Study of lncRNAs expression profile in the response to biological drugs in Psoriatic Arthritis: MEG3 could be a potential genomic biomarker of therapy efficacy.

We aimed to identify an expression profile of lncRNAs potentially related to treatment response in Psoriatic arthritis (PsA) patients, to be used as potential genomic biomarkers predictors of drug treatment effectiveness. In addition, we evaluated a possible association between lncRNAs genetic variants and the response to therapy using the clinical parameter of Disease Activity Index. For the expression study, we collected 48 treated PsA patients, monitoring the treatment response for 12 months. We initially used PCR Array and, then, we validated the results with qRT-PCR. We also retrospectively genotyped 163 treated PsA patients. Firstly, we observed a significant difference in the expression level between Responder and non-Responder patients, of 4 lncRNAs in the group of PsA patients treated with TNFi and of 3 lncRNAs in the group of patients treated with IL17i. Then, we confirmed a significant decrease of MEG3 expression in non-Responder patients compared to Responders, also considering separately the single groups of patients treated with TNFi and IL17i. In addition, our results seem to highlight a potential dose-dependent effect of rs941576 (MEG3) variant allele on Disease Activity Index. Our study suggests a possible role of the lncRNA MEG3 in the treatment response to biological drugs.

Large-scale DNA sequencing identifies rare variants associated with Systemic Lupus Erythematosus susceptibility in known risk genes.

The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies. Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher's exact test. Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools. Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.

The rs11568820 Variant in the Promoter Region of Vitamin D Receptor Gene Is Associated with Clinical Remission in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors.

The vitamin D receptor (VDR), binding to the active form of the vitamin, promotes the transcription of numerous genes involved in the proliferation of immune cells, cytokine production and lymphocyte activation. It is known that vitamin D deficiency can influence the risk of developing rheumatoid arthritis (RA) or modulate its disease activity. The aim of this study was to investigate a possible association between the rs11568820 (C > T) polymorphism in the promoter region of VDR gene and the response to therapy with anti-TNF drugs in patients with RA. A total of 178 consecutive Italian patients with RA treated with anti-TNF, naïve for biological therapy, were recruited. Disease activity data were evaluated using specific indices such as DAS28, CDAI and SDAI, measured at the start of therapy and subsequently at 22, 52, 104 and 240 weeks. A statistically significant association emerged between the rs11568820 variant allele of VDR gene and failure to remission assessed by CDAI and SDAI at 52 weeks, and by DAS28, CDAI and SDAI at 104 weeks of follow-up. Furthermore, the variant allele of this polymorphism was observed more frequently in patients who did not undergo sustained remission calculated by CDAI and SDAI. The variant T allele of rs11568820 in VDR gene is associated with a reduced remission rate with anti-TNFα drugs. These data suggest the role of VDR genetic variability in the response to therapy and in the achievement of remission.

Low expression levels of miRNA-155 and miRNA-499a are associated with obesity in Type 2 diabetes.

Background & aims: This study investigated a possible correlation between three circulating miRNAs, previously observed to be associated to diabetic polyneuropathy, and the obesity condition. Methods & results: The expression levels of miR-128a, miR-155 and miR499a were evaluated in 49 participants with Type 2 diabetes, divided into different groups based on the presence or absence of obesity and central obesity. The analyses revealed a significant decrease of miR-155 and miR-499a expression levels in obese subjects. In particular, the reduction appears to be even more significant in Type 2 diabetes subjects with central obesity. Conclusion: The results suggest that these miRNAs could be involved in obesity-driven pathogenetic mechanisms.

ATG5 gene expression analysis supports the involvement of autophagy in microangiopathic complications of type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) hyperglycaemia alters basal autophagy. Since autophagy is an essential cellular process, our aim was to investigate the ATG5 (autophagy-related 5) gene expression level and genetic variants in a cohort of diabetic patients, characterized for the presence of microangiopathic complications. METHODS AND RESULTS: the expression levels of ATG5 were evaluated in PBMCs from 48 T2D patients with an extensive evaluation for microangiopathic complications. Our analyses revealed a significant lower expression of ATG5 in T2D patients with retinopathy compared to those without retinopathy. We also highlighted a significant lower expression of ATG5 in T2D patients with early-cardiovascular autonomic neuropathy compared to those without it, after correction for sex, age, body mass index and levels of hemoglobin A1c. CONCLUSION: our results highlight that dysregulation in the autophagy process could be involved in the development of severe microangiopathic complications.

