Investigation of MBL2 and NOS3 functional gene variants in suspected COVID-19 PCR (-) patients.
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ABSTRACT:
SUBMITTER: Pehlivan S
PROVIDER: S-EPMC8477587 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is a hypothesis that a sufficient level of endothelial nitric oxide synthase is important for reliable protection against COVID-19. Theoretical ideas about the NOS3 gene demonstrated that it can have an effect on links of the complications pathogenesis in COVID-associated pneumonia. We determined the goal - to investigate the association of the NOS3 gene variants with the occurrence of the disease and its clinical course in patients of the intensive care unit.MethodsThe study group included 117 patients with a diagnosis of severe "viral COVID-19 pneumonia". Determination of NOS3 gene variants was performed using the PCR method. The probability of differences in the quantitative results were determined using ANOVA or Kruskal-Wallis test (depend of normality of studied parameters).ResultsOur results indicate that the presence of the NOS3 gene 4a allele increase the risk of complicated COVID-19-associated pneumonia (χ2 = 18.84, p = 0.00001, OR = 3.53 (1.95-6.39)). It was showed, that carriers of the 4aa genotype had a significantly higher ratio of SpO2/FiO2 on the first and second days after hospitalization (p = 0.017 and p = 0.03, respectively). Patients with the 4aa genotype also had the acid-base imbalances, as showed by indicators of base deficiency and standard bicarbonate, which were beyond the reference values. Potassium and sodium concentrations on the first and second day after hospitalization were also significantly lower in patients with 4aa genotype (p = 0.009 and p = 0.048, respectively), for whom, in the same time, the concentrations of C-reactive protein and total bilirubin were significantly higher (p = 0.002 and p = 0.033, respectively).ConclusionsOur results confirmed that the rs61722009 variant of the NOS3 gene is associated with an increased risk of severe СOVID-19-associated pneumonia and its adverse clinical course with potential progression of kidney and liver damage, and occurrence risk of systemic inflammatory response syndrome. These results require further research for the new metabolic strategy formation, in order to prevent the severe COVID-19 associated pneumonia and its complications.
| S-EPMC10082643 | biostudies-literature
Project description:The six types of pattern recognition molecules (PRMs) that initiate complement via the lectin pathway (LP) comprise collectins and ficolins. The importance of having various PRMs to initiate the LP is currently unclear. Mannan-binding lectin (MBL) is a collectin member of the LP PRMs. MBL deficiency is common with mild clinical consequence. Thus, the lack of MBL may be compensated for by the other PRMs. We hypothesized that variants FCN2?+?6424 and FCN3?+?1637delC that cause gene-dose-dependent reduction in ficolin-2 and ficolin-3 levels, respectively, may be rare in MBL-deficient individuals due to the importance of compensation within the LP. The aim of this study was to investigate the distribution and frequency of these variants among MBL2 genotypes in healthy subjects. The allele frequency of FCN2?+?6424 and FCN3?+?1637delC was 0.099 and 0.015, respectively, in the cohort (n?=?498). The frequency of FCN2?+?6424 tended to be lower among MBL-deficient subjects (n?=?53) than among MBL-sufficient subjects (n?=?445) (0.047 versus 0.106, P?=?0.057). In addition, individuals who were homozygous for FCN2?+?6424 were sufficient MBL producers. The frequency of FCN3?+?1637delC did not differ between the groups. The frequency of FCN2?+?6424 was similar in FCN3?+?1637delC carriers (n?=?15) versus wild type (n?=?498). Furthermore, subjects that were heterozygote carriers of both FCN2?+?6424 and FCN3?+?1637delC were sufficient MBL producers. In conclusion, FCN2?+?6424 carriers with MBL deficiency tend to be rare among healthy individuals. MBL-deficient individuals with additional LP PRM defects may be at risk to morbidity.
