Epigenome-wide association study of diabetic chronic kidney disease progression in the Korean population: the KNOW-CKD study.

Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein-protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 on AGTR1 and cg02990553 on KRT28 indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia for AGTR1) and biological pathways (keratinization and cornified envelope for KRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.

Proteomic analysis of tears in dry eye disease: A prospective, double-blind multicenter study.

PURPOSE: To identify specific dry eye disease (DED) tear biomarker(s) using tear proteomic analysis, clinical parameters, and their correlations before and after DED treatment. METHODS: A prospective, double-blinded, national multicenter clinical study was performed using data from 80 DED patients. The patients were treated with 0.1% cyclosporine (CsA, n = 28), 0.05% CsA (n = 26), or 3% diquafosol (DQS, n = 26) eye drops, and tear proteome changes and clinical outcomes (tear break-up time [TBUT], corneal erosion [Cor-Er], conjunctival erosion [Conj-Er], and symptom assessment in dry eye [SANDE] scores) were observed at 4, 8, and 12 weeks. For all clinical parameters, correlation analysis was performed between the three drug conditions and the differentially expressed proteins (DEPs) from the proteomic analysis. RESULTS: AFM, ALCAM, CFB, H1-4, PON1, RAP1B, and RBP4 were identified in all treatment groups and were downregulated after treatment. All clinical parameters significantly improved at 12 weeks than at baseline (p-value <0.0001); however, their values were not significantly different among groups, except for Cor-Er (p-value = 0.007). Compared with the DQS group, Cor-Er score significantly improved after treatment with 0.1% and 0.05% CsA. The seven DEPs identified in all groups were not consistently correlated with the clinical parameters (p-value >0.05). CONCLUSIONS: Despite differences in drug concentration and action mechanisms, the improvement levels of TBUT, Cor-Er, and SANDE scores were clinically adequate. However, useful tear protein biomarkers, clinically acceptable biomarker combinations correlating with clinical parameters, and clinically acceptable levels of specificity and sensitivity were not identified.

Clinical traits and systemic risks of familial diabetes mellitus according to age of onset and quantity: an analysis of data from the community-based KoGES cohort study.

OBJECTIVES: The aim of this study was to clarify the clinical trait of familial diabetes mellitus (DM) by analyzing participants' risk of DM according to the age of DM onset in parents and siblings, and to evaluate individuals' risk of DM-associated cardiometabolic diseases. METHODS: Altogether, 211,173 participants aged ≥40 years from the Korean Genome and Epidemiology Study were included in this study. The participants were divided into groups based on the number (1 or 2 relatives) and age of onset (no DM and early, common, or late onset) of familial DM. Participants' risk of DM was assessed using a Cox regression model with hazard ratios and 95% confidence intervals (CIs). A logistic regression model with odds ratios was used to evaluate associations among the participants' likelihood of acquiring cardiometabolic diseases such as hypertension, chronic kidney disease (CKD), and cardiovascular disease. RESULTS: The risk of developing DM was 2.02-fold (95% CI, 1.88 to 2.18) and 2.88-fold (95% CI, 2.50 to 3.33) higher, respectively, in participants with 1 and 2 family members diagnosed with familial DM. It was 2.72-fold (95% CI, 2.03 to 3.66) higher in those with early-onset familial DM. In the early-onset group, the respective risks of hypertension and CKD were 1.87-fold (95% CI, 1.37 to 2.55) and 4.31-fold (95% CI, 2.55 to 7.27) higher than in the control group. CONCLUSIONS: The risk of DM and related cardiometabolic diseases was positively associated with the number of family members diagnosed with DM and an early diagnosis in family members with DM.

Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

SIGNIFICANCE STATEMENT: eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. BACKGROUND: The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. METHODS: We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. RESULTS: SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. CONCLUSIONS: This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Identifying Genetic Variants and Metabolites Associated with Rapid Estimated Glomerular Filtration Rate Decline in Korea Based on Genome-Metabolomic Integrative Analysis.

Identifying the predisposing factors to chronic or end-stage kidney disease is essential to preventing or slowing kidney function decline. Therefore, here, we investigated the genetic variants related to a rapid decline in the estimated glomerular filtration rate (eGFR) (i.e., a loss of >5 mL/min/1.73 m2 per year) and verified the relationships between variant-related diseases and metabolic pathway signaling in patients with chronic kidney disease. We conducted a genome-wide association study that included participants with diabetes, hypertension, and rapid eGFR decline from two Korean data sources (N = 115 and 69 for the discovery and the validation cohorts, respectively). We identified a novel susceptibility locus: 4q32.3 (rs10009742 in the MARCHF1 gene, beta = −3.540, P = 4.11 × 10−8). Fine-mapping revealed 19 credible, causal single-nucleotide polymorphisms, including rs10009742. The pimelylcarnitine and octadecenoyl carnitine serum concentrations were associated with rs10009742 (beta = 0.030, P = 7.10 × 10−5, false discovery rate (FDR) = 0.01; beta = 0.167, P = 8.11 × 10−4, FDR = 0.08). Our results suggest that MARCHF1 is associated with a rapid eGFR decline in patients with hypertension and diabetes. Furthermore, MARCHF1 affects the pimelylcarnitine metabolite concentration, which may mediate chronic kidney disease progression by inducing oxidative stress in the endoplasmic reticulum.