The effect of genetic polymorphisms in STIM1 and ORAI1 on erythropoietin resistance in Egyptian patients with end-stage renal disease.

Chronic renal failure (CRF) is an incurable disease with unique challenges. Anemia is a frequent complication affecting dialysis patients. Erythropoietin (EPO) is used to treat anemia, but a poor response may result. We investigated genetic polymorphisms of store-operated calcium channel (SOC) signaling, an important erythropoietin-activated pathway that may induce EPO resistance in patients with renal failure. A total of 108 end stage renal disease (ESRD) patients were selected for this study. Patients were divided into two groups according to their erythropoietin resistance index (ERI): 39 patients with an ERI>10 and 69 patients with an ERI<10. We selected four tagging single nucleotide polymorphisms (tSNPs) in STIM1 and five in ORAI1 in our study. A polymerase chain reaction was performed, and genotyping against EPO resistance was correlated. Patients with the AG genotype of rs1561876 in STIM1, the TC genotype of rs6486795 in ORAI1, and the TG or GG genotypes of rs12320939 in ORAI1 were associated with an increased risk of erythropoietin resistance. Overall, we reported a moderately significant relationship between genetic polymorphisms of STIM1 and EPO resistance. We also reported a highly significant relationship between genetic polymorphisms of ORAI1 and EPO resistance. The (A-A-G) haplotype of STIM1 and the (G-T-G-T-A, G-C-G-C-G, or G-T-T-C-G) haplotypes of ORAI1 were significantly associated with EPO resistance.

A two­sample Mendelian randomization study of lipidome and lung cancer.

We analyzed the potential relationship between liposomes and lung cancer risk for the first time using MR analysis methods. The results showed that sterol ester, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, and triacylglycerol may affect lung cancer risk. However, molecules with different fatty acid compositions also affect lung cancer risk differently. These results may help researchers discover more mechanisms by which lipid metabolism disorders support lung cancer growth and potential targets of lipid metabolism, giving more theoretical support to lung cancer therapeutic approaches that target lipid metabolic pathways.

MALDI-TOF MS-based SNP assay used to determine the appropriate antidepression for Chinese patients.

Medicine remains the preferred primary treatment for depression, although some patients show remarkable individual variations in achieving satisfactory clinical outcomes during medication. Genetic polymorphisms cause approximately 40 % of individual differences in treatment response. Therefore, this study aimed to develop a technique to identify single nucleotide polymorphisms (SNPs) associated with the metabolism, effectiveness, and side effects of antidepressant medications in Chinese patients. Bibliometrics was used to search literature related to "depression" and "SNP" in Web of Science. The obtained SNP information was screened using the PharmGKB database. By designing and optimizing primers and conducting a compound amplification system, a method was established based on MALDI-TOF MS to detect polymorphisms associated with the antidepressant drugs, including sertraline, fluoxetine, citalopram, escitalopram, venlafaxine, fluvoxamine, paroxetine, and mirtazapine. The accuracy and sensitivity of the established method were verified by Sanger sequencing. A total of 10,043 articles were screened from the database, and 46 SNPs with a mutation frequency of >1 % in Asian populations and annotated with relevant clinical drugs were extracted from the PharmGKB database. This method was compared with the results of Sanger sequencing, and the accuracy of the detection results was 100 %. The MALDI-TOF MS-based SNP assay developed in this study can be a fast, convenient and effective way for patients to find the right medication for themselves. Moreover, we found that this SNP assay holds the promise of being a potential reference tool for assessing individualised differences in drug efficacy, not only for screening the causes of poor antidepressant efficacy in patients after taking medication, but also for advising physicians to understand individualised differences in drug efficacy.

Assessing the association between common functional Nuclear Factor Kappa-b gene polymorphisms (NFKB1, NFKBIZ, NFKBIA) and Alzheimer´s disease.

