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Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study. | LitMetric

AI Article Synopsis

  • - Patients with chronic kidney disease (CKD) experience increased oxidative stress and inflammation, which may lead to higher levels of advanced glycation end-products (AGEs), and the study investigates the genetic connection between measures of kidney function (eGFR) and soluble receptor for AGE (sRAGE).
  • - Researchers analyzed data from 4,182 individuals in the Long Life Family Study using whole-genome sequencing and transcriptome-wide association studies (TWAS) to identify 59 genetic loci and 17 genes that are related to both eGFR traits and sRAGE levels.
  • - The study found that specific genes associated with kidney function and aging also predicted kidney health outcomes, revealing that certain genetic variants promoting better kidney function

Article Abstract

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10) and 17 TWAS genes (Bonferroni-p < 2.73 × 10) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464144PMC
http://dx.doi.org/10.1111/acel.14261DOI Listing

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