Interferon-gamma (IFN-γ) intronic variant (rs2430561) is a risk factor for systemic lupus erythematosus: Observation from a meta-analysis.

BACKGROUND: The role of interferon-gamma (IFN-γ) in autoimmune disorders has been well documented. Elevated levels of IFN-γ are observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and are linked with disease severity. Single nucleotide polymorphism in the intronic region of the IFN-γ gene (+874 T>A rs2430561) has been associated with susceptibility to the development of RA and SLE; however, the reports remained contradictories. We conducted a meta-analysis using earlier published articles to reach a valid conclusion on the role of IFN-γ polymorphism (+874 T>A) in autoimmune diseases. MATERIALS AND METHODS: Various online databases such as PubMed, Google Scholar, Science Direct, and Scopus were searched to find eligible reports for inclusion in the present analysis. Two independent authors extracted eligible studies and data. The meta-analysis was performed by comprehensive meta-analysis software (CMA) v.3.1. Trial sequential analysis was performed to test whether enough case-control studies have already been conducted worldwide to reach a valid observation. RESULTS: Six published reports on the role of IFN-γ +874 T>A in SLE and four in RA were found after searching various databases. However, out of those six studies in SLE, in one study, the distribution of genotypes was not following the hardy-Weinberg equilibrium. In RA, three studies were deviated out of four reports. Thus, a total of five studies comprising 1440 SLE patients and 1748 controls were considered for the present meta-analysis. Meta-analysis showed a significant association between IFN-γ +874 T>A variants with susceptibility to SLE (homozygous comparison: p = 0.036, OR = 1.592, heterozygous model: p = 0.042, OR = 1.507, dominant model: p = 0.002, OR = 1.309). CONCLUSIONS: IFN-γ +874 T>A variant is associated with predisposition to SLE development.

Interleukin 17A rs2275913 polymorphism is associated with susceptibility to systemic lupus erythematosus: A meta and trial sequential analysis.

BACKGROUND: The role of cytokines in the development of systemic lupus erythematosus (SLE) has received much attention. Interleukin-17 A upregulates several inflammation-related genes and is thought to have a crucial role in SLE development. The susceptibility to SLE development has been linked to functional genetic variations of the IL-17A gene; nevertheless, the findings have been conflicting. We conducted a meta-analysis that included previously published reports to establish a definitive conclusion on the role of the IL-17A rs2275913 polymorphism in SLE propensity. MATERIALS AND METHODS: The PubMed, Google Scholar, and Scopus databases were used to find eligible published articles. All analyses were conducted using Comprehensive Meta-analysis V3.1. Funnel plots and Egger's regression analysis were used to assess publication bias. Q statistics and I2 test explored the heterogeneity among the included studies. Combined odds ratio, 95% confidence interval were calculated for each comparison model. RESULTS: Based on the inclusion and exclusion criteria, a total of four reports, comprising of 608 SLE patients and 815 healthy controls, were considered for the present meta-analysis. The homozygous comparison (AA vs. GG: combined odds ratio= 2.046, p = 0.005) and recessive genetic model (AA vs. GG+GA: combined odds ratio=1.901, p = 0.010) analysis revealed a significant association of rs2275913 with susceptibility to the development of SLE. However, other genetic comparisons (A vs. G, GA vs. GG, AA+GA vs. GG) failed to demonstrate such association. Furthermore, trial sequential analysis revealed a sufficient number of studies, including enough cases and controls that have already been considered to conclude the role of IL17-A rs2275913 polymorphism in SLE. CONCLUSIONS: IL-17A rs2275913 polymorphism is associated with susceptibility to SLE development.