The Nuclear Factor Kappa-b (NF-Κb) pathway has been implicated in the pathogenesis of Alzheimer´s disease (AD). We determined whether common variants in the NF-Κb genes were associated with the risk of developing late-onset AD (LOAD). A total of 639 Spanish LOAD and 500 controls were genotyped for the NFKB1 rs28362491/rs7667496, NFKBIA rs696, NFKBIZ rs3217713 and APOE-Ɛ2/3/4 polymorphisms. Rs7667496 C was increased in the patients (p<0.001) with the CC genotype showing a significant risk (CC vs T+, OR= 1.58, 95 %CI=1.25-2.01). The CC genotype was significantly associated with LOAD after correction by APOE-4+ genotypes, age and sex (p=0.0003, OR=1.88, 95 %CI=1.28-2.78). The NFKB1 rs28362491 I - rs7667496 C haplotype was significantly increased in the patients (p=0.02). NFKBIA and NFKBIZ variants were not associated with the risk of LOAD in our population. In conclusion, NFKB1 variants were associated with the risk of LOAD in our population. This finding encourages further studies to determine the involvement of the NF-kB components in LOAD.

The Association of SUR1 Polymorphisms with Acute Infarct Size: The MRI-GENIE Study.

BACKGROUND: The sulfonylurea receptor 1 (SUR1) is a known mediator of cerebral edema in large ischemic strokes, however, genetically induced response variability has yet to be evaluated. SUR1, encoded by the ABCC8 gene, is an ion channel regulator in ischemia-induced cerebral edema. Previous studies in severe traumatic brain injury demonstrated four tag single nucleotide polymorphisms (SNPs) of the ABCC8 gene to be associated with cerebral edema and functional outcome. We hypothesized that these four SNPs would also be associated with acute infarct size and functional outcome in non-lacunar ischemic stroke. METHODS: Using 2,205 MRI-GENetics Interface Exploration (MRI-GENIE) study subjects with acute non-lacunar ischemic strokes, we evaluated the association between the 4 ABCC8 tag-SNPs and stroke infarct size (as measured in a standardized fashion from MRIs using diffusion-weighted imaging), adjusting for age, sex and population stratification. Modified Rankin scale (mRS) outcome was available at 3-months for a subset of 798 strokes in MRI-GENIE and was evaluated as a dichotomous variable (0-2 vs 3-6), adjusting for age, sex, stroke severity (baseline NIH Stroke Scale (NIHSS) score), and population stratification. RESULTS: The candidate SNPs, rs7105832, rs2237982, rs11024286, rs4148622, were not statistically associated with DWI (beta= -0.065, -0.057, 0.037, 0.018; p=0.053, 0.078, 0.28, 0.61) or dichotomous mRS outcome (OR=0.80, 0.86, 1.14, 0.90; p=0.117, 0.289, 0.353, 0.502). CONCLUSION: rs7105832, rs2237982, rs11024286, rs4148622 polymorphisms of the ABCC8 gene did not demonstrate a significant effect on acute ischemic infarct size or 3-month functional outcome. Nonetheless, further studies with delayed imaging and more sensitive outcome measures remain warranted.

Influence of metalloproteinase-3 (-1171 5A>6A) polymorphism on periportal fibrosis in patients with schistosomiasis mansoni, Pernambuco, Brazil.

