Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization.

Prior research has established associations between immune cells, inflammatory proteins, and chronic kidney disease (CKD). Our Mendelian randomization study aims to elucidate the genetic causal relationships among these factors and CKD. We applied Mendelian randomization using genetic variants associated with CKD from a large genome-wide association study (GWAS) and inflammatory markers from a comprehensive GWAS summary. The causal links between exposures (immune cell subtypes and inflammatory proteins) and CKD were primarily analyzed using the inverse variance-weighted, supplemented by sensitivity analyses, including MR-Egger, weighted median, weighted mode, and MR-PRESSO. Our analysis identified both absolute and relative counts of CD28 + CD45RA + CD8 + T cell (OR = 1.01; 95% CI = 1.01-1.02; p < 0.001, FDR = 0.018) (OR = 1.01; 95% CI = 1.00-1.01; p < 0.001, FDR = 0.002), CD28 on CD39 + CD8 + T cell(OR = 0.97; 95% CI = 0.96-0.99; p < 0.001, FDR = 0.006), CD16 on CD14-CD16 + monocyte (OR = 1.02; 95% CI = 1.01-1.03; p < 0.001, FDR = 0.004) and cytokines, such as IL-17A(OR = 1.11, 95% CI = 1.06-1.16, p < 0.001, FDR = 0.001), and LIF-R(OR = 1.06, 95% CI = 1.02-1.10, p = 0.005, FDR = 0.043) that are genetically predisposed to influence the risk of CKD. Moreover, the study discovered that CKD itself may causatively lead to alterations in certain proteins, including CST5(OR = 1.16, 95% CI = 1.09-1.24, p < 0.001, FDR = 0.001). No evidence of reverse causality was found for any single biomarker and CKD. This comprehensive MR investigation supports a genetic causal nexus between certain immune cell subtypes, inflammatory proteins, and CKD. These findings enhance the understanding of CKD's immunological underpinnings and open avenues for targeted treatments.

Chromosome-Y haplogroups in Asturias (Northern Spain) and their association with severe COVID-19.

The main objective of this study was to determine whether the common Y-haplogroups were be associated with the risk of developing severe COVID-19 in Spanish male. We studied 479 patients who required hospitalization due to COVID-19 and 285 population controls from the region of Asturias (northern Spain), They were genotyped for several polymorphisms that define the common European Y-haplogroups. We compared the frequencies between patients and controls aged ≤ 65 and >65 years. There were no different haplogroup frequencies between the two age groups of controls. Haplogroup R1b was less common in patients aged ≤65 years. Haplogroup I was more common in the two patient´s groups compared to controls (p = 0.02). Haplogroup R1b was significantly more frequent among hypertensive patients, without difference between the hypertensive and normotensive controls. This suggested that R1b could increase the risk for severe COVID-19 among male with pre-existing hypertension. In conclusion, we described the Y-haplogroup structure among Asturians. We found an increased risk of severe COVID-19 among haplogroup I carriers, and a significantly higher frequency of R1b among hypertensive patients. These results indicate that Y-chromosome variants could serve as markers to define the risk of developing a severe form of COVID-19.

Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study.

BACKGROUND: The intricate etiology of autoimmune liver disease (AILD) involves genetic, environmental, and other factors that yet to be completely elucidated. This study comprehensively assessed the causal association between genetically predicted modifiable risk factors and AILD by employing Mendelian randomization. METHODS: Genetic variants associated with 29 exposure factors were obtained from genome-wide association studies (GWAS). Genetic association data with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were also obtained from publicly available GWAS. Univariate and multivariate Mendelian randomization analyses were performed to identify potential risk factors for AILD. RESULTS: Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10- 13) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055-2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131-0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023-1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094-1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127-1.303, P = 2.015 × 10- 7) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10- 5) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005-1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017-1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019-1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D3 (OR = 0.741, 95%CI 0.560-0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699-0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462-0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164-1.346, P = 1.394 × 10- 9), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10- 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10- 5) were positively associated with an increased risk of PSC. CONCLUSIONS: Evidence on the causal relationship between 29 genetically predicted modifiable risk factors and the risk of AIH, PBC, and PSC is provided by this study. These findings provide fresh perspectives on the management and prevention strategies for AILD.

