Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus.

Genome-wide association studies (GWAS) have identified many loci for systemic lupus erythematosus (SLE). However, identification of functionally relevant genes remains a challenge. The aim of this study was to highlight potential causal genes for SLE in the GWAS loci. By applying Mendelian randomization (MR) methods, such as summary data-based MR (SMR), generalized SMR and MR pleiotropy residual sum and outlier, we identified DNA methylations in 15 loci and mRNA expression of 21 genes that were causally associated with SLE. The identified genes enriched in 14 specific KEGG pathways (e.g. SLE, viral carcinogenesis) and two GO terms (interferon-γ-mediated signaling pathway and innate immune response). Among the identified genes, UBE2L3 and BLK variants were significantly associated with UBE2L3 and BLK methylations and gene expressions, respectively. UBE2L3 was up-regulated in SLE patients in several types of immune cells. Methylations (e.g. cg06850285) and mRNA expression of UBE2L3 were causally associated with SLE. Methylation site cg09528494 and mRNA expression of BLK were causally associated with SLE. BLK single nucleotide polymorphisms that were significantly associated with SLE were strongly associated with plasma cathepsin B level. Deep analysis identified that plasma cathepsin B level was causally associated with SLE. In summary, this study identified hundreds of DNA methylations and genes as potential risk factors for SLE. Genetic variants in UBE2L3 gene might affect SLE by influencing gene expression. Genetic variants in BLK gene might affect SLE by influencing BLK gene expression and plasma cathepsin B protein level.

Phosphorylation-related SNPs influence lipid levels and rheumatoid arthritis risk by altering gene expression and plasma protein levels.

OBJECTIVES: Phosphorylation-related single-nucleotide polymorphisms (phosSNPs) are missense SNPs that may influence protein phosphorylation. The aim of this study was to evaluate the effect of phosSNPs on lipid levels and RA. METHODS: We examined the association of phosSNPs with lipid levels and RA in large-scale genome-wide association studies (GWAS) and performed random sampling and fgwas analyses to determine whether the phosSNPs associated with lipid levels and RA were significantly enriched. Furthermore, we performed QTL analysis and Mendelian randomization analysis to obtain additional evidence to be associated with the identified phosSNPs and genes. RESULTS: We found 483 phosSNPs for lipid levels and 243 phosSNPs for RA in the GWAS loci (P < 1.0 × 10-5). SNPs associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, Total cholesterol (TC) and RA were significantly enriched with phosSNPs. Almost all of the identified phosSNPs showed expression quantitative trait loci (eQTL) effects. A total of 48 protein QTLs and 9 metabolite QTLs were found. The phosSNP rs3184504 (p.Trp262Arg) at SH2B3 was significantly associated with RA, SH2B3 expression level, and plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC, hypoxanthine and 80 proteins, including beta-2-microglobulin. SH2B3 was differentially expressed between RA cases and controls in peripheral blood mononuclear cells and synovial tissues. Mendelian randomization analysis showed that SH2B3 expression level was significantly associated with TC level and RA. Plasma beta-2-microglobulin level was causally associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC levels and RA. CONCLUSION: The findings suggested that phosSNPs may play important roles in lipid metabolism and the pathological mechanisms of RA. PhosSNPs may influence lipid levels and RA risk by altering gene expression and plasma protein levels.

Risk Factors and Clinical Outcomes of Renal Thrombotic Microangiopathy in Children with Lupus Nephritis in Terms of Pathological and Clinical Features.

BACKGROUND: Thrombotic microangiopathy (TMA) is an important risk factor for the prognosis of lupus nephritis (LN). Patients with LN complicated with TMA tend to be critically ill with high mortality and poor prognosis. In the present study, we retrospectively analyzed the clinical manifestations, laboratory results, renal pathological manifestations, and prognosis of children with LN-TMA and analyzed the risk factors for end-stage renal disease (ESRD) in children with LN-TMA. METHODS: Seventy-four patients with LN and renal TMA (rTMA) were selected and compared to 128 LN controls without TMA (1:2 ratio) matched according to demographics, pathological type and treatments. RESULTS: The mean values of systolic blood pressure, diastolic blood pressure (DBP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), urinary protein quantitation (PRO), urine red blood cells, N-acetyl-ß-D-glucosidase (NAG), retinol-binding protein, systemic lupus erythematosus disease activity score (SLEDAI), and activity index (AI) scores in the TMA group were all higher than those in the non-TMA group (p < 0.05 and p < 0.01). The mean values of complement C3, hemoglobin, platelets, estimated glomerular filtration rate, and chronic index (CI) score in the TMA group were all lower than those in the non-TMA group (p < 0.05 and p < 0.01). The number of cases of glomerular crescent, fibrous crescent, endocapillary proliferation, tubular atrophy, interstitial fibrosis, C3 and C1q deposition in the TMA group was higher than that in the non-TMA group (p < 0.05 and p < 0.01). The 3-year and 5-year renal survival rates in the TMA group (88.93% vs. 97.00%, p < 0.05) and TMA group (61.41% vs. 82.31%, p < 0.05) were significantly lower than those in the non-TMA group. Multivariate Cox regression analysis showed that serum creatinine before treatment (≥110 µmol/L), TMA and interstitial fibrosis were independent risk factors for the development of ESRD in LN children. CONCLUSION: The general condition of children with TMA is critical, and the prognosis is poor. Early detection, early treatment and the development of new treatments are key to improving LN-TMA outcomes in children.

