Effect of Uric Acid on the Development of Chronic Kidney Disease: The Korean Multi-Rural Communities Cohort Study

Objectives Several studies have investigated the effects of serum uric acid (SUA) levels on chronic kidney disease (CKD), with discrepant results. The effect of SUA levels on CKD development was studied in the Korean rural population. Methods A total of 9695 participants aged ≥40 years were recruited from 3 rural communities in Korea between 2005 and 2009. Of those participants, 5577 who participated in the follow-up and did not have cerebrovascular disease, myocardial infarction, cancer, or CKD at baseline were studied. The participants, of whom 2133 were men and 3444 were women, were grouped into 5 categories according to their quintile of SUA levels. An estimated glomerular filtration rate of <60 mL/min/1.73 m2 at the time of follow-up was considered to indicate newly developed CKD. The effects of SUA levels on CKD development after adjusting for potential confounders were assessed using Cox proportional hazard models. Results Among the 5577 participants, 9.4 and 11.0% of men and women developed CKD. The hazard ratio (HR) of CKD was higher in the highest quintile of SUA levels than in the third quintile in men (adjusted HR, 1.60; 95% confidence interval [CI], 1.02 to 2.51) and women (adjusted HR, 1.56; 95% CI, 1.14 to 2.15). Furthermore, CKD development was also more common in the lowest quintile of SUA levels than in the third quintile in men (adjusted HR, 1.83; 95% CI, 1.15 to 2.90). The effect of SUA was consistent in younger, obese, and hypertensive men. Conclusions Both high and low SUA levels were risk factors for CKD development in rural Korean men, while only high levels were a risk factor in their women counterparts

Genetic variants of interferon lambda-related genes and chronic kidney disease susceptibility in the Korean population

Background Chronic kidney disease (CKD) is a common condition leading to renal dysfunction and is closely related to increased cardiovascular and mortality risk. CKD is an important public health issue, and recent genetic studies have verified common CKD susceptibility variants. This research examines the interrelationship between candidate genes polymorphisms of interferon lambda (IFNL) induction, its signaling pathway, and CKD. Methods Seventy-five patients with advanced CKD and 312 healthy subjects (as controls) participated in this research. A replication set composed of 172 patients with advanced CKD and 365 controls was used for additional analysis. The genotype of single nucleotide polymorphisms (SNPs) was determined by the Axiom Genome-Wide Human Assay and SNaPshot assay. Results The SNP of IFNL3 was significantly associated with CKD in the codominant (p = 0.02) and dominant models (p = 0.02). In addition, the SNPs of IFNL2 were significantly associated with CKD in the dominant model (p = 0.03), and the SNP of interferon alpha receptor 2 (IFNAR2) was significantly associated with CKD in the log-additive model (p = 0.03). Concerning rs148543092, in the IFNL3 gene, a significant association was observed after pooling the original and replication sets. Conclusion These results indicate that SNPs in the IFNL induction and signal pathway may be associated with CKD risk in the Korean population. Finally, our results also show that the IFNL3 gene variant may be associated with CKD risk

Heterodimerization of Glycosylated Insulin-Like Growth Factor-1 Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1R Antibody

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells

Association between Three Waist Circumference-Related Obesity Metrics and Estimated Glomerular Filtration Rates

Studies that have assessed the associations between obesity and the estimated glomerular filtration rate (eGFR) have reported inconsistent results. This cross-sectional study was performed to investigate the associations between three waist circumference (WC)-related obesity metrics (waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and waist-to-height0.5 ratio (WHt.5R)) and eGFRs. This study included 2133 men and 3443 women who were older than 40 years with eGFRs ≥ 60 mL/min/1.73 m² from the Korean Multi-Rural Communities Cohort. We calculated the residual body mass index (BMI) to reduce multicollinearity among the obesity metrics and performed multiple linear regression. For both sexes, among the adjusted models, most of the general obesity metrics were significantly associated with eGFRs. Particularly for women, the WC-related and general obesity metrics had a stronger effect on eGFRs in the quartile models that included the BMI and the residual BMI, respectively. When WC-related obesity metrics had a stronger effect than the general obesity metric, for both sexes, WHtR showed a significant impact than WHt.5R and WHR on eGFRs. Reducing multicollinearity had an important role in assessing the obesity metrics’ association with eGFRs. Overall, applying the residual method in further studies might help with evaluating the obesity paradox on renal function

