Interpreting non-coding disease-associated human variants using single-cell epigenomics

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(8), P. 516 - 534

Published: May 9, 2023

Language: Английский

---

Genetics of diabetes-associated microvascular complications

Diabetologia, Journal Year: 2023, Volume and Issue: 66(9), P. 1601 - 1613

Published: July 14, 2023

Abstract Diabetes is associated with excess morbidity and mortality due to both micro- macrovascular complications, as well a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related hyperglycaemia in causal manner. However, some individuals (even severe hyperglycaemia) do not develop diseases, which, together evidence co-occurrence diseases families, suggests role for genetics. While genome-wide association studies (GWASs) produced firm multiple genetic variants underlying differential susceptibility type 1 2 diabetes, determinants mostly suggestive. Identified diabetic kidney disease (DKD) diabetes mirror chronic (CKD) without diabetes. As retinopathy neuropathy, reported risk currently lack large-scale replication. The associations between may be explained by hyperglycaemia. More extensive phenotyping, along adjustments unmeasured confounding, including early (fetal) late-life (hyperglycaemia, hypertension, etc.) environmental factors, urgently needed understand the genetics complications. Finally, reduced glycolysis, mitochondrial dysfunction DNA damage sustained cell regeneration protect against illustrating utility who have escaped these Graphical

Language: Английский

---

DNA methylation markers for kidney function and progression of diabetic kidney disease

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 15, 2023

Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation associated with baseline estimated glomerular filtration rate (eGFR) subsequent decline in kidney function (eGFR slope), respectively, 1,271 type 2 subjects. Here show 40 (30 previously unidentified) eight (all CpG sites individually reach significance eGFR slope, respectively. We also develop multisite analysis method, which selects 64 37 These models validated an of Native Americans diabetes. Our identified near genes enriched functional roles diseases, some renal damage. This study highlights risk stratification disease among individuals.

Language: Английский

---

Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(7), P. 1279 - 1291

Published: April 5, 2023

Significance Statement Although gene expression changes have been characterized in human diabetic kidney disease (DKD), unbiased tissue proteomics information for this condition is lacking. The authors conducted an aptamer-based proteomic analysis of samples from patients with DKD and healthy controls, identifying proteins levels that associate function (eGFR) or fibrosis, after adjusting key covariates. Overall, only modestly correlated protein levels. Kidney RNA matrix metalloproteinase 7 (MMP7) strongly fibrosis eGFR. Single-cell sequencing indicated tubule cells are important source MMP7. Furthermore, plasma MMP7 predicted future decline. These findings identify as a biomarker blood Background Diabetic (DKD) responsible close to half all ESKD cases. extensively samples, protein-level not available. Methods We collected 23 individuals ten gathered associated clinical demographics information, implemented histologic analysis. performed using the SomaScan platform quantified level 1305 analyzed by bulk single-cell (scRNA-seq). validated separate cohort well 11,030 samples. Results Globally, transcript showed modest correlation. Our identified 14 eGFR found 152 interstitial fibrosis. Of proteins, metalloprotease strongest association both correlation between was external datasets. primary validation Findings scRNA-seq pointed proximal tubules, connecting principal likely cellular sources increased expression. but also prospective Conclusions findings, which underscore value analysis, diagnostic marker

Language: Английский

---

GLP-1 receptor agonist attenuates tubular cell ferroptosis in diabetes via enhancing AMPK-fatty acid metabolism pathway through macropinocytosis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(4), P. 167060 - 167060

Published: Feb. 12, 2024

Language: Английский

---

Unraveling the epigenetic code: human kidney DNA methylation and chromatin dynamics in renal disease development

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 29, 2024

Abstract Epigenetic changes may fill a critical gap in our understanding of kidney disease development, as they not only reflect metabolic but are also preserved and transmitted during cell division. We conducted genome-wide cytosine methylation analysis 399 human samples, along with single-nuclear open chromatin on over 60,000 cells from 14 subjects, including controls, diabetes hypertension attributed chronic (CKD) patients. identified validated differentially methylated positions associated states, discovered that nearly 30% these alterations were influenced by underlying genetic variations, variants known to be association studies. regions showing both changes. These significantly gene expression changes, most notably those playing role metabolism expressed proximal tubules. Our study further demonstrated risk scores (MRS) can improve state annotation prediction development. Collectively, results suggest causal relationship between epigenetic pathogenesis, thereby providing potential pathways for the development novel stratification methods.

Language: Английский

---

QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 4, 2024

DNA methylation provides a crucial epigenetic mark linking genetic variations to environmental influence. We have analyzed array-based profiles of 160 human retinas with co-measured RNA-seq and >8 million variants, uncovering sites regulation in cis (37,453 quantitative trait loci 12,505 expression loci) 13,747 affecting gene expression, over one-third specific the retina. Methylation show non-random distribution enrichment biological processes related synapse, mitochondria, catabolism. Summary data-based Mendelian randomization colocalization analyses identify 87 target genes where gene-expression changes likely mediate genotype effect on age-related macular degeneration. Integrated pathway analysis reveals immune response metabolism including glutathione glycolysis. Our study thus defines key roles driving changes, prioritizes control suggests frameworks for degeneration pathology by genotype-environment interaction

Language: Английский

---

METTL3-Mediated N6-Methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis

Journal of the American Society of Nephrology, Journal Year: 2024, Volume and Issue: 35(10), P. 1312 - 1329

Published: June 10, 2024

Chemical modifications on RNA profoundly affect function and regulation. m6A, the most abundant modification in eukaryotes, plays a pivotal role diverse cellular processes disease mechanisms. However, its importance is understudied human CKD samples regarding influence pathological

Language: Английский

---

Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 29, 2024

Abstract Background Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY present kidney increases with age chronic disease. Results The likelihood a cell having varies depending on its location nephron. Cortical epithelial types have greater proportion than medullary or glomerular types, which may reflect their proliferative history. Proximal tubule cells are abundant type cortex susceptible hypoxic injury. A subset these acquires pro-inflammatory transcription chromatin accessibility profile associated expression HAVCR1 , VCAM1 PROM1 . These injured greatest presence predicts future function decline. Moreover, proximal more likely harbor additional large gains express pro-survival pathways. Spatial transcriptomics localizes pro-fibrotic microenvironment where they adopt secretory phenotype communicate infiltrating immune cells. Conclusions We hypothesize an indicator increased DNA damage potential marker cellular senescence can be applied datasets other tissues.

Language: Английский

---

Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease

Diabetes, Journal Year: 2024, Volume and Issue: 73(7), P. 1188 - 1195

Published: Feb. 23, 2024

Diabetic kidney disease (DKD) is the leading cause of end-stage disease. Because many genes associate with DKD, multiomics approaches were used to narrow list functional genes, gene products, and related pathways providing insights into pathophysiological mechanisms DKD. The Kidney Precision Medicine Project human single-cell RNA-sequencing (scRNA-seq) data set Mendeley Data on cortex biopsy proteomics used. R package Seurat was analyze scRNA-seq from a subset proximal tubule cells. PathfindR applied for pathway analysis in cell type-specific differentially expressed limma differential protein expression cortex. A total 790 identified cells, including 530 upregulated 260 downregulated transcripts. Compared proteins, 24 or proteins common. An integrated combining quantitative trait loci, genome-wide association study hits (namely, estimated glomerular filtration rate), plasma metabolomics performed using baseline metabolites predictive DKD progression our longitudinal Diabetes Heart Study samples. aldo-keto reductase family 1 member A1 (AKR1A1) revealed as potential molecular hub cellular dysfunction several cross-linked featured by deficiency this enzyme.

Language: Английский

---