In schistosomiasis mansoni (SM), periportal fibrosis (PPF) arises due to an inflammatory response exacerbated by parasite eggs in the intrahepatic portal space, culminating in the deposition of collagen and extracellular matrix proteins. This fibrosis results from a remodeling process of the extracellular matrix, in which metalloproteinases play a significant role. The study evaluated the association between MMP-3 polymorphism (-1171 5A>6A) (rs 3025058) and sociodemographic factors with PPF in individuals with SM. This is an analytical cross-sectional study involving 242 individuals infected with S. mansoni, of these 122 were diagnosed with hepatosplenic form (HS) and 119 hepatointestinal form (HI), all from the state of Pernambuco, Brazil. Polymerase chain reaction with restriction enzyme digestion (Psyl) was used to determine the MMP-3 polymorphism (-1171 5A>6A). There was a significant association between the male gender and the HS form (OR = 1.7623 95% CI [1.0481-2.9631]; p-value = 0.0439) as well as individuals aged over 41, also had a greater chance of developing this clinical form of the disease (OR = 2.8299; 95% CI [1.5211-5.2650]; p-value = 0.0014), with greater emphasis on individuals over 61 years old (OR= 8.5541; 95% CI [3.6895-19.8326], p-value= 0.0000). There was no statistically significant association between the MMP-3 polymorphism (-1171 5A>6A) between the clinical groups (5A6A CI [0.7144-1.9879] p-value 0.5882 5A5A CI [0.0912-2.9231] p-value 0.7331 5A6A / 5A5A CI [0.6904-1.8937] p-value 0.6949). In conclusion, the results showed no association between the MMP-3 polymorphism (-1171 5A>6A) and the development of PPF. In addition, males, and age over 41 were predictive factors for the HE form of the disease in this Brazilian population.

Fasciola hepatica and Fasciola hybrid form co-existence in yak from Tibet of China: application of rDNA internal transcribed spacer.

Fasciolosis is a parasitic disease affecting humans and livestock, caused by digenean trematodes of the genus Fasciola, primarily F. hepatica and F. gigantica. This study investigates the coexistence of these species and their hybrids in yaks from Tibet, China. We analyzed the nuclear rDNA internal transcribed spacer (ITS) regions, including ITS1 and ITS2, through Sanger sequencing and Next-Generation Sequencing (NGS) to assess single-nucleotide polymorphisms (SNPs). Our results reveal that one specimen (NM008B) is identical to pure F. hepatica, while another (NM008A) contains genetic information from both F. hepatica and F. gigantica, indicating potential hybridization or introgression. The morphological analysis reveals that the collected adult F. hepatica specimens exhibit distinct characteristics, while the hybrid specimens display "intermediate" features of F. hepatica and F. gigantica. This study is the first to document the coexistence of F. hepatica and hybrid Fasciola forms in a single yak. The findings underscore the complexities of hybridization dynamics and the necessity for advanced molecular techniques in accurately identifying Fasciola species. Future research should focus on mitochondrial DNA and other nuclear gene analysis to further elucidate the nature of these hybrids and their ecological implications.

mRNA for Body Fluid and Individual Identification.

Biological stains are one of the most important pieces of evidence, playing a multifaceted role in forensic investigations. An integral facet of forensic practice involves the identification of body fluids, typically achieved through chemical and enzymatic reactions. In recent decades, the introduction of mRNA markers has been posited as a pivotal advancement to augment the capabilities of body fluid identification (BFID). The mRNA coding region single-nucleotide polymorphisms (cSNPs) also present notable advantages, particularly in the task of individual identification. Here, we review the specificity and stability of mRNA markers in the context of BFID and the prowess of mRNA polymorphism in individual identification. Additionally, innovative methods for mRNA detection are discussed.

Shared genetic associations and etiology between obstructive sleep apnea and CVDs: A genome-wide cross-trait analysis and bidirectional Mendelian randomization analysis.