PCSK3 Overexpression in Sjögren's Syndrome Patients May Be Regulated by rs4932178 SNP in Its Promoter Region and Correlates with IFN-γ Gene Expression.

BACKGROUND: The PCSK3 gene encodes for the protease enzyme Furin, which promotes proteolytic maturation of important regulators of the immune response, and also enhances the secretion of interferon-γ (IFN). Several studies have suggested its possible involvement in the pathogenesis of chronic inflammatory diseases. METHODS: We investigated the PCSK3 gene expression level in peripheral blood mononuclear cells isolated from Sjögren's Syndrome (SS) patients and healthy controls and we evaluated a possible correlation with IFN-γ gene expression. Moreover, we also explored the variability of two PCSK3 genetic polymorphisms (rs4932178 and rs4702) to evaluate a possible association between these polymorphisms and the expression levels of this gene. RESULTS: We observed, by RT-qPCR, that the PCSK3 expression level was significantly higher in SS patients compared to the controls (p = 0.028), and we confirmed a positive correlation between PCSK3 and IFN-γ expression levels (p < 0.001). Moreover, we reported that the variant homozygous genotype of rs4932178 SNP is associated with a higher expression of the PCSK3 gene (p = 0.038) and with the SS susceptibility (p = 0.016). CONCLUSIONS: Our data suggest that Furin could play a role in SS development, also promoting IFN-γ secretion.

Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway.

BACKGROUND: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. METHODS: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. RESULTS: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10-4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. CONCLUSION: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. IMPACT: Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10-12). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease.

Expression analysis of miRNA hsa-let7b-5p in naso-oropharyngeal swabs of COVID-19 patients supports its role in regulating ACE2 and DPP4 receptors.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for worldwide coronavirus disease (COVID-19). We previously observed that Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4) are significantly overexpressed in naso-oropharyngeal swabs (NPS) of COVID-19 patients, suggesting their putative functional role in the disease progression. ACE2 and DPP4 overexpression in COVID-19 patients may be associated to epigenetic mechanism, such as miRNA differential expression. We investigated if hsa-let7b-5p, reported to target both ACE2 and DPP4 transcripts, could be involved in the regulation of these genes. We verified that the inhibition and overexpression of hsa-let7b-5p matched to a modulation of both ACE2 and DPP4 levels. Then, we observed a statistically significant downregulation (FC = -1.5; p < 0.05) of hsa-let7b-5p in the same COVID-19 and control samples of our previous study. This is the first study that shows hsa-let7b-5p low expression in naso-oropharyngeal swabs of COVID-19 patients and demonstrates a functional role of this miR in regulating ACE2 and DPP4 levels. These data suggest the involvement of hsa-let7b-5p in the regulation of genes necessary for SARS-CoV-2 infections and its putative role as a therapeutic target for COVID-19.

Impact of TRAF3IP2, IL10 and HCP5 Genetic Polymorphisms in the Response to TNF-i Treatment in Patients with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory rheumatic disease. The introduction of therapy with biological drugs is promising, even if the efficacy is very variable. Since the response to drugs is a complex trait, identifying genetic factors associated to treatment response could help define new biomarkers for a more effective and personalized therapy. This study aimed to evaluate the potential role of polymorphisms in genes involved in PsA susceptibility as predictors of therapy efficacy. Nine polymorphisms were analyzed in a cohort of 163 PsA patients treated with TNF-i. To evaluate the treatment response, the DAPsA score was estimated for each patient. The possible association between the selected SNPs and mean values of DAPsA differences, at 22 and 54 weeks from the beginning of the treatment, were evaluated by t-test. Patients carrying the variant allele of TRAF3IP2 seemed to respond better to treatment, both at 22 and 54 weeks. This variant allele was also associated with an improvement in joint involvement. In contrast, patients carrying the IL10 variant allele showed an improvement lower than patients with the wild-type genotype at 54 weeks. Our results suggest that polymorphisms in genes associated with PsA susceptibility could also play a role in TNF-i treatment response.

