IMB-Guided Rehabilitation Nursing in Patients with Diabetic Nephropathy Undergoing Maintenance Hemodialysis.

Objective: This study aims to analyze the application effect of IMB (Information-Motivation-Behavioral skills) model rehabilitation nursing, which focuses on enhancing patient knowledge, motivation, and skills for disease management in patients with diabetes and end-stage renal disease receiving maintenance hemodialysis and its impact on the patient's nutritional status. Methods: Eighty-four patients with diabetes and end-stage renal disease undergoing maintenance hemodialysis were selected as study subjects at our hospital. All patients met the inclusion criteria and were divided into two groups based on the nursing interventions received. The control group (n=42) received routine rehabilitation nursing intervention, while the observation group (n=42) received IMB-guided rehabilitation nursing intervention. The effects of nursing intervention, psychological conditions, nutritional status, and quality of life were evaluated using standardized measurement tools. Psychological conditions were assessed using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Nutritional status was evaluated through measurements of albumin (ALB), body composition analysis (BBC), hemoglobin (Hb), triceps skinfold thickness (TSF), arm circumference (A.C.), and arm muscle circumference (AMC). Quality of life was assessed using the SF-36 Health Survey. Comparative analysis was conducted to examine the differences between the two groups in terms of the aforementioned outcomes. Results: The results of the study revealed compelling data showcasing the effectiveness of the nursing intervention. Notably, after the nursing intervention, ALB (albumin) levels in the observation group increased by 12%, indicating a significant improvement in nutritional status. This increase signifies enhanced protein synthesis and improved overall metabolic functioning among the patients. Additionally, the SF-36 scores, reflecting the quality of life, demonstrated a substantial improvement of 15 points in the observation group following the nursing intervention. This improvement indicates a significant enhancement in various aspects of health-related quality of life, such as physical functioning, mental health, social functioning, and overall well-being. Furthermore, the total nursing effective rate in the observation group was an impressive 97.62%, surpassing the 80.95% rate in the control group. This statistically significant difference (P < .05) emphasizes the superior outcomes achieved through the nursing intervention in the observation group. Moreover, when comparing psychological conditions, the SAS scores in the observation group after the nursing intervention were significantly lower than those in the control group by 8 points (P < .05). Similarly, the SDS scores in the observation group showed a significant decrease of 10 points compared to the control group (P < .05). These findings indicate a substantial reduction in anxiety and depression levels among patients in the observation group. Conclusion: The findings of this study have significant implications for patient care and highlight potential areas for future research. The results suggest that integrating IMB-guided approaches into hemodialysis care protocols could significantly enhance patient well-being. The notable improvements in nutritional status, as indicated by the increase in ALB levels, and the substantial enhancement in quality of life, as reflected by the improvement in SF-36 scores, underscore the effectiveness of the nursing intervention. These findings have important implications for clinical practice, emphasizing the need for broader implementation of IMB-guided approaches in diverse clinical settings. By incorporating these interventions into routine hemodialysis care, healthcare providers can potentially improve patient outcomes and enhance their overall quality of life. Furthermore, these results also highlight potential areas for future research. Additional studies could explore the long-term effects of the nursing intervention on patient health outcomes, sustainability of the improvements observed, and the cost-effectiveness of implementing IMB-guided approaches in hemodialysis settings. Moreover, investigating the feasibility and efficacy of these interventions in different patient populations could further expand our understanding and inform tailored approaches for specific subgroups.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

The antioxidative effects of empagliflozin on high glucose­induced epithelial-mesenchymal transition in peritoneal mesothelial cells via the Nrf2/HO-1 signaling.

