⁵). Risk genotypes and haplotypes correlated with reduced adiponectin and increased obesity risk, with adiponectin levels significantly associated with the genotype–obesity relationships. A combined model including adiponectin, the two variants, and PRS outperformed single predictors. Conclusions:ADIPOQ rs1501299 and rs3774261 are associated with obesity in women with PCOS, with this association demonstrating a specific relationship with reduced adiponectin. Integrating genetic and biochemical markers improves metabolic risk profiling and supports personalized management. Full article

Grain weight, a highly heritable yield component, is a primary breeding target for enhancing wheat productivity. Unraveling the molecular dynamics underlying grain development is essential for identifying key regulators controlling this trait. In this study, we employed an integrated multi-omics approach to analyze transcriptomic and proteomic profiles in developing grains using pairwise near-isogenic lines with contrasting grain weight across four grain developmental stages. Our analysis revealed that early grain development, particularly at 7 days post-anthesis, serves as a critical window during which differential regulation of genes and proteins involved in carbohydrate biosynthesis and metabolic pathways establishes the final grain weight. By combining weighted gene co-expression network analysis (WGCNA) and K-means clustering, we identified a grain weight-associated module and pinpointed four high-confidence candidate genes. Among these, TaYAK1-2D, which encodes a YAK family protein kinase, was functionally validated as a positive regulator of grain weight through mutational analysis. Sequence analysis revealed two major natural haplotypes of TaYAK1-2D, with TaYAK1-2D-Hap2 being significantly associated with higher grain weight across multiple environments. Our findings not only delineate a crucial metabolic window governing grain weight but also provide both a novel genetic target and a practical haplotype marker for molecular breeding aimed at yield improvement in wheat. Full article

Kongshan cattle is an indigenous breed from Sichuan Province, China, characterized by their excellent meat quality, high fertility, strong disease resistance, and remarkable environmental adaptability. However, their genomic diversity has not been systematically studied. In this work, we performed whole-genome sequencing of 30 Kongshan cattle from a breeding farm and integrated these data with 113 representative commercial and indigenous cattle breeds worldwide to investigate their population structure and genetic diversity. We further analyzed the ancestral contributions to the development of the breed. The population structure revealed that Kongshan cattle possess four types of ancestral components: East Asian indicine (0.5974), East Asian taurine (0.3464), European taurine (0.0483), and Indian indicine (0.0079). The population also exhibits high nucleotide diversity, second only to pure East Asian indicine cattle. We inferred the ancestry of each variable site in the genome and, in combination with integrated haplotype score analysis, identified candidate genes related to meat quality (ME1, ENPP2, GPD2, PDZRN4, and TMTC2), immunity (MCM6, MAP3K6, PIP4K2A, CDC6, CDC25B, PTAFR, ZC3H10, and NEK6), and environmental adaptability (KCNJ15, BECN1, AOC2, DUSP5, and ST3GAL4). These findings provide valuable insights into the evolutionary history and ancestral origins of Kongshan cattle and contribute to the broader understanding, conservation, and sustainable utilization of indigenous Chinese cattle genetic resources. Full article

Recurrent pregnancy loss (RPL), also termed recurrent spontaneous abortion, is defined as the failure of ≥2 consecutive pregnancies before 20 weeks of gestation. Approximately 5% of pregnant couples experience RPL. The hyaluronan-binding protein 2 (HABP2) gene is involved in coagulation and plays an important role during pregnancy. In >50% of RPLs, the etiology remains unexplained. We collected 765 blood samples from 388 female RPL patients and 377 healthy female controls. To investigate the relationships between HABP2 polymorphisms and RPL, we examined six HABP2 variants (rs3832698 A>del, rs10885478 G>A, rs932650 T>C, rs7923349 G>T, rs1157916 G>A, and rs2240879 T>C) to clarify their association with RPL risk. The rs2240879 CC genotype was significantly associated with an increased RPL risk (p = 0.028). In haplotype analysis, the combination of rs3832698 del and rs2240879 T (del-T) was associated with elevated risk (p = 0.043); this risk persisted in combinations with additional polymorphisms (rs3832698 A>del, rs10885478 G>A, rs932650 T>C, rs7923349 G>T; del-A-T-T, p < 0.001; rs3832698 A>del, rs10885478 G>A, rs932650 T>C, rs7923349 G>T, rs1157916 G>A, rs2240879 T>C; del-A-C-T-G-T, p = 0.024). The rs3832698 and rs1157916 genotypes were significantly associated with prothrombin time (p = 0.020 and p = 0.012, respectively). We identified associations between HABP2 polymorphisms and RPL; rs2240879 was linked to an increased RPL risk. Additionally, rs3832698 was associated with an altered prothrombin time. These findings suggest that HABP2 represents a biomarker for RPL susceptibility. Full article