AIMS: To investigate the genetic correlations and potential causal relationships between obstructive sleep apnea (OSA) and various cardiovascular diseases (CVDs), aiming to enhance understanding of shared genetic mechanisms and improve recognition and treatment of OSA in patients with CVDs. METHODS: Utilizing genome-wide association study (GWAS) data, we analyzed shared genetics between OSA and CVDs using linkage disequilibrium score regression (LDSC), multi-trait analysis of GWAS (MTAG), and genotype-tissue expression analysis (GTEx TSEA). We further investigated causal relationships using Bayesian colocalization tests, bidirectional Mendelian randomization (MR), and latent causal variable (LCV) analysis. RESULTS: We found strong associations between OSA and multiple CVDs: coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and atrial fibrillation (AF). Novel SNPs related to CVDs were identified during single-trait MTAG analysis. By applying cross-trait MTAG, we identified 15 shared loci between OSA and CAD, 25 shared loci between OSA and MI, and 7 shared loci between OSA and HF. Shared genes are primarily expressed in the blood, heart, kidney, liver, muscle, and pancreas. MR analysis indicated a significant causal effect of OSA on HF and AF as a causal factor for OSA. LCV analysis suggested that AF was causally associated with OSA, while HF showed partial causality. CONCLUSIONS: Our study suggests strong genetic correlations between OSA and several CVDs. Further research is needed on the associations between OSA and CVDs, as well as the mechanisms of the identified loci.

This study explores the genetic links between obstructive sleep apnea (OSA) and cardiovascular diseases (CVDs). Key Findings: Strong genetic correlations were found between OSA and five CVDs: coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and atrial fibrillation (AF). Novel correlated and causal loci were identified. AF was identified as a causal factor for OSA, while OSA was a causal factor for HF. Future research is needed to explore these genetic mechanisms further and improve understanding of the connections between OSA and CVDs.

Implication of vasopressin receptor genes (AVPR1A and AVPR1B) in the susceptibility to polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex heterogenous disorder manifesting with various reproductive, endocrine, and metabolic derangements such as insulin resistance and hyperglycemia. The arginine vasopressin peptide (AVP), also called or antidiuretic hormone (ADH), modulates metabolic functions such as glucose hemostasis, insulin sensitivity, and lipid metabolism via binding to two central and peripheral receptors (AVPR1A and AVPR1B). In the present study, we aimed to detect whether the AVPR1A and AVPR1B genes confer risk for PCOS. METHODS: In peninsular Italian families, we tested 7 variants in the AVPR1B gene and 2 variants in the AVPR1A gene via Pseudomarker for linkage and linkage joint to association (i.e.., linkage disequilibrium) with PCOS. RESULTS: We identified two risk variants in each gene, significantly associated with the risk of PCOS. CONCLUSION: To the best of our knowledge, this is the first study to report risk variants in AVPR1A and AVPR1B genes in association with PCOS. However, replication in other ethnic groups as well as functional studies are needed to confirm these results.

Pediatric pharmacogenetics: profiling CYP2C8 polymorphisms at King Abdulaziz University Dental Clinic.

OBJECTIVES: Ibuprofen, a widely used non-steroidal anti-inflammatory (NSAID) for managing pain and inflammation in pediatric patients, is metabolized by the CYP2C8 enzyme. Studies suggest that the CYP2C8*2, *3, and *4 variations of the CYP2C8 gene diminish ibuprofen metabolism, increasing the risk of adverse reactions. The aim of this study was to determine the frequency of the CYP2C8*2, *3, and *4 alleles and genotypes in a pediatric population attending the King Abdulaziz University dental clinic and compare our findings to those of other populations. METHODS: A cross-sectional study was conducted with 140 healthy Saudi children ages 6-12. Saliva samples were collected using Oragene™ DNA Sample Collection Kits and analyzed for polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The study identified that CYP2C8*2 AA, AT, and TT genotypes occurred at frequencies of 87.86 %, 9.29 %, and 2.86 %, respectively. For CYP2C8*3, AA, AG, and GG genotypes were found in 87.14 , 8.75, and 4.29 % of subjects, respectively. The CYP2C8*4 allele was less frequent, with CC and CG genotypes at 97.86 % and 2.14 %, respectively, and the GG genotype was absent. Allele frequencies for CYP2C8*2, *3, and *4 were 7.5 %, 8.57 %, and 1.07 %, respectively. CONCLUSIONS: Our findings reveal that the allelic frequencies for the CYP2C8 polymorphisms in the Saudi pediatric cohort are substantially elevated compared to those reported in other Asian populations. This suggests Saudis may experience more varied drug responses, especially for medications that undergo metabolism by the CYP2C8 enzyme, like ibuprofen.

