Polymorphisms in ACE1, TMPRSS2, IFIH1, IFNAR2, and TYK2 Genes Are Associated with Worse Clinical Outcomes in COVID-19.

Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1, ACE2, DPP9, IFIH1, IFNAR2, IFNL4, TLR3, TMPRSS2, and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ACE1 Ins and rs12329760/TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ACE1 Ins/Ins genotype, rs2236757/IFNAR2 A/A genotype, and rs12329760/TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ACE1, rs1990760/IFIH1, rs2236757/IFNAR2, rs12329760/TMPRSS2, and rs2304256/TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients.

The rs2304256 Polymorphism in TYK2 Gene Is Associated with Protection for Type 1 Diabetes Mellitus.

BACKGROUND: Tyrosine kinase 2 (TYK2) is a candidate gene for type 1 diabetes mellitus (T1DM) since it plays an important role in regulating apoptotic and pro-inflammatory pathways in pancreatic ß-cells through modulation of the type I interferon signaling pathway. The rs2304256 single nucleotide polymorphism (SNP) in TYK2 gene has been associated with protection for different autoimmune diseases. However, to date, only two studies have evaluated the association between this SNP and T1DM, with discordant results. This study thus aimed to investigate the association between the TYK2 rs2304256 SNP and T1DM in a Southern Brazilian population. METHODS: This case-control study comprised 478 patients with T1DM and 518 non-diabetic subjects. The rs2304256 (C/A) SNP was genotyped by real-time polymerase chain reaction technique using TaqMan minor groove binder (MGB) probes. RESULTS: Genotype and allele frequencies of the rs2304256 SNP differed between T1DM patients and non-diabetic subjects (P<0.0001 and P=0.001, respectively). Furthermore, the A allele was associated with protection against T1DM under recessive (odds ratio [OR], 0.482; 95% confidence interval [CI], 0.288 to 0.806) and additive (OR, 0.470; 95% CI, 0.278 to 0.794) inheritance models, adjusting for human leukocyte antigen (HLA) DR/DQ genotypes, gender, and ethnicity. CONCLUSION: The A/A genotype of TYK2 rs2304256 SNP is associated with protection against T1DM in a Southern Brazilian population.

Catalytically Impaired TYK2 Variants are Protective Against Childhood- and Adult-Onset Systemic Lupus Erythematosus in Mexicans.

Type I interferon (IFN-I) pathway plays a central role in the systemic lupus erythematosus (SLE) pathogenesis. Recent data suggest that SLE is associated with variants in IFN-I genes, such as tyrosine kinase 2 (TYK2), which is crucial in anti-viral immunity. Here, five TYK2 single nucleotide polymorphisms (SNPs) were genotyped in 368 childhood-onset SLE Mexican patients and 516 sex-matched healthy controls. Allele frequencies were also estimated in four indigenous groups. SLE protection was associated with TYK2 risk infection variants affecting residually its catalytic domain, rs12720356 (OR = 0.308; p = 0.041) and rs34536443 (OR = 0.370; p = 0.034), but not with rs2304256, rs12720270, and rs280500. This association was replicated in a 506 adult-onset SLE patients sample (OR = 0.250; p = 0.005, and OR = 0.277; p = 0.008, respectively). The minor alleles of both associated SNPs had a lower frequency in Mestizos than in Spaniards and were absent or rare in indigenous, suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards. For the first time, we report genetic variants with a protective effect in childhood- and adult-onset SLE Mexican population. Our results suggest that the frequency of IFN-I alleles associated with SLE, may have been shaped in populations exposed to infectious diseases for long periods, and this could be an explanation why Native American ancestry is associated with a higher SLE prevalence and an earlier onset.

Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy.

Expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and mitochondrial oxidative phosphorylation in septic patients.