High glucose (HG)-induced epithelial-mesenchymal transition (EMT) and oxidative stress play an important role in peritoneal fibrosis, which could be regulated by the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. This study aimed to investigate whether empagliflozin could inhibit HG-induced EMT and oxidative stress via activating the Nrf2/HO-1 signaling pathway. We used HG-based peritoneal dialysis (PD) solution in rats and HG in human peritoneal mesothelial cells (HPMCs) to induce EMT in vivo and in vitro respectively. The peritoneal structure and function were evaluated by hematoxylin and eosin, Masson's trichrome staining, and the peritoneal equilibrium test. Oxidative stress was measured by assay kits. EMT was analyzed using immunohistochemistry and western blot. The PD rats showed decreased ultrafiltration capacity and increased levels of oxidative stress. Histopathological analysis revealed markedly peritoneal thickening, excessive collagen deposition, increased expression of α-SMA, Collagen-I, and Fibronectin, and decreased expression of E­cadherin. Empagliflozin significantly ameliorated the aforementioned changes. The protein expression levels of nuclear Nrf2 (N-Nrf2) and HO-1 increased in PD rats, which were further promoted by treatment with empagliflozin. In in vitro experiments, the EMT of HPMCs was induced with 60 mM glucose for 24 h and inhibited by empagliflozin. Empagliflozin suppressed oxidative stress and promoted the protein expression of N-Nrf2 and HO-1 in HG­stimulated HPMCs, which was reversed by the Nrf2 inhibitor. In conclusion, empagliflozin exerted a protective effect against HG-induced EMT and suppressed oxidative stress in PMCs by activating the Nrf2/HO-1 signaling pathway.

Corrigendum: Long-term kidney prognosis and pathological characteristics of late-onset lupus nephritis.

[This corrects the article DOI: 10.3389/fmed.2022.882692.].

Long-Term Kidney Prognosis and Pathological Characteristics of Late-Onset Lupus Nephritis.

Background: Arguments still exist on prognosis of late-onset SLE, especially their kidney function. The purpose of this study was to investigate long-term kidney outcomes in patients with late-onset lupus nephritis (LN). Methods: A retrospective long-term cohort study was conducted in adult Chinese patients with LN. The patients were divided into late- (>50 years) and early-onset (<50 years) LN groups. The baseline characteristics, especially the kidney pathological characteristics, were compared. The cohort was followed-up for kidney outcome defined as doubling of serum creatinine or ESRD. Cox regression analysis was used to examine the association between late onset LN and its outcomes. Results: A total of 1,264 patients were recruited, who were assigned to late-onset LN with 102 patients and early-onset LN with 1,162 patients. The late-onset LN group showed a worse baseline kidney function and more chronic pathological lesions than the early-onset LN group. During a follow-up time of 55 (3, 207) months, 114 (13.1%) deaths occurred, 107 (12.2%) had doubling of creatinine, and 80 (9.1%) developed end-stage kidney disease. The 5- and 10-year survival rates of the late-onset LN group were 67.6 and 50.5%, respectively, which were much worse than those of the early-onset LN group (89.8 and 84.6%, respectively). However, no significant difference was found on kidney survival (log-rank chi-square = 3.55, p = 0.06). Cox regression analysis showed that late-onset LN was an independent risk factor for patient survival (hazard ratio = 3.03, 95% CI (1.39, 6.58), p = 0.005). Increased baseline serum creatinine was an independent risk factor for kidney survival of patients with late-onset LN. Conclusions: Patients with late-onset LN had milder active lesions but severer chronic lesions in kidney pathology. They have poorer overall outcome but relatively favorable kidney outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03001973, 22 December 2016 retrospectively registered.

Epigenome-wide association study and network analysis for IgA Nephropathy from CD19+ B-cell in Chinese Population.

IgA nephropathy (IgAN) is the most common primary glomerular disease in China and worldwide. The proliferation of B cells is known to be associated with both risk and prognosis of IgAN, but the epigenetic mechanism underlying this association is unknown. In this study we carried out the first Epigenome-wide Association Study (EWAS) by using the latest Infinium Methylation EPIC BeadChip on 184 B cell-specific samples (92 case/control pairs) for Chinese IgAN population. After rigorous data normalization and residual batch effect correction, linear mixed effect model was used to detect methylation CpG sites associated with IgAN adjusting for age, gender and smoking. False discovery rate (FDR) less than 10% was used to account for multiple testing. Weighted gene co-methylation networks were generated to identify gene modules highly correlated with IgAN. A permutation test was performed to account for the potential effect of overfitting. After adjusting clinical covariates and potential technical batch effects, three CpGs corresponding to PCDH17, TERT, WDR82 genes and three in the intergenic regions passed the genome-wide significant threshold. Methylation network analysis identified an additional IgAN associated gene module, containing 72 significant CpGs including GALNT6, IQSEC1, CDC16 and SYS1, involved in the pathway related to tubular atrophy/interstitial fibrosis of IgAN. These results suggested important DNA methylation and gene targets in CD19+ B cells for the pathogenesis of IgAN.

SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway.

Autosomal dominant polycystic kidney disease (ADPKD) is a complex process, involving the alteration of multiple genes and signaling pathways, and the pathogenesis of ADPKD remains largely unknown. Here, we demonstrated the suppressive role of sorting nexin 9 (SNX9) during ADPKD development. Sorting nexin 9 expression was detected in the kidney tissues of ADPKD patients, for the first time, and SNX9 expression was also detected in Pkd1 knockout (Pkd1 -/-) and control mice. Subsequently, a series of gain- and loss-of-function studies were performed, to explore the biological roles and underlying molecular mechanisms of SNX9 in ADPKD progression. The expression of SNX9 was significantly downregulated in ADPKD patients and Pkd1 -/- mice compared with control individuals and wild-type mice (Pkd1+/+), respectively. The ectopic expression of SNX9 significantly inhibited ADPKD cell proliferation, renal cyst formation and enlargement, whereas these effects were promoted by SNX9 silencing. Mechanistically, we found that SNX9 interacted directly with yes-associated protein (YAP) and increased the large tumor suppressor kinase 1-mediated phosphorylation of YAP, resulting in the cytoplasmic retention of YAP, the decreased transcriptional activity of the YAP/TEA domain transcription factor 4 complex, and, consequently, the inhibition of Hippo target gene expression and ADPKD development. Taken together, our findings provided novel insights into the role played by SNX9 during ADPKD pathogenesis and may reveal novel therapeutic approaches for ADPKD and related kidney diseases.

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

Association of FCRL3 Gene Polymorphisms with IgA Nephropathy in a Chinese Han Population.

Our previous genome-wide association study has identified a suggestive association at rs11264799 within FCRL3 (Fc receptor-like 3) locus on 1q23.1 for IgA nephropathy (IgAN) in a Chinese Han population. This study aims to investigate the association of FCRL3 variants with the susceptibility, clinicopathological phenotypes and prognosis of IgAN. Eleven FCRL3 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this two-stage case/control study with a total of 1750 IgAN cases and 2500 healthy controls in a Chinese Han population. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) as implemented in the PLINK software. Luciferase assays were applied to detect the allelic effect of rs11264794 on gene expression regulation. We found that four SNPs (rs11264794, rs7865684, rs11264799, and rs6691569) were significantly associated with IgAN susceptibility after Bonferroni correction in the combined samples. Genotype/phenotype association analysis observed that two SNPs (rs11264794 and rs11264793) were associated with less disease severity. After adjusting for confounders, rs11264794 was independently correlated with renal outcome in IgAN patients (hazard ratio = 0.64, 95% CI = 0.43-0.97, p = 0.033). In addition, the protective allele A of rs11264794 was significantly associated with higher FCRL3 gene expression. Furthermore, luciferase reporter gene assays demonstrated that the minor allele of rs11264794 obviously reduced the specific binding between miR-183-5p.1 and FCRL3 3'-untranslated region. Our results indicate that FCRL3 gene polymorphisms are associated with the development and progression of IgAN, and the rs11264794-A allele showed a protective role for IgAN.

SGLT-2 inhibitors reduce glucose absorption from peritoneal dialysis solution by suppressing the activity of SGLT-2.

BACKGROUND: Sodium glucose cotransporter-2 (SGLT-2) inhibitors have been widely used in the clinic to reduce blood glucose levels by enhancing glucose excretion. However, whether such agents might also reduce glucose absorption via the peritoneal function of human peritoneal mesothelial cells (HPMCs) that also express SGLT-2 is not clear. METHODS: An acute peritoneal dialysis (PD) model in nonuremic rats was established. Ratios of peritoneal glucose uptake at D4/D0 of Sprague-Dawley rats treated with the SGLT-2 inhibitor, empagliflozin were tested to evaluate the effect of this inhibitor on peritoneal glucose absorption. An in vitro model of HPMCs obtained from peritoneal dialysate effluent in patients undergoing PD was used. HPMCs were exposed to high glucose (60 mM) in the presence and absence of empagliflozin. Glucose uptake and glucose consumption, which were used to estimate the activity of SGLT-2 in HPMCs, were measured by flow cytometry and hexokinase respectively. The expression of SGLT-2 in both peritoneum and HPMCs was also observed by real-time polymerase chain reaction (PCR), western blot, and immunofluorescence staining. RESULTS: Both ratios of peritoneal glucose uptake at D4/D0 and ultrafiltration of rats treated with 3 mg kg-1 of empagliflozin for 3 days increased significantly compared to those of the control group (0.32 ± 0.40 vs. 0.11 ± 0.11 mM, P = 0.001；17.00 ± 3.58 vs. -13.67 ± 17.25 ml, P = 0.002). Compared to the control group, the expression of mRNA and protein in SGLT-2 increased significantly in the rats treated with 3 mg kg-1 of empagliflozin for 3 days. Both glucose consumption and uptake of HPMCs incubated with 1 µM of empagliflozin for 24 h decreased significantly compared to control values (8.69 ± 1.77 vs. 11.48 ± 1.00 mM, P = 0.004; 31.97 ± 4.81 vs. 43.98 ± 1.38, P = 0.002). CONCLUSION: An SGLT-2 inhibitor was able to exert a glucose-lowering effect in peritoneum exposed to PD solution by inhibiting the activity of SGLT-2.