Evaluation of a microfluidic-based point-of-care prototype with customized chip for detection of bacterial clusters.

Bacterial infection clusters cause high mortality rates and healthcare costs due to excessive therapy and hygiene measures. The aim of this study was to develop an automated real-time PCR-based point-of-care (POC) system with a customized microfluidic chip that facilitates fast detection of bacterial cluster isolates by targeting cluster-specific single-nucleotide polymorphisms (SNPs). For cluster detection of Acinetobacter baumannii, Staphylococcus aureus, and Escherichia coli, nine TaqMan real-time PCR assays targeting cluster-specific SNPs were designed. Additionally, for DNA input control, a universal PCR amplifying the 16S rDNA was constructed. All reactions were implemented into a microfluidic chip that was analyzed by a POC prototype enabling automated sample processing, fluid handling, and signal detection. Performance of the prototype was evaluated using 45 chips loaded with defined bacterial solutions, including swab eluates. For seven PCRs, implementation into the microfluidic chip was successful, leading to correct identification of all SNPs specific for A. baumannii and E. coli cluster isolates and delineation of all non-cluster strains within 70 min. The remaining three reactions failed in the chip, which resulted in misidentification of the S. aureus cluster. Sensitivity, specificity, and accuracy of the prototype were 43%, 88%, and 55%, respectively. The detection limit was PCR dependent and ranged between 103 and 105 colony-forming units/mL. Once optimized, the microfluidic POC system for cluster detection could be applied as time-saving and easy-to-use method to complement whole-genome sequencing efforts during screening for bacterial clusters. IMPORTANCE: Especially in medical facilities, where morbid people are nursed in close distance to each other, pathogenic bacteria can accumulate and spread. To contain such infection clusters, usually time- and labor-intensive large-scale screening assays are conducted, where patients and patient-side surfaces are sampled, and PCR or whole-genome sequencing analyses are conducted to confirm or deny cluster affiliation of cultivated bacteria. Hence, fast solutions with easy application are required to complement the current state-of-the-art technology for cluster surveillance. Here, we developed a fully automated microfluidic point-of-care prototype that identified bacterial cluster isolates within 70 min from bacterial solutions, including swab eluates. The system requires only low hands-on time and can be applied apart from laboratory infrastructures near the patient, which considerably reduces the time from sampling to result. This ensures fast implementation of hygiene measures and quick containment of the infection cluster, which would enhance patients' safety and outcome.

Does strain-level persistence of lactobacilli in long-term back-slopped sourdoughs inform on domestication of food-fermenting lactic acid bacteria?

Sourdoughs are maintained by back-slopping over long time periods. To determine strain-level persistence of bacteria, we characterized four sourdoughs from bakeries over a period of 3.3, 11.0, 18.0, and 19.0 years. One sourdough included isolates of Levilactobacillus spp. and Fructilactobacillus spp. that differed by fewer than 10 single-nucleotide polymorphisms (SNPs) from the isolates obtained 3.3 years earlier and thus likely represent the same strain. Isolates of Levilactobacillus parabrevis differed by 200-300 SNPs; their genomes were under positive selection, indicating transmission from an external source. In two other sourdoughs, isolates of Fructilactobacillus sanfranciscensis that were obtained 11 and 18 years apart differed by 19 and 29 SNPs, respectively, again indicating repeated isolation of the same strain. The isolate of Fl. sanfranciscensis from the fourth sourdough differed by 45 SNPs from the isolate obtained 19 years previously. We thus identified strain-level persistence in three out of four long-term back-slopped sourdoughs, making it possible that strains persisted over periods that are long enough to allow bacterial speciation and domestication.IMPORTANCEThe assembly of microbial communities in sourdough is shaped by dispersal and selection. Speciation and domestication of fermentation microbes in back-slopped food fermentations have been documented for food-fermenting fungi including sourdough yeasts but not for bacteria, which evolve at a slower rate. Bacterial speciation in food fermentations requires strain-level persistence of fermentation microbes over hundreds or thousands of years. By documenting strain-level persistence in three out of four sourdoughs over a period of up to 18 years, we demonstrate that persistence over hundreds or thousands of years is possible, if not likely. We thus not only open a new perspective on fermentation control in bakeries but also support the possibility that all humans, despite their cultural diversity, share the same fermentation microbes.