BACKGROUND AND OBJECTIVES: Sepsis is a complex disease that is characterized by activation and inhibition of different cell signaling pathways according to the disease stage. Here, we evaluated genes involved in the TLR signaling pathway, oxidative phosphorylation and oxidative metabolism, aiming to assess their interactions and resulting cell functions and pathways that are disturbed in septic patients. MATERIALS AND METHODS: Blood samples were obtained from 16 patients with sepsis secondary to community acquired pneumonia at admission (D0), and after 7 days (D7, N = 10) of therapy. Samples were also collected from 8 healthy volunteers who were matched according to age and gender. Gene expression of 84 genes was performed by real-time polymerase chain reactions. Their expression was considered up- or down-regulated when the fold change was greater than 1.5 compared to the healthy volunteers. A p-value of ≤ 0.05 was considered significant. RESULTS: Twenty-two genes were differently expressed in D0 samples; most of them were down-regulated. When gene expression was analyzed according to the outcomes, higher number of altered genes and a higher intensity in the disturbance was observed in non-survivor than in survivor patients. The canonical pathways altered in D0 samples included interferon and iNOS signaling; the role of JAK1, JAK2 and TYK2 in interferon signaling; mitochondrial dysfunction; and superoxide radical degradation pathways. When analyzed according to outcomes, different pathways were disturbed in surviving and non-surviving patients. Mitochondrial dysfunction, oxidative phosphorylation and superoxide radical degradation pathway were among the most altered in non-surviving patients. CONCLUSION: Our data show changes in the expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and oxidative phosphorylation. Importantly, distinct patterns are clearly observed in surviving and non-surviving patients. Interferon signaling, marked by changes in JAK-STAT modulation, had prominent changes in both survivors and non-survivors, whereas the redox imbalance (iNOS signaling, oxidative phosphorylation and superoxide radical degradation) affecting mitochondrial functions was prominent in non-surviving patients.

Lack of association between TYK2 and STAT3 genes and Crohn's disease in the Malaysian population.

This study aimed to investigate the potential association of TYK2 and STAT3 genes with the susceptibility to Crohn's disease (CD) among Malaysians. DNA samples were obtained from 80 CD patients and 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism methods were employed for genotyping, followed by statistical analysis. In our current study, none of the single nucleotide polymorphisms of either TYK2 or STAT3 was statistically associated with the susceptibility to CD in our local population (P > 0.05). In contrast, there was a statistically significant association between the G/G homozygotes of the STAT3 rs2293152 and the healthy control group (χ(2) = 6.229, P < 0.05). In conclusion, our study does not support the role of the TYK2 and STAT3 genes influencing CD susceptibility.

TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility.

INTRODUCTION: Tyrosine kinase 2 gene (TYK2) is part of the janus kinase (JAK) that binds to the type I interferon-α receptor (IFNAR) on the cell surface of IFN-producing cells, and have crucial importance in the etiology of autoimmune and inflammatory diseases. Many polymorphisms of the TYK2 gene have been identified, and recently, a number of case-control studies were conducted to investigate the association of these polymorphisms with autoimmune and inflammatory diseases, with conflicting results. Based on these observations, we hypothesized that the TYK2 polymorphisms (rs34536443, rs2304256, rs280523, rs12720270 and rs12720356) might be involved in the pathogenesis of endometriosis and/or infertility. METHODS: Genetic association study comprising 275 infertile women with endometriosis, 92 women with idiopathic infertility and 307 fertile women as controls. TYK2 polymorphisms were identified by TaqMan PCR. Genotype distribution, allele frequency and haplotype analysis of the TYK2 polymorphisms were performed. A p-value <0.05 was considered significant. RESULTS: Single-marker analysis revealed that TYK2 rs34536443 was significantly associated with protection against endometriosis-related infertility, especially in moderate/severe disease (p = 0.002; OR = 0.24, 95% IC = 0.09-0.62). No difference was found considering the infertile group without endometriosis. No associations were found considering rs2304256, rs280523, rs12720270 and rs12720356 either for endometriosis-related infertility group or idiopathic infertility group. Haplotype analysis of five TYK2 polymorphisms identified a haplotype "CTATG" associated with protection against endometriosis-related infertility, especially in moderate/severe disease (p = 0.027). CONCLUSION: This is the first study to report an association between TYK2 polymorphisms and endometriosis and/or infertility. These findings require replication in other populations but suggest the TYK2 rs34536443 polymorphisms and "CTATG" haplotype can be associated with a decreased susceptibility to endometriosis-related infertility in Brazilian women.