The Impacts of the Clinical and Genetic Factors on Chronic Damage in Caucasian Systemic Lupus Erythematosus Patients.

Objective: The purpose of this study was to determine the distribution of organ damage in a cohort of systemic lupus erythematosus (SLE) patients and to evaluate the roles of clinical and genetic factors in determining the development of chronic damage. Methods: Organ damage was assessed by the SLICC Damage Index (SDI). We analyzed a panel of 17 single-nucleotide polymorphism (SNPs) of genes already associated with SLE, and we performed a phenotype−genotype correlation analysis by evaluating specific domains of the SDI. Results: Among 175 Caucasian SLE patients, 105 (60%) exhibited damage (SDI ≥1), with a median value of 1.0 (IQR 3.0). The musculoskeletal (26.2%), neuropsychiatric (24.6%) and ocular domains (20.6%) were involved most frequently. The presence of damage was associated with higher age, longer disease duration, neuropsychiatric (NP) manifestations, anti-phospholipid syndrome and the positivity of anti-dsDNA. Concerning therapies, cyclophosphamide, mycophenolate mofetil and glucocorticoids were associated with the development of damage. The genotype−phenotype correlation analysis showed an association between renal damage, identified in 6.9% of patients, and rs2205960 of TNFSF4 (p = 0.001; OR 17.0). This SNP was significantly associated with end-stage renal disease (p = 0.018, OR 9.68) and estimated GFR < 50% (p = 0.025, OR 1.06). The rs1463335 of MIR1279 gene was associated with the development of NP damage (p = 0.029; OR 2.783). The multivariate logistic regression analysis confirmed the associations between TNFSF4 rs2205960 SNP and renal damage (p = 0.027, B = 2.47) and between NP damage and rs1463335 of MIR1279 gene (p = 0.014, B = 1.29). Conclusions: Our study could provide new insights into the role of genetic background in the development of renal and NP damage.

A multilocus genetic study evidences the association of autoimmune-related genes with Psoriatic Arthritis in Italian patients.

Psoriatic Arthritis (PsA) is an immune-mediated rheumatic disease caused by the interaction between environmental factors and genetic predisposition. Many of the risk loci associated with PsA susceptibility are shared with other autoimmune diseases, suggesting an involvement of the same pathways in these diseases. We investigated the association between nine selected polymorphisms and PsA susceptibility and their possible role in the modulation of the disease activity. We analysed 163 patients with PsA and 298 age and sex-matched healthy subjects. Our results showed the associations of five polymorphisms with the disease development: rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3), rs27524 (ERAP1), rs7574865 (STAT4) and rs1800872 (IL10). Patients carrying the variant allele of TRAF3IP2 polymorphism had a higher number of tender/swollen joints and a higher Disease Activity Index for PsA score. The multilocus genetic risk profile showed a higher probability to develop the disease in subjects with at least four risk alleles.

Fever in systemic lupus erythematosus: associated clinical features and genetic factors.

OBJECTIVES: Fever has been recently included in the new 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). Thus, we investigated the possible association of fever with other clinical disease manifestations. Then, we analysed a panel of 30 SNPs to verify their possible contribution to the pathogenesis of this constitutional symptom. METHODS: In this retrospective study we collected clinical/laboratory features in a SLE cohort, including the occurrence of fever (body temperature >37.5°C, excluding infective aetiology). A phenotype-genotype correlation analysis was carried out. RESULTS: We evaluated 167 patients (M/F 12/155, median age at the disease diagnosis 30 years, IQR 17; median disease duration 240 months, IQR 156). Seventy patients (41.9%) reported fever, significantly associated with: serositis and haematological manifestations (p=0.02 and p=0.00001, respectively). A significant association between fever and leukopenia (p=0.003), haemolytic anaemia (p=0.04), and thrombocytopenia (p=0.04) was observed. In addition, significantly higher median SLICC Damage Index (SDI) values were observed in patients with fever in comparison with those without [2 (IQR 3) vs. 1 (IQR 2); p=0.005]. The genotype/phenotype analysis showed an association between fever and the rs13361189 of Immunity Related GTPase M (IRGM) gene (p=0.003; OR 3.89, CI 1.16-13.03), confirmed also in multivariate logistic regression analysis (p=0.028, B=1.39). CONCLUSIONS: The association between IRGM rs13361189 polymorphism and the occurrence of inflammatory fever, could provide new insights into the role of genetic background in the pathogenesis of this SLE-related feature.