Serine protease inhibitor A3 (SERPINA3), also called α-1-antichymotrypsin, is a serine protease involved in placental dysfunction. This study examines SERPINA3 polymorphisms and haplotypes for associations with maternal hypertensive disorders of pregnancy (HDPs) and preeclampsia with severe features (sPE) or Hemolysis, Elevated Liver Enzymes, and Low Platelet (HELLP) syndrome in mother–baby dyads (HDP) and mother–father–baby triads (sPE/HELLP). This retrospective case–control study examined two patient cohorts, HDPs and severe PE/HELLP syndrome. The HDP population included cases (n = 142) and controls (n = 168) of mother–baby dyads recruited from a large, urban, safety-net hospital in Los Angeles. The sPE/HELLP syndrome population included cases (n = 189) and controls (n = 28) of mother–father–baby triads recruited through HELLP syndrome research websites. Cases were verified by medical chart abstraction when possible. Two SERPINA3 SNPs, rs4934 and rs1884082, were genotyped from saliva samples, mouthwash, or buccal swabs. The Haplin package in R was used to perform genetic association analyses. No evidence of increased risk related to individual SERPINA3 SNPs or haplotypes for the developing HDPs or sPE/HELLP was found in individual nor combined cohorts. In the HDP cohort, the g-a haplotype (relative to T-G haplotype) was borderline significant for increased risk of HDPs when carried by the child (double dose: RR = 1.58, 95% CI: (1.00, 2.52), p = 0.05). We observed significant parent-of-origin (PoO) effects in the combined cohort: specifically, an increased risk of HDPs/sPE/HELLP if the mother carries a double copy for both rs4934 (RR = 3.03, 95% CI (1.50, 6.09), p < 0.01) and rs1884082 (RR = 2.38, 95% CI (1.22, 4.71), p = 0.01). A reduced risk of HDPs/sPE/HELLP was observed for rs4934 (RR = 0.54, 95% CI (0.31, 0.98), p = 0.04) and rs1884082 (RR = 0.52, 95% CI (0.30, 0.91), p = 0.02) with child carriage of the maternally inherited allele. In contrast, child carriage of a paternally inherited copy of the variant allele for rs4934 increased risk of HDPs/sPE/HELLP (RR = 1.54, 95% CI (1.09, 2.20), p = 0.02). There was no evidence that SERPINA3 gene polymorphisms and haplotypes were associated with risk of HDPs or sPE/HELLP. However, significant PoO effects were observed in the combined cohort analysis, with child carriage of rs4934 that is maternally inherited decreasing HDPs/sPE/HELLP risk while a paternally inherited copy increases risk, suggesting a role for maternal–fetal genomic incompatibility. Full article

Atherogenic dyslipidemia (AD) is a high-risk phenotype for cardiovascular disease, characterized by elevated triglycerides, increased small dense low-density lipoprotein cholesterol (sdLDL-C), and frequently coexisting hypertension. Although FTO gene variants have been implicated in lipid dysregulation, their role in AD among Latin American women remains poorly defined. We conducted a case–control study in 219 working perimenopausal women (97 AD cases and 122 controls). Sociodemographic, clinical, and biochemical variables were assessed. Three FTO SNPs (rs9939609, rs9940128, and rs8050136) were genotyped. Associations were evaluated using logistic regression models adjusted for age and BMI, with gene–environment interactions tested for smoking. Linkage disequilibrium (LD) and haplotype analyses were also performed. Women with AD exhibited significantly higher triglycerides, LDL-C, and sdLDL-C, along with increased hypertension prevalence, but no differences in BMI or glycemia. Multivariable models identified LDL-C (aOR ≈ 8), triglycerides, sdLDL-C, and systolic blood pressure as the strongest determinants of AD. The rs8050136 AA genotype was associated with a fourfold higher risk (aOR = 4.12; 95% CI: 1.49–11.95, p = 0.007). Smoking independently doubled AD risk (aOR = 2.33) and amplified the effect of rs8050136. Adjusted haplotype analysis revealed that the A-A-A (aOR = 5.33; 95% CI: 1.42–20.00) and A-G-A combinations (aOR = 2.54; 95% CI: 1.01–6.38) were significantly associated with AD. FTO polymorphisms, particularly rs8050136 and the A-A-A and A-G-A haplotypes, contribute independently and supra-additively to AD risk. The observed gene–environment interaction with smoking emphasizes the multifactorial nature of AD and supports genotype-based risk stratification and targeted preventive strategies in precision cardiovascular medicine. Full article