| S-EPMC4842218 | biostudies-literature
Project description:COVID-19 modified the healthcare system. Nasal-pharyngeal swab (NPS), with real-time reverse transcriptase-polymerase (PCR), is the gold standard for the diagnosis; however, there are difficulties related to the procedure that may postpone it. The study aims to evaluate whether other elements than the PCR-NPS are reliable and confirm the diagnosis of COVID-19. This is a cross-sectional study on data from the Lung Unit of Pavia (confirmed) and at the Emergency Unit of Palermo (suspected). COVID-19 was confirmed by positive NPS, suspected tested negative. We compared clinical, laboratory and radiological variables and performed Logistic regression to estimate which variables increased the risk of COVID-19. The derived ROC-AUCcurve, assessed the accuracy of the model to distinguish between COVID-19 suspected and confirmed. We selected 50 confirmed and 103 suspected cases. High Reactive C-Protein (OR: 1.02; CI95%: 0.11-1.02), suggestive CT-images (OR: 11.43; CI95%: 3.01-43.3), dyspnea (OR: 10.48; CI95%: 2.08-52.7) and respiratory failure (OR: 5.84; CI95%: 1.73-19.75) increased the risk of COVID-19, whereas pleural effusion decreased the risk (OR: 0.15; CI95%: 0.04-0.63). ROC confirmed the discriminative role of these variables between suspected and confirmed COVID-19 (AUC 0.91). Clinical, laboratory and imaging features predict the diagnosis of COVID-19, independently from the NPS result.
| S-EPMC9181151 | biostudies-literature
Project description:BackgroundIn recent years, the elucidation of splicing abnormalities as a cause of hereditary diseases has progressed. However, there are no comprehensive reports of suspected splicing variants in the CLCN5 gene in Dent disease cases. We reproduced gene mutations by mutagenesis, inserted the mutated genes into minigene vectors, and investigated the pathogenicity and onset mechanisms of these variants.MethodsWe conducted functional splicing assays using a hybrid minigene for six suspected splicing variants (c.105G>A, c.105+5G>C, c.106-17T>G, c.393+4A>G, c.517-8A>G, c.517-3C>A) in CLCN5. We extracted information on these variants from the Human Gene Mutation Database. We reproduced minigene vectors with the insertion of relevant exons with suspected splicing variants. We then transfected these minigene vectors into cultured cells and extracted and analyzed the mRNA. In addition, we conducted in silico analysis to confirm our minigene assay results.ResultsWe successfully determined that five of these six variants are pathogenic via the production of splicing abnormalities. One showed only normal transcript production and was thus suspected of not being pathogenic (c.106-17T>G).ConclusionWe found that five CLCN5 variants disrupted the original splice site, resulting in aberrant splicing. It is sometimes difficult to obtain mRNA from patient samples because of the fragility of mRNA or its low expression level in peripheral leukocytes. Our in vitro system can be used as an alternative to in vivo assays to determine the pathogenicity of suspected splicing variants.
| S-EPMC7935734 | biostudies-literature
Project description:PURPOSE:The COVID-19 pandemic has reformed global healthcare delivery. On 25 March 2020, Intercollegiate guidelines were published in the UK to promote safe surgical provision during the COVID-19 outbreak advocating non-operative management or avoidance of laparoscopy when surgery is essential. The effects of this on the investigation and management of appendicitis remain unknown. METHODS:We performed a multicentre, prospective, observational study from the start of the new guidelines to the 6th of May 2020. We included all patients referred to surgical teams with suspected appendicitis. A recent historical cohort was identified for comparison. The primary outcome was the impact of the COVID-19 pandemic on the use of non-operative management in appendicitis. Secondary outcomes included imaging, negative appendicectomy rate (NAR), length of stay (LOS) and 30-day complications. RESULTS:A total of 63/164 (38%) patients compared to 79/191 (41%) were diagnosed with appendicitis before and after the guidelines were introduced (p?=?0.589). CT scanning increased (71/164 vs 105/191; p?=?0.033) while ultrasound scanning decreased (71/164 vs 62/191; p?=?0.037). Appendicitis was more likely to be managed non-operatively (11/63 vs 51/79; p?<?0.001) and, of those managed surgically, with an open approach (3/52 vs 26/28 p?<?0.001). The NAR also reduced (5/52 vs 0/28; p?=?0.157). LOS was shorter in non-operatively managed patients (1 day vs 3 days; p?<?0.001) without a difference in complications (10/51 vs 4/28; p?=?0.760). CONCLUSION:Introduction of the guidelines was associated with changes in practice. Despite these changes, short-term complications did not increase and LOS decreased. Questions remain on the longer-term complication rates in non-operatively managed patients.