Genetics, Epigenetics, and Gender Impact in Axial-Spondyloarthritis Susceptibility: An Update on Genetic Polymorphisms and Their Sex Related Associations.

Spondyloarthritis (SpA) is a group of chronic inflammatory rheumatic disease that can be divided into predominantly axial or predominantly peripheral involvement, with or without associated psoriasis, inflammatory bowel disease or previous infection. Axial SpA (axSpA) encompasses ankylosing spondylitis (AS) with radiological sacroiliitis, and a type without radiographic sacroiliitis, called "non-radiographic axial SpA" (nr-axSpA). Males and females show large differences in their susceptibility to SpA, such as distinctions in clinical patterns, phenotypes and in therapeutical response, particularly to TNF inhibitors (TNFi). Several studies indicate that AS women have doubled risk to failure TNFi compared with males. This diversity in drugs' efficacy among women and men may be caused by differences in the balance of sex hormones and in gene-specific expression likely triggered by X-chromosome instability and gene-specific epigenetic modifications. Evidence reported that polymorphisms in microRNAs on X- and other chromosomes, such as miR-146a, miR-155, miR-125a-5p, miR-151a-3p and miR-22-3p, miR-199a-5p could be involved in the different clinical presentation of SpA, as well as disease activity. In addition, association with non-response to TNFi treatment and presence of IRAK3 and CHUCK genes in SpA patients was recently detected. Finally, polymorphisms in genes involved in IL-23/IL-17 pathway, such as in drug pharmacodynamics and pharmacokinetics may have a role in response to TNFi, IL17i, and IL23i. A major understanding of genomic variability could help in the development of new therapeutic targets or in taking advantages of different mechanisms of action of biological drugs. Moving from the multifactorial etiology of disease, the present review aims at evaluating genetic and epigenetic factors and their relationship with sex and bDMARDs response, helping to investigate the different expression among males and females of genes on X- and other chromosomes, as well as mi-RNA, to highlight relationships between sex and occurrence of specific phenotypes and symptoms of the disease. Moreover, the role of the epigenetic modification in relation to immune-regulatory mechanisms will be evaluated.

Emerging Role of microRNAs and Long Non-Coding RNAs in Sjögren's Syndrome.

Sjögren's Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies.

mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. METHODS: This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. RESULTS: CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. CONCLUSIONS: In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

VDR Polymorphisms in Autoimmune Connective Tissue Diseases: Focus on Italian Population.