Association between Interleukin-6 Gene Polymorphism (rs1800795 and rs1800796) and Type 2 Diabetes Mellitus in a Ghanaian Population: A Case-Control Study in the Ho Municipality.

Background: There is no conclusive evidence on the association between interleukin- (IL-) 6 gene polymorphism and type 2 diabetes mellitus (type 2 DM). Thus, this study is aimed at evaluating the role of rs1800795 and rs1800796 polymorphisms in the pathogenesis of type 2 DM among Ghanaians in the Ho Municipality. Materials and Methods: We recruited into this hospital-based case-control study 174 patients with type 2 DM (75 DM alone and 99 with DM+HTN) and 149 healthy individuals between 2018 and 2020. Demographic, lifestyle, clinical, anthropometric, and haemodynamic variables were obtained. Fasting blood samples were collected for haematological, biochemical, and molecular analyses. Genomic DNA was extracted, amplified using Tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique, and genotyped for IL-6 gene polymorphism. Logistic regression analyses were performed to assess the association between IL-6 gene polymorphism and type 2 DM. Results: The minor allele frequency (MAF) of the rs1800795 and rs1800796 polymorphisms was higher in DM alone (57.5%, 62.0%) and DM with HTN groups (58.3%, 65.3%) than controls (33.1%, 20.0%). Carriers of the rs1800795GC genotype (aOR = 2.35, 95% CI: 1.13-4.90, p = 0.022) and mutant C allele (aOR = 2.41, 95% CI: 1.16-5.00, p = 0.019) as well as those who carried the rs1800796GC (aOR = 8.67, 95% CI: 4.00-18.90, p < 0.001) and mutant C allele (aOR = 8.84, 95% CI: 4.06-19.26, p = 0.001) had increased odds of type 2 DM. For both polymorphisms, carriers of the GC genotype had comparable levels of insulin, HOMA-IR, and fasting blood glucose (FBG) with those who carried the GG genotype. IL-6 levels were higher among carriers of the rs1800796GC variant compared to carriers of the rs1800796GG variant (p = 0.023). The rs1800796 polymorphism, dietary sugar intake, and exercise status, respectively, explained approximately 3% (p = 0.046), 3.2% (p = 0.038, coefficient = 1.456), and 6.2% (p = 0.004, coefficient = -2.754) of the variability in IL-6 levels, suggesting weak effect sizes. Conclusion: The GC genotype and mutant C allele are risk genetic variants associated with type 2 DM in the Ghanaian population. The rs1800796 GC variant, dietary sugar intake, and exercise status appear to contribute significantly to the variations in circulating IL-6 levels but with weak effect sizes.

Exploring inflammatory bowel disease therapy targets through druggability genes: a Mendelian randomization study.

Background: Inflammatory bowel disease is an incurable group of recurrent inflammatory diseases of the intestine. Mendelian randomization has been utilized in the development of drugs for disease treatment, including the therapeutic targets for IBD that are identified through drug-targeted MR. Methods: Two-sample MR was employed to explore the cause-and-effect relationship between multiple genes and IBD and its subtypes ulcerative colitis and Crohn's disease, and replication MR was utilized to validate this causality. Summary data-based Mendelian randomization analysis was performed to enhance the robustness of the outcomes, while Bayesian co-localization provided strong evidential support. Finally, the value of potential therapeutic target applications was determined by using the estimation of druggability. Result: With our investigation, we identified target genes associated with the risk of IBD and its subtypes UC and CD. These include the genes GPBAR1, IL1RL1, PRKCB, and PNMT, which are associated with IBD risk, IL1RL1, with a protective effect against CD risk, and GPX1, GPBAR1, and PNMT, which are involved in UC risk. Conclusion: In a word, this study identified several potential therapeutic targets associated with the risk of IBD and its subtypes, offering new insights into the development of therapeutic agents for IBD.

Association between gut microbiota and spinal stenosis: a two-sample mendelian randomization study.

