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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 (LLFS). | LitMetric

AI Article Synopsis

  • - Patients with chronic kidney disease (CKD) experience increased oxidative stress and chronic inflammation, leading to higher levels of advanced glycation end-products (AGE) and connections to aging factors like soluble receptor for AGE (sRAGE) and estimated glomerular filtration rate (eGFR).
  • - A study involving whole-genome sequencing of 4,182 individuals found 59 genetic loci and 17 genes associated with both eGFR and sRAGE, indicating shared genetic influences that relate to kidney function and disease.
  • - The research showed that individuals from a healthy-aging cohort (Long Life Family Study) had a higher occurrence of protective genetic variants for eGFR traits compared to broader populations, highlighting potential genetic factors that

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 (AGE). 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 genomewide association study (GWAS) -values in 4,182 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 1,209 individuals. We identified 59 pleiotropic GWAS loci ( <5×10 ) and 17 TWAS genes (Bonferroni- <2.73×10 ) for eGFR traits and sRAGE. TWAS genes, and , were associated with eGFR and sRAGE located within GWAS loci, lncRNA- and , 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 <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 kidney diseases. 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/PMC10793516PMC
http://dx.doi.org/10.1101/2023.12.27.23300583DOI Listing

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