Role of interleukin-6 and interferon-α in systemic lupus erythematosus: A case-control study and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting various organ systems with unknown etiology. Interleukin-6 (IL-6) and interferon-alpha (IFN-α) have been shown to have a major role in disease pathogenesis, and they correlate with SLE disease activity, but reports in the literature are conflicting. The present study aims to investigate the significance of IL-6 and IFN-α levels in SLE pathogenesis in an eastern Indian cohort. MATERIAL AND METHODS: 70 SLE patients fulfilled SLICC 2012 criteria, and 40 age- and gender-matched healthy controls (HC) were enrolled. Baseline characteristics along with disease activity were recorded for all patients. Levels of IL-6 and IFN-α were measured by using ELISA. For the meta-analysis, published articles were searched through different databases. Two independent researchers extracted data, and the meta-analysis was performed with CMA v3.1. RESULTS: The plasma levels of IL-6 and IFN-α in SLE patients were significantly elevated compared to HC (IL-6: p < .0001, IFN-α: p = 0.01). SLEDAI score correlated positively with plasma IL-6 (p < .0001, r = 0.46) and IFN-α levels (p < .0001; r = 0.47). Meta-analysis of previous reports, including our case-control data, revealed higher IL-6 (p < .0001) and IFN-α (p = .005) in SLE patients compared to HC. Furthermore, IL-6 (p < .0001, r = 0.526) and IFN-α (p < .0001; r = 0.371) levels positively correlated with the disease activity. CONCLUSION: IL-6 and IFN-α levels are elevated in SLE and they correlate with disease activity. Further studies with a larger sample size in different populations are required to validate our findings.

Association of MBL-2 gene polymorphisms with systemic lupus erythematosus: an updated meta-analysis and trial sequential analysis.

OBJECTIVES: Mannose-binding lectin (MBL), an essential innate immune molecule, enhances the opsonization process and activates the complement system. Genetic variations at the promoter and coding region of the MBL-2 gene have been associated with susceptibility to systemic lupus erythematosus (SLE); however, reports remained inconsistent. The present study performs a meta-analysis of published peer-reviewed articles to draw a definitive conclusion. MATERIALS AND METHODS: Published peer-reviewed articles on the association of MBL-2 gene polymorphisms and SLE were screened on various databases such as PubMed (Medline), ScienceDirect, and Google Scholar. A total of 23 eligible articles were included in the present study, comprising 3074 SLE patients and 3985 controls. Genotype and/or allele data for MBL-2 polymorphisms (A > B, A > C, A > D, A > O, Y > X and H > L) were extracted and analyzed by Comprehensive Meta-Analysis software (CMA V3.1). RESULTS: The overall analysis revealed a significant association of MBL-2 (A > O) polymorphism with a predisposition to SLE in allele contrast (p = 0.000; OR = 1.261), homozygous (p = 0.005; OR = 1.482), heterozygous (p = 0.004; OR = 1.247), dominant (p = 0.000; OR = 1.303) and recessive (p = 0.025; OR = 1.356) genetic comparison model. Similar results were also observed in the comparison of allele and the dominant genetic model of MBL-2 (A > B) polymorphism in overall (allele: p = 0.000, OR = 1.46, dominant: p = 0.001, OR = 1.31) and in the Asian cohorts (allele: p = 0.007, OR = 1.43, dominant: p = 0.008, OR = 1.32). Interestingly, MBL-2 (Y-221X) polymorphism exhibited protection against the development of SLE in heterozygous (p = 0.005, OR = 0.619) and dominant genetic comparison (p = 0.01, OR = 0.672) models. CONCLUSIONS: MBL-2 variants (A > O and A > B) are associated with predisposition to SLE. Conversely, promoter polymorphism (Y-221X) offers protection against SLE development.