Introduction: Considerable evidence has unveiled a potential correlation between gut microbiota and spinal degenerative diseases. However, only limited studies have reported the direct association between gut microbiota and spinal stenosis. Hence, in this study, we aimed to clarify this relationship using a two-sample mendelian randomization (MR) approach. Materials and Methods: Data for two-sample MR studies was collected and summarized from genome-wide association studies (GWAS) of gut microbiota (MiBioGen, n = 13, 266) and spinal stenosis (FinnGen Biobank, 9, 169 cases and 164, 682 controls). The inverse variance-weighted meta-analysis (IVW), complemented with weighted median, MR-Egger, weighted mode, and simple mode, was used to elucidate the causality between gut microbiota and spinal stenosis. In addition, we employed mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the MR-Egger intercept test to assess horizontal multiplicity. Cochran's Q test to evaluate heterogeneity, and "leave-one-out" sensitivity analysis to determine the reliability of causality. Finally, an inverse MR analysis was performed to assess the reverse causality. Results: The IVW results indicated that two gut microbial taxa, the genus Eubacterium fissicatena group and the genus Oxalobacter, have a potential causal relationship with spinal stenosis. Moreover, eight potential associations between genetic liability of the gut microbiota and spinal stenosis were implied. No significant heterogeneity of instrumental variables or horizontal pleiotropy were detected. In addition, "leave-one-out" sensitivity analysis confirmed the reliability of causality. Finally, the reverse MR analysis revealed that no proof to substantiate the discernible causative relationship between spinal stenosis and gut microbiota. Conclusion: This analysis demonstrated a possible causal relationship between certain particular gut microbiota and the occurrence of spinal stenosis. Further studies focused on the mechanism of gut microbiota-mediated spinal stenosis can lay the groundwork for targeted prevention, monitoring, and treatment of spinal stenosis.

[Research progress on Toll-like receptor 2 (TLR2) with Mycobacterium tuberculosis infection].

Toll-like receptor 2 (TLR2) is a pattern recognition receptor expressed on the surface of leukocytes. Various ligands can activate or inhibit TLR2, therefore regulating the inflammation and apoptosis of immune cells. Mycobacterium tuberculosis (MTB) typically parasitizes macrophages. Further, after infecting the body, MTB can interact with TLR2 on the surface of various immune cells, including macrophages, leading to the release of cytokines that can affect the state and proliferation of MTB in the body. Additional research is needed to understand the polymorphism of TLR2 at the molecular level. Current studies indicate that the majority of TLR2 polymorphisms are not associated with susceptibility to MTB infection. This review provides an overview of the researches related to TLR2 and its ligands, the immune regulation activities of TLR2 following MTB infection, and the association of TLR2 polymorphism with susceptibility to MTB.

Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Association between genetic variants of GRM7 (rs1396409 and rs9883258) and treatment outcomes in Schizophrenic Egyptian patients.

BACKGROUND AND AIM: This study evaluated the association between rs1396409 and rs9883258 and the risk of schizophrenia (SCZ) and treatment outcomes in Egyptian patients. METHODS: This study included 88 patients with SCZ and 88 healthy controls. Lipid profile was assayed. Genotyping of rs1396409 and rs9883258 polymorphisms was analyzed using real-time PCR. RESULTS: The rs1396409 AG genotype frequency was significantly associated with SCZ risk (p = 0.002). Also, significant increased risk of SCZ was observed under allelic (p = 0.001), dominant (p = 0.001) and overdominant (p = 0.001) genetic model of rs1396409. However, rs9883258 AA genotype revealed nonsignificant association with SCZ. Cases with the rs1396409AG genotype exhibited hypertriglyceridemia (p < 0.001) and hypercholesterolemia (p = 0.001). In total, 72.3% and 74.5% of the cases presented with rs1396409 AG have negative symptoms (p = 0.022) and exhibited poor drug response (p = 0.023), respectively; all cases with rs1396409 GG genotype attempted suicide (p = 0.002) and are drug-free (p = 0.003). SCZ patients with negative symptoms had hypercholesterolemia (p = 0.008) mainly low-density lipoproteins (LDLc) (p = 0.016), and those with cognitive symptoms presented with low level of high-density lipoprotein (HDLc) (p = 0.023). Moreover, the multivariate regression analysis revealed that both rs1396409 G allele and HDLc were predictors of SCZ (p = 0.003 and 0.001, resp.). CONCLUSION: The current study concluded that metabotropic glutamate receptor 7 (GRM7) rs1396409 AG could be a potential biomarker for SCZ diagnosis. It also revealed an independent association between the GRM7 rs1396409 G allele, HDLc and SCZ development.

