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 × 10-8) and 17 TWAS genes (Bonferroni-p < 2.73 × 10-6) 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 × 10-8. 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.
摘要：
慢性肾脏病（CKD）患者的氧化应激和慢性炎症增加，这可能会增加晚期糖基化终产物（AGEs）的产生。高可溶性AGE受体(sRAGE)和低估计肾小球滤过率(eGFR)水平与CKD和衰老相关。我们评估了从肌酐和胱抑素C计算的eGFR是否与sRAGE共享多效性遗传因素。我们对长寿家庭研究（LLFS）的4182名个体（年龄范围：24-110岁）进行了全基因组测序和相关荟萃分析。我们还对1209名个体的子集进行了全血全转录组关联研究(TWAS)。我们确定了eGFR性状和sRAGE的59个多效性GWAS基因座（p<5×10-8）和17个TWAS基因（Bonferroni-p<2.73×10-6）。TWAS基因,LSP1和MIR23AHG，与位于GWAS基因座内的eGFR和SRAGE相关，lncRNA-KCNQ1OT1和CACNA1A/CCDC130。GWAS变体是肾小球和肾小管中的eQTL，和GWAS基因预测肾癌。TWAS基因在肾脏中含有eQTL，预测的肾癌，和具有p<5×10-8的肾功能相关表型的连接的增强子-启动子变体。此外,在LLFS中检测到eGFR性状的保护性变异的等位基因频率高于ALFA-欧洲人和TOPMed，表明健康老龄化LLFS的肾功能优于一般人群。整合基因组注释和转录基因活性揭示了肾脏功能和衰老相关过程中遗传元件的富集。已确定的eGFR和sRAGE的多效性基因座和基因表达表明了它们潜在的共同遗传效应，并突出了它们在肾脏和衰老相关信号通路中的作用。
