Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. METHODS: Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. RESULTS: We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein-Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. CONCLUSIONS: This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report.

BACKGROUND: X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. CASE PRESENTATION: We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFß1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFß1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment. CONCLUSIONS: Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.

The antioxidant and antiglycation activities of selected spices and other edible plant materials and their decay in sugar-protein systems under thermal stress.

Antiglycation activities of herbs and spices, have been described in relation to their in vivo anti-diabetic or anti-aging activity at physiological temperature. Under the hypothesis that those natural antioxidants may inhibit the formation of Maillard intermediates, the behavior of several hydroalcoholic plant extracts was analyzed in sugar-protein systems. Allspice, thyme, green pepper and black pepper extracts were the most efficient inhibitors, decreasing furosine formation by 60, 45, 40 and 30%, respectively. 5-hydroxymethyl-2-furfural formation decreased in the presence of the extracts and protein glycation was inhibited by the thyme extract in advanced stages. Antiglycation activities were related to polyphenols content, to radical scavenging and to iron-reducing power. In the protein-sugar systems studied at the time in which 4000 ppm of furosine were formed, the antioxidant activity dropped between 30 and 40%. Polyphenols inhibit Maillard intermediates formation, revealing the incidence of oxidative pathways, but they are depleted as a function of time.

Antioxidant and anti-glycation potential of green pepper (Piper nigrum): Optimization of ß-cyclodextrin-based extraction by response surface methodology.

Green pepper (Piper nigrum) presents high levels of functional compounds, with antioxidant and anti-glycation properties. Thus, the optimization of the ß-cyclodextrin-based extraction of functional compounds from green pepper through Response Surface Methodology was performed. The optimum extraction conditions were assessed by optimizing total polyphenolic content (TPC) and antioxidant activity (DPPH• and FRAP methods). 15 mM for ß-CD solution, 5 min of ultrasonication and 41 °C were the optimum extraction conditions, with the TPC of 24.9 mg GAE/mL and the anti-radical activities were 3.1 mg GAE/mL (DPPH• assay) and 0.45 mg GAE/mL (FRAP method). This natural extract obtained through eco-friendly techniques proved to be effective to reduce the formation of hydroxymethylfurfural, a glycation marker, at 70 and 80 °C. GPE presented higher TPC than black and white pepper. The relationship between the antioxidant and anti-glycation properties was confirmed and green pepper and can be proposed as a natural potential anti-glycation agent.

Pervasive Inter-Individual Variation in Allele-Specific Expression in Monozygotic Twins.

Despite being developed from one zygote, heterokaryotypic monozygotic (MZ) co-twins exhibit discordant karyotypes. Epigenomic studies in biological samples from heterokaryotypic MZ co-twins are of the most significant value for assessing the effects on gene- and allele-specific expression of an extranumerary chromosomal copy or structural chromosomal disparities in otherwise nearly identical germline genetic contributions. Here, we use RNA-Seq data from existing repositories to establish within-pair correlations for the breadth and magnitude of allele-specific expression (ASE) in heterokaryotypic MZ co-twins discordant for trisomy 21 and maternal 21q inheritance, as well as homokaryotypic co-twins. We show that there is a genome-wide disparity at ASE sites between the heterokaryotypic MZ co-twins. Although most of the disparity corresponds to changes in the magnitude of biallelic imbalance, ASE sites switching from either strictly monoallelic to biallelic imbalance or the reverse occur in few genes that are known or predicted to be imprinted, subject to X-chromosome inactivation or A-to-I(G) RNA edited. We also uncovered comparable ASE differences between homokaryotypic MZ twins. The extent of ASE discordance in MZ twins (2.7%) was about 10-fold lower than the expected between pairs of unrelated, non-twin males or females. The results indicate that the observed within-pair dissimilarities in breadth and magnitude of ASE sites in the heterokaryotypic MZ co-twins could not solely be attributable to the aneuploidy and the missing allelic heritability at 21q.

Maternal 5mCpG Imprints at the PARD6G-AS1 and GCSAML Differentially Methylated Regions Are Decoupled From Parent-of-Origin Expression Effects in Multiple Human Tissues.

A hallmark of imprinted genes in mammals is the occurrence of parent-of-origin-dependent asymmetry of DNA cytosine methylation (5mC) of alleles at CpG islands (CGIs) in their promoter regions. This 5mCpG asymmetry between the parental alleles creates allele-specific imprinted differentially methylated regions (iDMRs). iDMRs are often coupled to the transcriptional repression of the methylated allele and the activation of the unmethylated allele in a tissue-specific, developmental-stage-specific and/or isoform-specific fashion. iDMRs function as regulatory platforms, built through the recruitment of chemical modifications to histones to achieve differential, parent-of-origin-dependent chromatin segmentation states. Here, we used a comparative computational data mining approach to identify 125 novel constitutive candidate iDMRs that integrate the maximal number of allele-specific methylation region records overlapping CGIs in human methylomes. Twenty-nine candidate iDMRs display gametic 5mCpG asymmetry, and another 96 are candidate secondary iDMRs. We established the maternal origin of the 5mCpG imprints of one gametic (PARD6G-AS1) and one secondary (GCSAML) iDMRs. We also found a constitutively hemimethylated, nonimprinted domain at the PWWP2AP1 promoter CGI with oocyte-derived methylation asymmetry. Given that the 5mCpG level at the iDMRs is not a sufficient criterion to predict active or silent locus states and that iDMRs can regulate genes from a distance of more than 1 Mb, we used RNA-Seq experiments from the Genotype-Tissue Expression project and public archives to assess the transcriptional expression profiles of SNPs across 4.6 Mb spans around the novel maternal iDMRs. We showed that PARD6G-AS1 and GCSAML are expressed biallelically in multiple tissues. We found evidence of tissue-specific monoallelic expression of ZNF124 and OR2L13, located 363 kb upstream and 419 kb downstream, respectively, of the GCSAML iDMR. We hypothesize that the GCSAML iDMR regulates the tissue-specific, monoallelic expression of ZNF124 but not of OR2L13. We annotated the non-coding epigenomic marks in the two maternal iDMRs using data from the Roadmap Epigenomics project and showed that the PARD6G-AS1 and GCSAML iDMRs achieve contrasting activation and repression chromatin segmentations. Lastly, we found that the maternal 5mCpG imprints are perturbed in several hematopoietic cancers. We conclude that the maternal 5mCpG imprints at PARD6G-AS1 and GCSAML iDMRs are decoupled from parent-of-origin transcriptional expression effects in multiple tissues.