Atopic Dermatitis: Disease Background and Risk Factors.

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

Spectrum of NMDA Receptor Variants in Neurodevelopmental Disorders and Epilepsy.

N-methyl-D-aspartate receptors (NMDAR) are ligand-gated ion channels mediating excitatory neurotransmission and are important for normal brain development, cognitive abilities, and motor functions. Pathogenic variants in the Glutamate receptor Ionotropic N-methyl-D-aspartate (GRIN) genes (GRIN1, GRIN2A-D) encoding NMDAR subunits have been associated with a wide spectrum of neurodevelopmental disorders and epilepsies ranging from treatable focal epilepsies to devastating early-onset developmental and epileptic encephalopathies. Genetic variants in NMDA receptor genes can cause a range of complex alterations to receptor properties resulting in various degrees of loss-of-function, gain-of-function, or mixtures thereof. Understanding how genetic variants affect the function of the receptors, therefore, represents an important first step in the ongoing development towards targeted therapies. Currently, targeted treatment options for GRIN-related diseases are limited. However, treatment with memantine has been reported to significantly reduce seizure frequency in a few individuals with developmental and epileptic encephalopathies harboring de novo gain-of-function GRIN2A missense variants, and supplementary treatment with L-serine has been associated with improved motor and cognitive performance as well as reduced seizure frequency in patients with GRIN2B loss-of-function missense variants as well as GRIN2A and GRIN2B null variants.

The causal role of multiple psycho-emotional disorders in gastroesophageal reflux disease: A two-sample Mendelian randomized study.

BACKGROUND: Observational studies have previously shown a potential link between psycho-emotional disorders, such as mood swings, highly strung, anxious feelings, and gastroesophageal reflux disease (GERD). However, the credibility of these associations could be influenced by various confounding factors. Consequently, our study sought to employ a Mendelian randomization (MR) approach to elucidate a potential causal relationship between psycho-emotional disorders and GERD. METHOD: Information on independent genetic variants linked to mood swings, highly strung, and anxious feelings was gathered from European populations participating in the IEU Open GWAS research. The FinnGen Consortium provided the genome-wide association study (GWAS) summary statistics for GERD. Our analysis employed the inverse variance weighted (IVW) method under the random effects model as the main analytical method. To further bolster our findings, we employed the weighted median and MR Egger methods. In addition, we conducted a series of sensitivity analyses. RESULTS: Our study supports the existence of a causal relationship between psycho-emotional disorders and GERD. Mood swings, highly strung, and anxious feelings adversely affected GERD risk (mood swings: OR 2.21, 95% CI 1.19-5.59, p = 3.09 × 10-2; highly strung: OR 5.63, 95% CI 1.77-17.94, p = 3.42 × 10-3; anxious feelings: OR 2.48, 95% CI 1.08-4.33, p = 2.89 × 10-2). CONCLUSION: This Mendelian randomization study provides robust support for the notion that mood swings, highly strung and anxious feelings, are associated with an increased risk of developing GERD.

The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen.

Background: Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs. Methods: We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases. Results: The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P IVW-FE = 1.01 × 10-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P IVW-MRE = 9.88 × 10-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10-3). Conclusion: The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.

Deciphering the role of CX3CL1-CX3CR1 in aortic aneurysm pathogenesis: insights from Mendelian randomization and transcriptomic analyses.