Clinical outcomes and clinico-pathological correlations in children with MPO-ANCA-associated glomerulonephritis showing renal arteritis.

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

Serum IgE levels are a risk factor with prognosis of pediatric minimal change disease.

Background: Minimal change disease (MCD) is one of the most common primary glomerular disorders with high serum IgE levels. This study was aimed to investigate the clinical features of different serum IgE levels in pediatric MCD and evaluate the prognostic significance of serum IgE levels with regard to remission and relapse in pediatric cohort. Methods: This study enrolled 142 new-onset children diagnosed with biopsy-proven MCD from January 2010 to December 2021 at the Jinling Hospital in Nanjing, China. These cases were divided into three groups according to serum IgE levels. MCD patients' demographics, clinical parameters, and follow-up data were collected and analyzed. The primary and secondary outcomes were defined as the time to the first complete remission (CR) and the first relapse. Results: The results manifested that 85.2% (121/142) of MCD children had high serum IgE levels (IgE > 90.0 IU/ml). A total of 142 patients were divided into the normal-, low-, and high-IgE groups based on the normal reference value level (90.0 IU/ml) and median serum IgE level (597.5 IU/ml). The high-IgE group had a significantly lower cumulative rate of the first CR (log-rank, P = 0.032) and a higher rate of the first relapse (log-rank, P = 0.033) than the normal-IgE and low-IgE groups. Multivariate Cox analysis showed that IgE ≥597.5 IU/ml was independently associated with the delayed first CR [hazard ratio (HR) = 0.566, 95% confidence interval (CI) = 0.330-0.972, P = 0.039] and the early first relapse (HR = 2.767, 95% CI = 1.150-6.660, P = 0.023). Conclusions: Serum IgE levels were an independent correlation factor for pediatric MCD-delayed remissions and early relapses.

Bowman capsule rupture in children with myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis predicts poor renal survival.

Background: Recent developments indicated that Bowman capsule rupture (BCR) is observed in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN). We aimed to explore the relationship between BCR and clinical manifestations, pathological changes, and prognosis in children with myeloperoxidase (MPO)-AAGN. Methods: A total of 56 children with MPO-AAGN were divided into BCR (+) and BCR (-) groups according to the status of Bowman's capsule. Clinical and histological features and renal outcomes were compared, and the predictive value of BCR for end-stage kidney disease (ESKD) of MPO-AAGN was evaluated. Results: After retrospective analysis of the data, 24 children (42.9%) were found to have BCR. The results showed that BCR positively correlated with intrarenal immune cell infiltrates, obsolescence and crescents in glomeruli, tubulointerstitial inflammation, tubulitis, and tubular atrophy negatively correlated with normal glomeruli and immunoglobulin G deposition in the kidney. The clinical features and kidney pathological changes were more severe in the BCR (+) group than BCR (-) group, and the renal survival rate was significantly poorer in the BCR (+) group than BCR (-) group (χ2 = 5.45, p = 0.02). Moreover, estimated glomerular filtration rate (≤15 mL/min/1.73 m2), BCR and ANCA renal risk score (ARRS) were independent risk factors for the development of ESKD in children with MPO-AAGN. After combining BCR with the Berden classification and ARRS, our data suggested that the Berden classification + BCR and ARRS + BCR showed better predictive values for ESKD than those of the Berden classification and ARRS, respectively. Conclusion: BCR is an important pathological lesion that correlates with severe clinical manifestations, pathological changes, and poor prognosis in children with MPO-AAGN.