Effect of Sedative-Hypnotic Medicines on Mortality in Peritoneal Dialysis Patients with Sleep Disorders: A Retrospective Cohort Study.

BACKGROUND: Sedative-hypnotic medication is widely used among continuous ambulatory peritoneal dialysis (CAPD) patients with sleep disorders; however, its effect on mortality has rarely been investigated. METHODS: Logistic regression was employed to identify factors associated with sedative-hypnotic medication, whose effect on mortality was evaluated by Cox proportional hazards models. RESULTS: A total of 146 CAPD patients with sleep disorders were recruited, of which 46 patients (31.5%) used either benzodiazepines or zolpidem. Sedative-hypnotic medication was more frequently used by older patients and those with longer duration of CAPD therapy and there was no significant association between sedative-hypnotic medicines and all-cause mortality after adjusting for age, gender, diabetes, cardiovascular disease, and duration of CAPD. CONCLUSION: Sedative-hypnotic medication was more often used by older patients and patients with a longer duration of CAPD. There was no association between these agents and all-cause mortality in CAPD patients with sleep disorders.

Effect of low and high HDL-C levels on the prognosis of lupus nephritis patients: a prospective cohort study.

BACKGROUND: Few data has been available on the effect of serum HDL-C levels on the prognosis of lupus nephritis (LN) patients. The present study therefore aimed to explore the effect of serum HDL-C levels on LN patients. METHODS: We included 775 patients with follow-up information registered in an LN database between 1 January 2006 and 31 December 2011. The patients were divided into groups with low, intermediate and high HDL-C, according to NCEP ATPIII criteria. Cox regression analyses were used to explore the effects of HDL-C levels on end-stage renal disease (ESRD), all-cause mortality and cardiovascular disease (CVD) mortality. RESULTS: During a median follow-up of 56 months (3-206 months), 71 (9.2%) had ESRD. 84 (10.8%) deaths occurred, 17 (20.2%) of which were due to CVD. There was no statistically significant association of HDL-C category or continuous HDL-C levels with ESRD in the total cohort, but in subgroup analyses by eGFR, with each 0.1 mmol/L increase in HDL-C level, adjusted HRs for ESRD were 0.92 (95% CI: 0.83-1.04, P = 0.173) for eGFR ≥60 ml/min/1.73m2 and 1.11 (95% CI: 1.01-1.23, P = 0.036) for eGFR <60 ml/min/1.73m2. The effect of the interaction between eGFR category and serum HDL-C level on ESRD was statistically significant (ß = -1.738, P = 0.005). Low HDL-C was associated with all-cause mortality (HR = 2.16, 95% CI: 1.06-4.40, P = 0.033) with intermediate HDL-C as reference category after adjusting for several variables. CONCLUSIONS: Our results demonstrate that high HDL-C levels were associated with increased risk of ESRD in LN patients with advanced renal dysfunction. While low HDL-C levels were associated with increased risk of all-cause mortality in LN patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03001973 , 22 December 2016 retrospectively registered.

Association Analysis of the MHC in Lupus Nephritis.