| S-EPMC7652586 | biostudies-literature
Project description:The aim of this study was to analyze the association of different clinical contributors of hypoxic-ischemic encephalopathy with NOS3 gene polymorphisms. A total of 110 children with hypoxic-ischemic encephalopathy and 128 control children were selected for this study. Association of gender, gestational age, birth weight, Apgar score, cranial ultrasonography, and magnetic resonance imaging findings with genotypic data of six haplotype-tagging single nucleotide polymorphisms and the most commonly investigated rs1800779 and rs2070744 polymorphisms was analyzed. The TGT haplotype of rs1800783, rs1800779, and rs2070744 polymorphisms was associated with hypoxic-ischemic encephalopathy. Children with the TGT haplotype were infants below 32 weeks of gestation and they had the most severe brain damage. Increased incidence of the TT genotype of the NOS3 rs1808593 SNP was found in the group of hypoxic-ischemic encephalopathy patients with medium and severe brain damage. The probability of brain damage was twice as high in children with the TT genotype than in children with the TG genotype of the same polymorphism. Furthermore, the T allele of the same polymorphism was twice as frequent in children with lower Apgar scores. This study strongly suggests associations of NOS3 gene polymorphism with intensity of brain damage and severity of the clinical picture in affected children.
| S-EPMC4181222 | biostudies-literature
Project description:BackgroundThe relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms.MethodsWe used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non-small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided.ResultsWe found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (P(interaction) = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients.ConclusionThe functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.
| S-EPMC6278934 | biostudies-literature
Project description:BackgroundManagement of large numbers of reverse transcriptase-polymerase chain reactions (RT-PCR) for diagnosis of coronavirus 2019 disease (COVID-19) requires robust infrastructures, located in dedicated premises with a high standard of biosafety procedures, and well-trained personnel. The handling of a "run-of-river sample" to obtain rapid reporting of results is challenging.MethodsWe studied the clinical performance of the Idylla™ SARS-CoV-2 Test (index test) on a platform capable of fully automated nucleic acid testing including extraction, amplification, and detection in a single-use cartridge to establish the diagnosis of COVID-19. The study was conducted on a prospective cohort of 112 volunteers with recent symptoms and an unknown SARS-CoV-2 status who came to free screening centers of the Nice metropolitan area. All subjects underwent bilateral nasopharyngeal sampling. One sample was processed using the index test, the other using the standard of care RT-PCR. Samples were treated blind.ResultsMost of the participants (70%) were sampled within 4 days of symptom onset. Forty-five (40.2%) were positive for COVID-19. No clinical symptoms were distinguished between SARS-CoV-2 RT-PCR positive and negative subjects except anosmia and dysgeusia. Positive and negative agreement between the index and the standard of care test was 100%.ConclusionsThe Idylla™ SARS-CoV-2 Test is very sensitive, specific, rapid and easy to use in a near-patient RT-PCR approach to distinguish between symptomatic SARS-CoV-2 positive and negative patients in selected settings.
| S-EPMC8263856 | biostudies-literature
Project description:Since SARS-CoV-2-based disease (COVID-19) spreads as a pandemic, the necessity of a highly sensitive molecular diagnosis that can drastically reduce false negatives reverse transcription PCR (rtPCR) results, raises as a major clinical need. Here we evaluated the performance of a ddPCR-based assay to quantify SARS-CoV-2 titer in 55 suspected COVID-19 cases with negative rtPCR results thanks to in-house ddPCR assay (targeting RdRp and host RNaseP). Samples were collected at ASST-GOM Niguarda between February and May 2020 at hospital admission. Clinical and imaging data were obtained for clinical staging and definition of disease severity. Patients were mainly female (45.5%) with a median age of 73 (57-84) years. ddPCR-based assay detected SARS-CoV-2 genome in nasopharyngeal samples of 19 (34.5%) patients (median viral-load: 128 copies/mL, IQR: 72-345). In 15 of them (78.9%), chest CT showed a classical COVID-19 bilateral interstitial pneumonia; 14 patients (73.7%) showed severe COVID-19 manifestations. ddPCR did not identify any trace of SARS-CoV-2 genome in the respiratory samples of the remaining 36 patients. The serological assay performed in a subgroup of 34 patients at the later stage of illness (from 3 days to 90 days after) confirmed the presence of SARS-CoV-2 antibodies in all patients tested positive for SARS-CoV-2 in ddPCR (100%). Contrariwise, negative tests were observed in 95.0% ddPCR negative patients (P<0.001). Thanks to a ddPCR-based assay, we achieved a rapid and accurate SARS-CoV-2 diagnosis in rtPCR-negative respiratory samples of individuals with COVID-19 suspect, allowing the rapid taking care and correct management of these patients.
| S-EPMC7478621 | biostudies-literature
Project description: Not available
| S-BSST563 | biostudies-other