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Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs/miRs) are involved in the pathogenesis of diabetes mellitus and its chronic complications, and their circulating levels have emerged as potential biomarkers for the development and progression of diabetes. However, few studies have examined the expression of miRNAs in diabetic retinopathy (DR) in humans. This case‐control study aimed to investigate whether the plasma levels of miR‐29b and miR‐200b are associated with DR in 186 South Brazilians with type 2 diabetes (91 without DR, 46 with non‐proliferative DR and 49 with proliferative DR). We also included 20 healthy blood donors to determine the miRNA expression in the general population. Plasma levels of miR‐29b and miR‐200b were quantified by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). Proliferative DR was inversely associated with plasma levels of miR‐29b (unadjusted OR = 0.694, 95% CI: 0.535‐0.900, P = 0.006) and miR‐200b (unadjusted OR = 0.797, 95% CI: 0.637‐0.997, P = 0.047). However, these associations were lost after controlling for demographic and clinical covariates. In addition, patients with type 2 diabetes had lower miR‐200b levels than blood donors. Our findings reinforce the importance of addressing the role of circulating miRNAs, including miR‐29 and miR‐200b, in DR. [ABSTRACT FROM AUTHOR]

Background/Aims: The -1082A>G polymorphism (rs1800896) in the interleukin-10 (IL10) gene has been associated with type 2 diabetes and diabetic retinopathy, but its relationship with diabetic kidney disease (DKD) is uncertain. The aim of this case-control study was to investigate whether the -1082A>G polymorphism is associated with DKD in white Brazilians with type 2 diabetes mellitus. Methods: Genotyping was done by real-time polymerase chain reaction for 597 type 2 diabetic outpatients. The definition of DKD was based on estimated glomerular filtration rate (eGFR) and albuminuria, and the patients were grouped in three categories: no DKD (n=249), mild to moderate DKD (n=222), and severe DKD (n=126). Results: The frequency of the minor (G) allele in subjects without DKD did not differ from that observed in subjects with DKD (0.35 vs 0.39, respectively; P = 0.192). Genotype frequencies in subjects without DKD were not significantly different from those observed among patients with mild to moderate DKD or severe DKD. However, considering only the eGFR categories as an indicator of renal function, the AG genotype was independently associated with an increased risk of mildly to moderately decreased eGFR (G3a category) and GG genotype was independently associated with increased risk of kidney failure (G5 category) as compared with AA genotype. Conclusion: Our findings support the hypothesis that the -1082A>G polymorphism in the IL10 gene might be associated with DKD in white Brazilians with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Circulating microRNAs (miRNAs/miRs) have emerged as potential disease biomarkers; however, their expression in diabetic retinopathy (DR) has been evaluated only recently in humans. Whilst it is recognized that sequence variants in miRNA genes (miRSNPs) can alter the miRNA-mediated regulation of gene expression, there are almost no studies on the association of miRSNPs with DR. In this case-control study, we investigated whether the functional polymorphisms rs531564 G>C (MIR124-1), rs4636297 A>G (MIR126) and 2910164 C>G (MIR146A) are associated with DR in 1,025 Brazilians with type 2 diabetes. We also evaluated whether the plasma levels of miR-124, miR-126 and miR-146a are associated with DR and with miRSNPs in 182 patients. Blood donors were included to determine the prevalence of miRSNPs (n = 104) and miRNA expression (n = 20) in the general population. Genotyping was done by real-time PCR and plasma levels were quantified by RT-qPCR. Genotype and allele frequencies in diabetic subjects did not significantly differ from those of blood donors, and the minor allele frequencies were similar to those reported in other populations. The MIR126 heterozygous genotype was more frequent in patients without DR than in those with DR (52% versus 44%, respectively, p = 0.040), and remained associated with this complication after controlling for clinical covariates. MiR-126 was markedly downregulated in diabetic subjects as compared to blood donors and even more reduced among those with DR (mean log2 fold-change of -0.7 ± 1.7, -1.1 ± 2.0 and -1.7 ± 1.6 for subjects without DR, with nonproliferative DR or with proliferative DR, p = 0.002). Patients carrying the A allele of the rs4636297 polymorphism had almost twice higher levels of miR-126 than patients with GG genotype. MiR-126 and miR-146a were strongly correlated and the levels of miR-146a were also lower in diabetic subjects than in blood donors. Overall, our findings reinforce that gene variants and expression of miRNAs are associated with DR in type 2 diabetes. Disclosure: E.R. Polina: None. R.C. Sbruzzi: None. F.M. de Oliveira: None. D. Crispim: None. M.D. Enoia: None. L.H. Canani: Research Support; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. K.G. Santos: None. Funding: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (1994-2551/13-4); Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (14-0645) [ABSTRACT FROM AUTHOR]

COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.