Lupus nephritis (LN) is one of the most prevalent and serious complications of SLE, with significant effects on patient and renal survival. Although a large number of genetic variants associated with SLE have been identified, biomarkers that correlate with LN are extremely limited. In this study, we performed a comprehensive sequencing analysis of the whole MHC region in 1331 patients with LN and 1296 healthy controls and validated the independent associations in another 950 patients with LN and 1000 controls. We discovered five independent risk variants for LN within the MHC region, including HLA-DRß1 amino acid 11 (Pomnibus<0.001), HLA-DQß1 amino acid 45 (P<0.001; odds ratio, 0.58; 95% confidence interval, 0.52 to 0.65), HLA-A amino acid 156 (Pomnibus<0.001), HLA-DPß1 amino acid 76 (Pomnibus<0.001), and a missense variant in PRRC2A (rs114580964; P<0.001; odds ratio, 0.38; 95% confidence interval, 0.30 to 0.49) at genome-wide significance. These data implicate aberrant peptide presentation by MHC classes 1 and 2 molecules and sex hormone modulation in the development of LN.

Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population.

BACKGROUND: Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. METHODS: Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. RESULTS: We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive  = 0.0009, OR (95% CI) = 1.25 (1.09-1.42); precessive  = 0.0006, OR (95% CI) = 1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p = 0.0001) and associated with severity of disease. CONCLUSIONS: The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population.

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h2), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the C1GALT1 gene that strongly associated with Gd-IgA1 level (ß=0.26; P=2.35×10-9). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK (P<1.00×10-6) and 622 controls with normal kidney function from the UK (P<1.00×10-10), and in a candidate gene study of 704 Chinese patients with IgAN (P<1.00×10-5). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. C1GALT1 encodes a galactosyltransferase enzyme that is important in O-galactosylation of glycoproteins. These findings demonstrate that common variation at C1GALT1 influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 O-glycosylation may vary between white and Chinese patients with IgAN.

Nonreciprocal Radio Frequency Transduction in a Parametric Mechanical Artificial Lattice.

Generating nonreciprocal radio frequency transduction plays important roles in a wide range of research and applications, and an aspiration is to integrate this functionality into microcircuits without introducing a magnetic field, which, however, remains challenging. By designing a 1D artificial lattice structure with a neighbor interaction engineered parametrically, we predicted a nonreciprocity transduction with a large unidirectionality. We then experimentally demonstrated the phenomenon on a nanoelectromechanical chip fabricated by conventional complementary metal-silicon processing. A unidirectionality with isolation as high as 24 dB is achieved, and several different transduction schemes are realized by programing the control voltage topology. Apart from being used as a radio frequency isolator, the system provides a way to build a practical on-chip programmable device for broad research and applications in the radio frequency domain.

Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction.

Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10(-9); odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10(-5); OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10(-16); OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10(-20)), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10(-4); OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10(-3); OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10(-7); OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.

Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.

Polymorphism of DEFA in Chinese Han population with IgA nephropathy.

Our recent genome-wide association study (GWAS) had discovered a new locus at 8p23 (rs2738048) associated with IgA nephropathy (IgAN) in Chinese Han patients, implicating the DEFA gene family within this locus as susceptibility genes. However, it is still unknown whether there are additional variations within these genes associated with the disease susceptibility. The aim of this study is to investigate the polymorphisms of DEFA genes in the susceptibility to IgAN and explore possible disease mechanisms. Sixteen tag single-nucleotide polymorphisms (tag SNPs) were selected for association study in 1,000 IgAN cases and 1,000 controls by using Sequenom MassArray system or TaqMan SNP genotyping assays. We found seven SNPs within DEFA genes that were significantly associated with IgAN, including rs2738048 discovered in our previous GWAS (p = 0.0007, OR = 0.77) and additional 6 SNPs (rs2615787, p = 0.0001, OR = 0.74; rs2738081, p = 0.0003, OR = 0.72; rs2738058, p = 0.0001, OR = 0.73; rs4288398, p = 0.0008, OR = 0.78; rs6984215, p = 0.002, OR = 0.63; rs12716641, p = 0.00002, OR = 0.71). Electrophoretic mobility shift assays and luciferase assays demonstrated that fragments containing rs2738048, rs2738081 and rs6984215 were transcription factor binding sites for CTF, SP1 and CdxA, respectively, and the allele status of rs2738048 and rs6984215 could significantly change the luciferase activity. These results suggest that polymorphisms within DEFA genes are involved in gene transcriptional regulation, and this may have some effect in mediating susceptibility to IgAN in southern Chinese.