Background: The crucial role of inflammation in aortic aneurysm (AA) is gaining prominence, while there is still a lack of key cytokines or targets for effective clinical translation. Methods: Mendelian randomization (MR) analysis was performed to identify the causal relationship between 91 circulating inflammatory proteins and AA and between 731 immune traits and AA. Bulk RNA sequencing data was utilized to demonstrate the expression profile of the paired ligand-receptor. Gene enrichment analysis, Immune infiltration, and correlation analysis were employed to deduce the potential role of CX3CR1. We used single-cell RNA sequencing data to pinpoint the localization of CX3CL1 and CX3CR1, which was further validated by multiplex immunofluorescence staining. Cellchat analysis was utilized to infer the CX3C signaling pathway. Trajectory analysis and the Cytosig database were exploited to determine the downstream effect of CX3CL1-CX3CR1. Results: We identified 4 candidates (FGF5, CX3CL1, IL20RA, and SCF) in multiple two-sample MR analyses. Subsequent analysis of the expression profile of the paired receptor revealed the significant upregulation of CX3CR1 in AA and its positive correlation with pro-inflammatory macrophages. Two sample MR between immune cell traits and AA demonstrated the potential causality between intermediate monocytes and AA. We finally deciphered in single-cell sequencing data that CX3CL1 sent by endothelial cells (ECs) acted on CX3CR1 of intermediated monocytes, leading to its recruitment and pro-inflammatory responses. Conclusion: Our study presented a genetic insight into the pathogenetic role of CX3CL1-CX3CR1 in AA, and further deciphered the CX3C signaling pathway between ECs and intermediate monocytes.

Interaction between MARK3 (rs11623869), PLCB4 (rs6086746) and GEMIN2 (rs2277458) variants with bone mineral density and serum 25-hidroxivitamin D levels in Mexican Mestizo women.

Introduction: Understanding the genetic factors contributing to variations in bone mineral density (BMD) and vitamin D could provide valuable insights into the pathogenesis of osteoporosis. This study aimed to evaluate the association of single nucleotide variants in MARK3 (rs11623869), PLCB4 (rs6086746), and GEMIN2 (rs2277458) with BMD in Mexican women. Methods: The gene-gene interaction was evaluated in these variants in serum 25(OH)D levels and BMD. A genetic risk score (GRS) was created on the basis of the three genetic variants. Genotyping was performed using predesigned TaqMan assays. Results: A significant association was found between the rs6086746-A variant and BMD at the total hip, femoral neck, and lumbar spine, in women aged 45 years or older. However, no association was observed between the variants rs11623869 and rs2277458. The rs11623869 × rs2277458 interaction was associated with total hip (p=0.002) and femoral neck BMD (p=0.013). Similarly, for vitamin D levels, we observed an interaction between the variants rs6086746 × rs2277458 (p=0.021). GRS revealed a significant association with total hip BMD (p trend=0.003) and femoral neck BMD (p trend=0.006), as well as increased vitamin D levels (p trend=0.0003). These findings provide evidence of the individual and joint effect of the MARK3, PLCB4, and GEMIN2 variants on BMD and serum vitamin D levels in Mexican women. Discussion: This knowledge could help to elucidate the interaction mechanism between BMD-related genetic variants and 25OHD, contributing to the determination of the pathogenesis of osteoporosis and its potential implications during early interventions.

Association of the C3953T (rs1143634) variant of the interleukin 1 beta gene with the features of a complicated course of COVID-19-associated pneumonia.

BACKGROUND: The pro-inflammatory cytokine IL-1 plays an important role in severe COVID-19. A change in IL-1 production may be associated with a mutation in the IL1Β gene. Our study analyzed the impact of the IL1Β gene variants (rs1143634) on disease progression in patients with severe COVID-19 pneumonia, taking into account treatment strategies. METHODS AND RESULTS: The study enrolled 117 patients with severe COVID-19 pneumonia. The IL1Β gene variants were identified using the polymerase chain reaction-restriction fragment length polymorphism method. In the group of patients, the following genotype frequencies were found based on the investigated rs1143634 variant of the IL1Β gene: CC-65.8%, CT-28.2%, and TT-6.0%. Our results showed that the group of patients with the T allele of the IL1Β gene had higher leukocyte counts (p = 0.040) and more pronounced lymphopenia (p = 0.007). It was determined that patients carrying the T allele stayed on ventilators significantly longer (p = 0.049) and required longer treatment with corticosteroids (p = 0.045). CONCLUSION: Identifying variants of the IL1Β gene can be used as a predictive tool for assessing the severity of COVID-19 pneumonia and tailoring personalized treatment strategies. Further research with a larger patient cohort is required to validate these findings.