Background/Objectives: Direct oral anticoagulants (DOACs) have transformed the prevention of thromboembolic events, but their efficacy and safety remain highly variable across individuals. DD217, a novel oral direct factor Xa inhibitor, has demonstrated potent anticoagulant activity in preclinical and clinical studies. No pharmacogenetic data are currently available for this compound. Based on in silico predictions of metabolic pathways and transporter involvement, and evidence from other DOACs, we hypothesized that variants in CYP2C and P-glycoprotein genes may contribute to variability in pharmacokinetics (PK) and clinical outcomes. Methods: Fifty-two patients undergoing total knee arthroplasty were enrolled, of whom 34 received the investigational drug (40 mg/day, n = 16; 60 mg/day, n = 18). DNA was extracted from peripheral blood cells, and genotyping of CYP2C9, CYP2C19, CYP2C8, CYP3A4, CYP3A5, and ABCB1 was performed by real-time PCR. Pharmacokinetics (PK) parameters (T_max, AUC_last, C_max) were assessed. In silico docking and pathway modeling predicted CYP2C and P-glycoprotein (ABCB1) involvement in drug disposition. Associations of genetic variants with PK parameters and adverse events (thrombosis, bleeding) were analyzed. Results: Carriers of reduced-function CYP2C9 alleles (intermediate [IM] or poor metabolizers [PM]) in the 60 mg group had a significantly shorter T_max compared with normal metabolizers (p = 0.005227), with trends toward higher AUC_last (p = 0.06926) and C_max (p = 0.1259). No significant associations were observed for CYP2C19, CYP3A4/5, or CYP2C8. In contrast, ABCB1 polymorphisms were associated with systemic exposure: carriers of the C allele at rs1045642 had higher AUC_last and C_max compared to TT (wild-type) homozygotes, while rs2032582 T allele carriers showed lower exposure (p < 0.05). At the haplotype level, the C–G–C–T combination of ABCB1 was more frequent in patients with thrombotic events at the 40 mg dose (p = 0.038). Overall, 5 thrombosis events and 1 bleedings were recorded on DD217, with no consistent associations to single SNPs. Conclusions: This first pharmacogenetic evaluation of DD217 shows that CYP2C9 variants are associated with differences in early-phase pharmacokinetics (T_max), while ABCB1 polymorphisms appear to modulate systemic exposure (AUC_last, C_max) and may influence thrombotic risk. These observations are consistent with in silico predictions of metabolic and transporter pathways. Despite limitations in sample size and event frequency, the study highlights the feasibility and importance of early pharmacogenetic evaluation during the drug development cycle of novel DOACs. Full article

Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment in Rwanda, but the emergence of drug resistance threatens their efficacy. This study conducted genomic surveillance of Plasmodium falciparum isolates collected in Kigali between October 2021 and June 2023 to assess resistance markers. Using Oxford Nanopore Technology and Sanger sequencing methods, we analyzed 250 clinical isolates focusing on mutations in the pfcrt, pfmdr1, pfdhfr, pfdhps, and Pfkelch13 genes. Resistance-associated mutations were highly prevalent: pfcrt 76T (26%) and pfmdr1 184F (72.8%) were common, indicating continued lumefantrine pressure. All isolates carried mutations in pfdhfr and pfdhps, with the IRNI-SAEAA and IRNI-SAEGA haplotypes found in 45.6% and 24.8% of samples, respectively, suggesting sustained antifolate resistance. Pfkelch13 mutations were present in 50.4% of isolates, including validated R561H (25.6%), A675V and candidate P441L mutations. Novel haplotypes, including K189T + R561H (24.8%), were identified for the first time in Rwanda. The BTB/POZ domain mutation H384R was observed in 6.4% of isolates, raising questions about its potential functional role. These findings highlight complex and evolving resistance patterns and emphasize the urgent need for continued molecular surveillance and functional validation to inform malaria control strategies in Rwanda. Full article