Polymorphic positions 349 and 725 of the autoimmunity-protective allotype 10 of ER aminopeptidase 1 are key in determining its unique enzymatic properties.

Introduction: ER aminopeptidase 1 (ERAP1) is a polymorphic intracellular aminopeptidase with key roles in antigen presentation and adaptive immune responses. ERAP1 allotype 10 is highly protective toward developing some forms of autoimmunity and displays unusual functional properties, including very low activity versus some substrates. Methods: To understand the molecular mechanisms that underlie the biology of allotype 10, we studied its enzymatic and biophysical properties focusing on its unique polymorphisms V349M and Q725R. Results: Compared to ancestral allotype 1, allotype 10 is much less effective in trimming small substrates but presents allosteric kinetics that ameliorate activity differences at high substrate concentrations. Furthermore, it is inhibited by a transition-state analogue via a non-competitive mechanism and is much less responsive to an allosteric small-molecule modulator. It also presents opposite enthalpy, entropy, and heat capacity of activation compared to allotype 1, and its catalytic rate is highly dependent on viscosity. Polymorphisms V349M and Q725R significantly contribute to the lower enzymatic activity of allotype 10 for small substrates, especially at high substrate concentrations, influence the cooperation between the regulatory and active sites, and regulate viscosity dependence, likely by limiting product release. Conclusions: Overall, our results suggest that allotype 10 is not just an inactive variant of ERAP1 but rather carries distinct enzymatic properties that largely stem from changes at positions 349 and 725. These changes affect kinetic and thermodynamic parameters that likely control rate-limiting steps in the catalytic cycle, resulting in an enzyme optimized for sparing small substrates and contributing to the homeostasis of antigenic epitopes in the ER.

Influence of genetic polymorphism on sports talent performance versus non-athletes: a systematic review and meta-analysis.

BACKGROUND: Talented athletes exhibit remarkable skills and performance in their respective sports, setting them apart from their peers. It has been observed that genetic polymorphisms can influence variations in sports performance, leading to numerous studies aimed at validating genetic markers for identifying sports talents. This study aims to evaluate the potential contribution of genetic factors associated with athletic performance predisposition in identifying sports talents. METHODS: A systematic review was conducted following the PRISMA framework, utilizing the PICO methodology to develop the research question. The search was limited to case-control studies published between 2003 and June 2024, and databases such as Medline, LILACS, WPRIM, IBECS, CUMED, VETINDEX, Web of Science, Science Direct, Scopus and Scielo were utilized. The STREGA tool was employed to assess the quality of the selected studies. RESULTS: A total of 1,132 articles were initially identified, of which 119 studies were included in the review. Within these studies, 50 genes and 94 polymorphisms were identified, showing associations with sports talent characteristics such as endurance, strength, power, and speed. The most frequently mentioned genes were ACTN3 (27.0%) and ACE (11.3%). CONCLUSION: The ACE I/D and ACTN3 R577X polymorphisms are frequently discussed in the literature. Although athletic performance may be influenced by different genetic polymorphisms, limitations exist in associating them with athletic performance across certain genotypes and phenotypes. Future research is suggested to investigate the influence of polymorphisms in elite athletes from diverse backgrounds and sports disciplines.

The Role of FTO Risk Haplotype in Overweight/Obesity and Lipid Parameters-Results From the Central China Population Study.