Vitamin D is an important hormone involved in various physiologic processes, and its activity is linked to binding with vitamin D receptor (VDR). Genetic polymorphisms in the VDR gene could modulate the expression or function of the receptor and, consequently, alter the effects of vitamin D. Variants in VDR gene have been associated with susceptibility to many illnesses sensitive to vitamin D administration and to autoimmune disorders, but no data are available regarding autoimmune connective tissue diseases in Italian population. We analyzed three VDR polymorphisms in 695 Italian patients with autoimmune connective tissue diseases (308 with systemic lupus erythematosus (SLE), 195 with primary Sjogren's syndrome (pSS), and 192 with rheumatoid arthritis (RA)) and in 246 healthy controls with the aim to evaluate a possible association of VDR SNPs with susceptibility to these diseases in the Italian population. Genotyping of rs2228570, rs7975232, and rs731236 in VDR gene was performed by an allelic discrimination assay. A case/control association study and a genotype/phenotype correlation analysis have been performed. We observed a higher risk to develop SLE for rs2228570 TT genotype (P = 0.029, OR = 1.79). No association was observed between susceptibility to pSS or RA and this SNP, although this variant is significantly less present in RA patients producing autoantibodies. For rs7975232 SNP, we observed a significant association of the variant homozygous genotype with SLE (P = 0.009, OR = 1.82), pSS (P = 0.046, OR = 1.66), and RA (P = 0.028, OR = 1.75) susceptibility. Moreover, we reported associations of this genotype with clinical phenotypes of SLE and pSS. Lastly, the GG genotype of rs731236 was associated with a lower RA susceptibility (P = 0.045, OR = 0.55). Our results show that the explored VDR polymorphisms are significantly associated with autoimmune connective tissue disorders and support the hypothesis that the genetic variability of VDR gene may be involved in susceptibility to these diseases in Italian population.

Altered expression of miR-142, miR-155, miR-499a and of their putative common target MDM2 in systemic lupus erythematosus.

Aim: To evaluate genetic and expression variability of three miRNAs potentially involved in systemic lupus erythematosus (SLE) and to identify any miRNA's target gene. Materials & methods: Gene polymorphisms and expression levels of three miRNAs have been evaluated in a cohort of SLE patients and controls. Results: miR-142 and miR-499a were significantly down-expressed in patients (p = 0.005 and p = 0.02, respectively). A trend for down-expression of miR-155 was also observed (p = 0.07). The lower expression of miR-142 was associated with the rs2632516 polymorphism variant allele (p = 0.002). Predictive analyses identified a target gene common to the three miRNAs, MDM2, whose higher expression was seen in patients compared with controls (p = 0.03). Conclusion: The three miRNAs and MDM2 might be involved in SLE.

Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis.

The COVID-19 pandemic has strengthened the interest in the biological mechanisms underlying the complex interplay between infectious agents and the human host. The spectrum of phenotypes associated with the SARS-CoV-2 infection, ranging from the absence of symptoms to severe systemic complications, raised the question as to what extent the variable response to coronaviruses (CoVs) is influenced by the variability of the hosts' genetic background.To explore the current knowledge about this question, we designed a systematic review encompassing the scientific literature published from Jan. 2003 to June 2020, to include studies on the contemporary outbreaks caused by SARS-CoV-1, MERS-CoV and SARS-CoV-2 (namely SARS, MERS and COVID-19 diseases). Studies were eligible if human genetic variants were tested as predictors of clinical phenotypes.An ad hoc protocol for the rapid review process was designed according to the PRISMA paradigm and registered at the PROSPERO database (ID: CRD42020180860). The systematic workflow provided 32 articles eligible for data abstraction (28 on SARS, 1 on MERS, 3 on COVID-19) reporting data on 26 discovery cohorts. Most studies considered the definite clinical diagnosis as the primary outcome, variably coupled with other outcomes (severity was the most frequently analysed). Ten studies analysed HLA haplotypes (1 in patients with COVID-19) and did not provide consistent signals of association with disease-associated phenotypes. Out of 22 eligible articles that investigated candidate genes (2 as associated with COVID-19), the top-ranked genes in the number of studies were ACE2, CLEC4M (L-SIGN), MBL, MxA (n = 3), ACE, CD209, FCER2, OAS-1, TLR4, TNF-α (n = 2). Only variants in MBL and MxA were found as possibly implicated in CoV-associated phenotypes in at least two studies. The number of studies for each predictor was insufficient to conduct meta-analyses.Studies collecting large cohorts from different ancestries are needed to further elucidate the role of host genetic variants in determining the response to CoVs infection. Rigorous design and robust statistical methods are warranted.

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients.

BACKGROUND: Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East respiratory syndrome ( MERS-CoV ), the severe acute respiratory syndrome corona virus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis. METHODS: As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children's Hospital, Rome. We used a large control group consisting of 1000 individuals (500 males and 500 females). RESULTS: We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient. CONCLUSIONS: Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.