SDC mediates DNA methylation-controlled clock pace by interacting with ZTL in Arabidopsis

Molecular bases of eukaryotic circadian clocks mainly rely on transcriptional-translational feedback loops (TTFLs), while epigenetic codes also play critical roles in fine-tuning circadian rhythms. However, unlike histone modification codes that play extensive and well-known roles in the regulation of circadian clocks, whether DNA methylation (5mC) can affect the circadian clock, and the associated underlying molecular mechanisms, remains largely unexplored in many organisms. Here we demonstrate that global genome DNA hypomethylation can significantly lengthen the circadian period of Arabidopsis. Transcriptomic and genetic evidence demonstrate that SUPPRESSOR OF drm1 drm2 cmt3 (SDC), encoding an F-box containing protein, is required for the DNA hypomethylation-tuned circadian clock. Moreover, SDC can physically interact with another F-box containing protein ZEITLUPE (ZTL) to diminish its accumulation. Genetic analysis further revealed that ZTL and its substrate TIMING OF CAB EXPRESSION 1 (TOC1) likely act downstream of DNA methyltransferases to control circadian rhythm. Together, our findings support the notion that DNA methylation is important to maintain proper circadian pace in Arabidopsis, and further established that SDC links DNA hypomethylation with a proteolytic cascade to assist in tuning the circadian clock

Association between Interferon-Inducible Protein 6 () Polymorphisms and Hepatitis B Virus Clearance

CD8+ T cells are key factors mediating hepatitis B virus (HBV) clearance. However, these cells are killed through HBV-induced apoptosis during the antigen-presenting period in HBV-induced chronic liver disease (CLD) patients. Interferon-inducible protein 6 (IFI6) delays type I interferon-induced apoptosis in cells. We hypothesized that single nucleotide polymorphisms (SNPs) in the IFI6 could affect the chronicity of CLD. The present study included a discovery stage, in which 195 CLD patients, including chronic hepatitis B (HEP) and cirrhosis patients and 107 spontaneous recovery (SR) controls, were analyzed. The genotype distributions of rs2808426 (C > T) and rs10902662 (C > T) were significantly different between the SR and HEP groups (odds ratio [OR], 6.60; 95% confidence interval [CI], 1.64 to 26.52, p = 0.008 for both SNPs) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). The distribution of diplotypes that contained these SNPs was significantly different between the SR and HEP groups (OR, 6.58; 95% CI, 1.63 to 25.59; p = 0.008 and OR, 0.15; 95% CI, 0.04 to 0.61; p = 0.008, respectively) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). We were unable to replicate the association shown by secondary enrolled samples. A large-scale validation study should be performed to confirm the association between IFI6 and HBV clearance

Decoding the Roles of Amyloid-β (1-42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-β (1-42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer’s disease and a primary target for disease treatment. Determining the essential domains of amyloid-β (1-42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents. In this study, we identified three key hydrophobic sites (17LVF1932IGL34, and 41IA42) on amyloid-β (1-42) and investigated their involvement in the self-assembly process of the protein. Based on these findings, we designed candidate inhibitor peptides of amyloid-β (1-42) aggregation. Using the designed peptides, we characterized the roles of the three hydrophobic regions during amyloid-β (1-42) fibrillar aggregation and monitored the consequent effects on its aggregation property and structural conversion. Furthermore, we used an amyloid-β (1-42) double point mutant (I41N/A42N) to examine the interactions between the two C-terminal end residues with the two hydrophobic regions and their roles in amyloid self-assembly. Our results indicate that interchain interactions in the central hydrophobic region (17LVF19) of amyloid-β (1-42) are important for fibrillar aggregation, and its interaction with other domains is associated with the accessibility of the central hydrophobic region for initiating the oligomerization process. Our study provides mechanistic insights into the self-assembly of amyloid-β (1-42) and highlights key structural domains that facilitate this process. Our results can be further applied toward improving the rational design of candidate amyloid-β (1-42) aggregation inhibitors.11Nscopu