Background: Fat mass and obesity-associated gene (FTO) genes rs9939609 is strongly associated with obesity and rs17817449 is an important and potential gene for obesity, have been well established. We aim to evaluate the relationship between FTO gene and overweight/obesity and confirm the influence of obesity on glucose and lipid metabolism parameters. Methods: We investigated 183 normal weight subjects and 193 individuals with overweight/obesity. Firstly, the effect of overweight/obesity on glucose and lipid metabolism parameters was analyzed. Then, the FTO genes rs9939609 and rs17817449 were counted to explore whether polymorphisms were associated with overweight/obesity and metabolic parameters. Results: Significant differences existed in glucose and lipid parameters between the group with overweight/obesity and control group. The rs9939609 and rs17817449 were strongly correlated with overweight/obesity. Haplotype analysis revealed that GA and GT haplotypes had 2.99 and 1.81 fold risk of overweight/obesity. FTO polymorphism also has effects on glucose and lipid metabolism parameters. Conclusions: There is a linkage imbalance between rs9939609 and rs17817449 in a Central China general population cohort, which also reflected the influence of FTO gene on the risk of overweight/obesity and total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) disorders. The new findings could provide new clues to predict obesity and metabolic diseases.

Expression interplay of genes coding for calcium-binding proteins and transcription factors during the osmotic phase provides insights on salt stress response mechanisms in bread wheat.

Bread wheat is an important crop for the human diet, but the increasing soil salinization is reducing the yield. The Ca2+ signaling events at the early stages of the osmotic phase of salt stress are crucial for the acclimation response of the plants through the performance of calcium-sensing proteins, which activate or repress transcription factors (TFs) that affect the expression of downstream genes. Physiological, genetic mapping, and transcriptomics studies performed with the contrasting genotypes Syn86 (synthetic, salt-susceptible) and Zentos (elite cultivar, salt-tolerant) were integrated to gain a comprehensive understanding of the salt stress response. The MACE (Massive Analysis of cDNA 3'-Ends) based transcriptome analysis until 4 h after stress exposure revealed among the salt-responsive genes, the over-representation of genes coding for calcium-binding proteins. The functional and structural diversity within this category was studied and linked with the expression levels during the osmotic phase in the contrasting genotypes. The non-EF-hand category from calcium-binding proteins was found to be enriched for the susceptibility response. On the other side, the tolerant genotype was characterized by a faster and higher up-regulation of genes coding for proteins with EF-hand domain, such as RBOHD orthologs, and TF members. This study suggests that the interplay of calcium-binding proteins, WRKY, and AP2/ERF TF families in signaling pathways at the start of the osmotic phase can affect the expression of downstream genes. The identification of SNPs in promoter sequences and 3' -UTR regions provides insights into the molecular mechanisms controlling the differential expression of these genes through differential transcription factor binding affinity or altered mRNA stability.

Correlations between the long noncoding RNA MEG3 and clinical characteristics for diabetic kidney disease in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus (T2DM) that leads to systemic inflammation. Maternally expressed gene 3 (MEG3) is a tumor suppressor that is involved in inflammation regulation. The current study investigated the association between DKD and the prevalence of the single-nucleotide polymorphisms (SNPs) of MEG3. METHODS: A total of 706 and 735 patients were included in the DKD and non-DKD groups, respectively. The five SNPs of MEG3, namely rs4081134 (G/A), rs10144253 (T/C), rs7158663 (G/A), rs3087918 (T/G), and rs11160608 (A/C), were genotyped using TaqMan allelic discrimination. RESULTS: Our results revealed that, in the DKD group, the distribution of the GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.703, 95% CI: 0.506-0.975, P = 0.035). In addition, in the pre-ESRD DKD subgroup, the distribution of the TG + GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.637, 95% CI: 0.421-0.962, P = 0.032). In addition, among men in the DKD subgroup, the distribution of the GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.630, 95% CI: 0.401-0.990, P = 0.045). Glycated hemoglobin (HbA1c) level was significantly higher in all T2DM patients with the wild-type genotype of the MEG3 SNP rs3087918 (P = 0.020). In addition, HbA1c levels were significantly higher in male patients and male DKD patients with the wild-type genotype of the MEG3 SNP rs3087918 (P = 0.032 and 0.031, respectively). CONCLUSION: MEG3 SNP rs3087918 is significantly less prevalent in patients with DKD, and the SNP rs3087918 of MEG3 is associated with lower HbA1c levels.