Elevated toll-like receptor 9 is associated with disease severity and kidney involvement in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with the activation of both innate and adaptive immune system. Infection is a significant environmental factor that is responsible for the development of SLE. Toll-like receptors (TLRs) are responsible for recognizing pathogens, and the expression of TLRs has been found to differ in SLE patients. Additionally, various infections have been reported to influence TLR expression. This study aimed to explore the relationship between TLRs and the onset, severity, and symptoms of SLE in the eastern Indian population. METHODS: The study included 70 SLE patients and a control group matched for age and sex. RT-PCR was used to evaluate mRNA expression of TLRs 2, 4, 7, and 9. Statistical analyses were performed using GraphPad Prism software v.10.2.3. RESULTS: Patients with SLE expressed significantly higher levels of TLR2 (p < 0.0001) and TLR9 (p = 0.012) than healthy controls. In lupus nephritis, TLR9 expression was higher than in SLE patients without kidney involvement (p = 0.037). Furthermore, a significant relationship was found between TLR9 expression and systemic lupus erythematosus disease activity index (SLEDAI) scores (p < 0.0001, Spearman's r = 0.47), implying the potential role of TLRs in SLE development. However, mRNA expression of TLR4 and TLR7 was not associated with SLE, clinical indices, or disease severity. CONCLUSIONS: TLR9 is associated with SLE pathogenesis and clinical severity, making it a promising molecule for targeted therapy in SLE management.

Toll-like receptor-2 (TLR-2) rs111200466 variant offers protection against SARS-CoV-2 infections and mortality: a worldwide epidemiological correlation analysis.

Recently Toll-like receptor-2 has been shown to sense the envelope protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and initiate the production of inflammatory molecules. The expression and function of the TLR2 has been associated with several functional polymorphisms such as a 23 bp ins/del (rs111200466), Arg677Trp (rs121917864), and Arg753Gln (rs5743708). In the present study, we hypothesized that the TLR2 common functional variants would be associated with the worldwide incidence and mortality rate of SARS-CoV-2. The frequency of TLR2 polymorphisms and coronavirus disease-19 (COVID-19) were acquired from multiple databases, including genomAD, 1000 genome, dbSNP, and worldometer, respectively. The Spearman rank correlation coefficient analysis revealed a significant inverse correlation between the del allele of rs111200466 polymorphism with susceptibility to SARS-CoV-2 infection and related mortality at different times. In conclusion, the TLR2 rs111200466 minor allele (del) may be linked with susceptibility to SARS-CoV-2 infections and bad outcomes. However, further case-control studies in different populations are required to validate our observations.

TNF-α promoter variant (G-308A) is associated with susceptibility to P. falciparum infection and severe malaria: a meta-analysis and trial sequential analysis.

Tumor necrosis factor-alpha (TNF-α) plays an essential role in Plasmodium falciparum infection, with lower levels associated with susceptibility to infection and higher levels linked with organ failure in severe malaria. Genetic polymorphisms in the promoter region of the TNF-α gene (G-308A and G-238A) affect plasma TNF-α levels. Numerous case-control studies have been conducted to determine the possible association between TNF-α polymorphisms and susceptibility to malaria infection and clinical severity; however, the results are inconsistent. Various databases such as Google Scholar, Science Direct, PubMed, and Scopus were searched for relevant articles for the present meta-analysis. Data were extracted from the eligible studies based on inclusion and exclusion criteria. Meta-analysis was carried out with CMA v.3.3.070 software, and combined odds ratio, 95% confidence interval, and p values were calculated. Further, a trial sequential analysis was also performed to test whether enough number of case and controls have been enrolled to date to draw a valid conclusion. Allele (OR = 9.757, p value=.049) and heterozygous (OR = 8.98, p value=.016) comparison model revealed the TNF-α G-308A variant as a susceptible genetic factor for P. falciparum infection. Similarly, a significant association of TNF-α G-308A polymorphism with P. falciparum malarial severity was also observed (A versus G: OR = 1.761, p value = .000; and GG + GA versus GG: OR = 1.769, p value = .000). However, no association of TNF-α (G-238A) polymorphism was observed with infection and severity of P. falciparum or Plasmodium vivax malaria. TNF-α G-308A variant is associated with susceptibility to P. falciparum infection and clinical severity. However, further studies on different populations are required.

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) polymorphisms are linked to systemic lupus erythematosus: an updated meta-analysis.