A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome.

We describe a Turkish patient with tyrosine kinase 2 deficiency who suffered from disseminated Bacille Calmette-Guerin infection, neurobrucellosis, and cutaneous herpes zoster infection. Tyrosine kinase 2 deficiency should be considered in patients susceptible to herpes viruses and intramacrophage pathogens even in the absence of atopy, high serum IgE, and staphylococcal disease.

The granulocyte colony stimulating factor (G-CSF) activates Jak/STAT and MAPK pathways in a trophoblastic cell line.

Granulocyte colony-stimulating factor receptor (G-CSFR) has been found in placenta tissues, although its functional role has not yet been defined. In order to explore the molecular pathways induced by G-CSF in this tissue, we first reveal the presence of G-CSFR in the JEG-3 human trophoblastic cell line and then examined the phosphorylation of Janus tyrosine kinases (Jak), signal transducers and activators of transcription (STAT) proteins and mitogen-activated protein kinases (MAPK) after G-CSF binding to receptors. We showed that Jak1, Jak2, Tyk2, and STAT3 were phosphorylated after incubation with G-CSF. Phosphorylation of p38 and p44/42 MAPK was also activated by G-CSF, and specifically blocked in the presence of the corresponding inhibitors. Similar intracellular pathways were induced by G-CSF in a myeloid leukemia NFS-60 cell line that was studied in parallel. Conversely to cytokine action in myeloid cells, G-CSF did not induce a proliferative response in JEG-3 cells. When the effect of G-CSF on cellular viability was evaluated, cytokine-stimulated JEG-3 cells were protected from foetal serum starvation. In addition, when JEG-3 cells deprived of serum were incubated at different times in the presence of G-CSF, a progressive decrease in the percentage of hypodiploid cells was observed. In summary, we identified the molecular pathways activated after G-CSF binding to trophoblastic cell receptors and showed that G-CSF behaved as a protective cytokine, which supports JEG-3 cells survival.

Expression and function of IL-10R in mononuclear cells from patients with systemic lupus erythematosus.

OBJECTIVE: To assess the expression and function of the receptor for interleukin-10 (IL-10R) in immune cells from patients with systemic lupus erythematosus (SLE). METHODS: We assessed the expression and function of IL-10R in peripheral blood mononuclear cells (PBMCs) from 19 SLE patients and 15 healthy controls. The expression of IL-10R was assessed by flow cytometry, and the function of this receptor was determined by analysing both the activation of Jak-1, Tyk-2, Stat-1, and Stat-3 (Western blot) and the induction of gene expression (cDNA array test of 242 genes of cytokines, apoptosis and intracellular signalling) upon stimulation with IL-10. RESULTS: We found similar levels of IL-10R expression in SLE patients and controls. In addition, variable levels of Jak-1, Tyk-2, Stat-1, and Stat-3 activation were induced by IL-10 in PBMCs from SLE patients and controls, with no significant differences in protein phosphorylation or kinetics of activation. However, clear-cut differences in the gene expression induced through IL-10R were observed in SLE patients and controls, mainly in the genes involved in apoptosis and those encoding for cytokines and their receptors. CONCLUSIONS: Our data suggest that despite normal levels of IL-10R expression, and an apparent lack of abnormalities in the intracellular signals induced through this receptor, immune cells from SLE patients exhibit an aberrant pattern of gene expression induced through the IL-10R.