Relationships Between Polymorphisms in HLA-G 3'UTR Region and COVID-19 Disease Severity.

The objective of this study is to investigate the the relationships between HLA-G gene variants and sHLA-G with susceptibility to SARS-CoV-2 infection. In this case-control study, 65 Patients with COVID-19 were and 67 healthy controls were genotyped for their main functional polymorphisms namely, the 14-bp Ins/Del (rs371194629), +3003C/T (rs1707), +3010C/G (rs1710), +3027A/C (rs17179101), +3035C/T (rs17179108), +3142C/G (rs1063320), +3187A/G (rs9380142) and +3196C/G (rs1610696) in the exon 8 of the 3' untranslated regions (3' UTRs) using sanger sequencing method. Associations were assessed for five inheritance models (codominant, dominant, recessive, over-dominant and log-additive). Moreover, the levels of plasma soluble HLA-G (sHLA-G) were explored using ELISA method. Our results revealed that the 14-bp INS/DEL polymorphism was strongly associated with COVID-19 symptoms development for almost all tested inheritance models (p < 0.001). Inversely, the (+3196C/G) polymorphism exhibited a protective effect against COVID-19. In addition, three haplotypes; UTR-1, UTR-3, and UTR-5 were found associated with COVID-19 symptoms (p < 0.05), The level of HLA-G in the serum was significantly higher in COVID-19 individuals than in healthy individuals (p < 0.001).These findings suggest that HLA-G gene polymorphisms in the regulatory 3'UTR region of the HLA-G gene may influence the host immune response to SARS-CoV-2 infection. A deeper comprehension of the functional effect of these associated polymorphisms could be useful in identifying high-risk individuals and in developing adaptive treatments for patients.

MDA5 Is a Major Determinant of Developing Symptoms in Critically Ill COVID-19 Patients.

Apart from the skin and mucosal immune barrier, the first line of defense of the human immune system includes MDA5 (ifih1 gene) which acts as a cellular sensor protein for certain viruses including SARS-CoV-2. Upon binding with viral RNA, MDA5 activates cell-intrinsic innate immunity, humoral responses, and MAVS (mitochondrial antiviral signaling). MAVS signaling induces type I and III interferon (IFN) expressions that further induce ISGs (interferon stimulatory genes) expressions to initiate human cell-mediated immune responses and attenuate viral replication. SARS-CoV-2 counteracts by producing NSP1, NSP2, NSP3, NSP5, NSP7, NSP12, ORF3A, ORF9, N, and M protein and directs anti-MDA5 antibody production presumably to antagonize IFN signaling. Furthermore, COVID-19 resembles several diseases that carry anti-MDA5 antibodies and the current COVID-19 vaccines induced anti-MDA5 phenotypes in healthy individuals. GWAS (genome-wide association studies) identified several polymorphisms (SNPs) in the ifih1-ifn pathway genes including rs1990760 in ifih1 that are strongly associated with COVID-19, and the associated risk allele is correlated with reduced IFN production. The genetic association of SNPs in ifih1 and ifih1-ifn pathway genes reinforces the molecular findings of the critical roles of MDA5 in sensing SARS-CoV-2 and subsequently the IFN responses to inhibit viral replication and host immune evasion. Thus, MDA5 or its pathway genes could be targeted for therapeutic development of COVID-19.