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) molecule controls T cell immune response. Functional single nucleotide polymorphisms (SNPs) in the CTLA-4 gene have been associated with several autoimmune diseases, including systemic lupus erythematosus (SLE).  However, the genetic association of the CTLA-4 variants with vulnerability to SLE remained contradictory. We have conducted a current meta-analysis by combining the findings of prior published articles in order to make a conclusive statement. Various literature databases were screened with appropriate keywords to obtain relevant articles, and eligible reports were obtained using well-defined inclusion and exclusion criteria. Meta-analysis was performed by Comprehensive Meta-analysis V 3.3, and various statistical parameters such as odds ratio, 95% confidence interval, and probability values were computed. A total of 3847 SLE patients and 5278 healthy controls were considered in the present meta-analysis from 26 individual reports. A significant association of CTLA-4 +49 A/G (G vs. A: p=0.03, OR=1.47) and -1722 T/C (p=0.02, OR=0.87) polymorphisms were observed with susceptibility and resistance against the development of SLE, respectively. However, the other two SNPs in the CTLA-4 gene (-318 C/T and -1661 A/G) failed to establish a connection. Interestingly, subgroup analysis revealed an association of CTLA-4 +49 A/G with a predisposition to SLE only in the Asian population (G vs. A: p=0.04, OR=1.26, GG vs. AA: p=0.02, OR=1.84, AG vs AA: p=0.01, OR=1.44, GG+AG vs AA: p=0.01, OR=1.52) and not in Caucasians. The current meta-analysis suggests a significant CTLA-4 +49 A/G variant association with susceptibility to SLE development in overall and Asian populations. In contrast, the other variant, -1722 T/C, is linked with protection against SLE. However, further case-control studies in diverse ethnic populations are requisite.

ACE deletion allele is associated with susceptibility to SARS-CoV-2 infection and mortality rate: An epidemiological study in the Asian population.

BACKGROUND: Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) is believed to have emerged from Wuhan, China, and spreads over 215 countries worldwide. The spike protein of SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE-2) receptors and enter the host cells. Several reports have been highlighted the importance of ACE-2 on the pathogenesis of COVID-19. In the present study, we hypothesize that a functional insertion/deletion polymorphism in the ACE gene could be associated with SARS-CoV-2 infection and mortality. MATERIALS AND METHODS: PubMed and Google scholar search engines were used to obtained data on the prevalence of ACE I/D polymorphism in different countries of the Asia continent. Data on COVID-19 infection rate (per million), mortality/million, and percentage of recovery were acquired form worldometer website. The Spearman rank correlation test performed to investigate the correlation of allele 'D' with SARS-CoV-2 infection, mortality rate, and recovery percentage. RESULTS: Epidemiological investigation revealed a significant positive correlation of D allele of ACE polymorphism with SARS-CoV-2 infection (r = 0.502, p = 0.008, n = 26) and mortality rate (r = 0.620, p = 0.002, n = 22) in Asian population. However, no significant role of ACE I/D polymorphism was observed with recovery rate of patients from SARS-CoV-2 infection (r = -0.208, p = 0.352, n = 22). CONCLUSIONS: Allele D of ACE insertion/deletion polymorphism is associated with the rate of infection and mortality in the Asian population.

Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study.

BACKGROUND: The role of vitamin D in the susceptibility and severity of various viral diseases has been well documented. Recently, some reports highlighted the possible importance of vitamin D in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although India receives adequate sunlight throughout the year, the majority of Indians are deficient in vitamin D levels. In the present study, we hypothesized that vitamin D deficiency would be associated with the SARS-CoV-2 infection rate and mortality in the Indian population. MATERIALS AND METHODS: SARS-CoV-2 infection and mortality data were obtained from the Government of India's official website (accessed on 16th August 2020). Various literature databases like PubMed and Google Scholar were searched to find the mean of 25-hydroxyvitamin D [25(OH)D] levels in different states and union territories of India, Pearson correlation was carried out to investigate the possible link between mean 25(OH)D levels and SARS-CoV-2 infection and mortality per million of the population. RESULTS: An inverse correlation was observed between the mean level of 25(OH)D and SARS-CoV-2 infection rate (r = -0.43, p = 0.02) and mortality rate (r = -0.42, p = 0.02). CONCLUSIONS: The present observational study revealed an association of vitamin D with SARS-CoV-2 infection and related mortality. Further studies are required to validate our observations.