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

BACKGROUND: Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. METHODS: We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. RESULTS: The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. CONCLUSIONS: Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Genetic predictors for bacterial vaginosis in women living with and at risk for HIV infection.

PROBLEM: Bacterial vaginosis (BV) disproportionally impacts Black and Hispanic women, placing them at risk for HIV, sexually transmitted infections and preterm birth. It is unknown whether there are differences by genetic ancestry in BV risk or whether polymorphisms associated with BV risk differ by ancestry. METHODS: Women's Interagency HIV Study (WIHS) participants with longitudinal Nugent scores were dichotomized as having (n = 319, Nugent 7-10) or not having BV (n = 367, Nugent 0-3). Genetic ancestry was defined by clustering of principal components from ancestry informative markers and further stratified by BV status. 627 single nucleotide polymorphisms (SNPs) across 41 genes important in mucosal defense were identified in the WIHS GWAS. A logistic regression analysis was adjusted for nongenetic predictors of BV and self-reported race/ethnicity to assess associations between genetic ancestry and genotype. RESULTS: Self-reported race and genetic ancestry were associated with BV risk after adjustment for behavioral factors. Polymorphisms in mucosal defense genes including syndecans, cytokines and toll-like receptors (TLRs) were associated with BV in all ancestral groups. CONCLUSIONS: The common association of syndecan, cytokine and TLR genes and the importance of immune function and inflammatory pathways in BV, suggests these should be targeted for further research on BV pathogenesis and therapeutics.

Pulmonary tuberculosis epidemiology and genetics in Kazakhstan.

Background: Tuberculosis (TB) is a major public health emergency in many countries, including Kazakhstan. Despite the decline in the incidence rate and having one of the highest treatment effectiveness in the world, the incidence rate of TB remains high in Kazakhstan. Social and environmental factors along with host genetics contribute to pulmonary tuberculosis (PTB) incidence. Due to the high incidence rate of TB in Kazakhstan, our research aimed to study the epidemiology and genetics of PTB in Kazakhstan. Materials and methods: 1,555 participants were recruited to the case-control study. The epidemiology data was taken during an interview. Polymorphisms of selected genes were determined by real-time PCR using pre-designed TaqMan probes. Results: Epidemiological risk factors like diabetes (χ2 = 57.71, p < 0.001), unemployment (χ2 = 81.1, p < 0.001), and underweight-ranged BMI (<18.49, χ2 = 206.39, p < 0.001) were significantly associated with PTB. VDR FokI (rs2228570) and VDR BsmI (rs1544410) polymorphisms were associated with an increased risk of PTB. A/A genotype of the TLR8 gene (rs3764880) showed a significant association with an increased risk of PTB in Asians and Asian males. The G allele of the rs2278589 polymorphism of the MARCO gene increases PTB susceptibility in Asians and Asian females. VDR BsmI (rs1544410) polymorphism was significantly associated with PTB in Asian females. A significant association between VDR ApaI polymorphism and PTB susceptibility in the Caucasian population of Kazakhstan was found. Conclusion: This is the first study that evaluated the epidemiology and genetics of PTB in Kazakhstan on a relatively large cohort. Social and environmental risk factors play a crucial role in TB incidence in Kazakhstan. Underweight BMI (<18.49 kg/m2), diabetes, and unemployment showed a statistically significant association with PTB in our study group. FokI (rs2228570) and BsmI (rs1544410) polymorphisms of the VDR gene can be used as possible biomarkers of PTB in Asian males. rs2278589 polymorphism of the MARCO gene may act as a potential biomarker of PTB in Kazakhs. BsmI polymorphism of the VDR gene and rs2278589 polymorphism of the MARCO gene can be used as possible biomarkers of PTB risk in Asian females as well as VDR ApaI polymorphism in Caucasians.

A comprehensive genetic map of cytokine responses in Lyme borreliosis.

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource.