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

IF 7.8 1区医学 Q1 Biochemistry, Genetics and Molecular Biology

Aging Cell Pub Date : 2024-06-26 DOI:10.1111/acel.14261

Mary F. Feitosa, Shiow J. Lin, Sandeep Acharya, Bharat Thyagarajan, Mary K. Wojczynski, Allison L. Kuipers, Alexander Kulminski, Kaare Christensen, Joseph M. Zmuda, Michael R. Brent, Michael A. Province

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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.

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利用相关荟萃分析发现肾功能与高级糖化终产物可溶性受体之间的基因组和转录组多效性：长寿家庭研究

慢性肾脏病（CKD）患者的氧化应激和慢性炎症增加，这可能会增加高级糖化终产物（AGEs）的产生。 AGE 可溶性受体（sRAGE）高和估计肾小球滤过率（eGFR）低与 CKD 和衰老有关。我们评估了根据肌酐和胱抑素 C 计算出的 eGFR 是否与 sRAGE 有共同的多向遗传因素。我们对长寿家庭研究（LLFS）中的 4182 人（年龄范围：24-110 岁）进行了全基因组测序，并对全基因组关联研究（GWAS）的 p 值进行了关联荟萃分析。我们还对 1209 人的全血进行了转录组关联研究（TWAS）。我们为 eGFR 特质和 sRAGE 确定了 59 个多向性 GWAS 位点（p -8）和 17 个 TWAS 基因（Bonferroni-p -6）。TWAS 基因 LSP1 和 MIR23AHG 与 eGFR 和 sRAGE 相关，分别位于 GWAS 基因位点 lncRNA-KCNQ1OT1 和 CACNA1A/CCDC130 内。GWAS变异是肾小球和肾小管中的eQTL，GWAS基因预测了肾癌。TWAS 基因在肾脏中存在 eQTLs，预测了肾癌，并在 p -8 时将增强子-启动子变异与肾功能相关表型联系起来。此外，与 ALFA-Europeans 和 TOPMed 相比，在 LLFS 中检测到了更高等位基因频率的保护性变体，这表明健康老龄化的 LLFS 比普通人群的肾功能更好。基因组注释和转录基因活动的整合揭示了肾功能和衰老相关过程中遗传因子的丰富性。已确定的 eGFR 和 sRAGE 的多效应位点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。

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来源期刊

Aging Cell 生物-老年医学

CiteScore

14.40

自引率

2.60%

发文量

212

审稿时长

8 weeks

期刊介绍： Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.