Department of Internal Medicine, National Medical Center, Seoul, Korea.
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
J Am Soc Nephrol. 2023 May 1;34(5):857-875. doi: 10.1681/ASN.0000000000000066. Epub 2023 Jan 5.
eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD.
The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated.
We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes.
SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes.
This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.
eGFR 斜率已被用作 CKD 进展的替代结局。然而，CKD 患者中与 eGFR 斜率相关的遗传标记尚不清楚。我们旨在确定与 eGFR 斜率相关的遗传易感基因座。两阶段全基因组关联研究鉴定了 TPPP 和 FAT1-LINC02374 中的单核苷酸多态性 (SNP)，其中 22 个 SNP 被用来推导多基因风险评分，这些评分通过破坏附近转录因子的结合来标记 eGFR 的下降。这项工作首次确定了 TPPP 和 FAT1-LINC02374 对 CKD 进展的影响，为 CKD 患者 eGFR 下降提供了预测标志物。
CKD 的发病率与遗传因素有关。然而，与 CKD 进展相关的遗传标记尚未完全阐明。
我们对 1738 名 CKD 患者进行了全基因组关联研究，这些患者主要来自韩国 CKD 患者结局研究。结果是 eGFR 斜率。我们对来自慢性肾功能不全队列研究的 2498 名 CKD 患者进行了发现的单核苷酸多态性 (SNP) 的复制研究，这些 SNP 的 P<10-6。几个表达数量性状基因座 (eQTL) 研究、途径富集分析、表观遗传结构的探索以及预测转录因子 (TF) 结合位点的破坏探索了这些基因座的潜在生物学意义。我们开发并评估了多基因风险评分 (PRS) 对新发 CKD 结局的影响。
两个新基因座 TPPP 和 FAT1-LINC02374 中的 SNP 得到了复制(rs59402340 在 TPPP 中的 SNP，Pdiscovery=7.11×10-7，PCRIC=8.13×10-4，Pmeta=7.23×10-8；rs28629773 在 FAT1-LINC02374 中的 SNP，Pdiscovery=6.08×10-7，PCRIC=4.33×10-2，Pmeta=1.87×10-7)。eQTL 研究表明，复制的 SNP 调节了与肾功能相关的附近基因的表达水平。此外，这些 SNP 位于基因增强子区域附近，预测会破坏 TF 的结合。基于独立显著的前 22 个 SNP 的 PRS 与 CKD 结局显著相关。
这项研究表明，TPPP 和 FAT1-LINC02374 基因座中的 SNP 标记可能是 CKD 患者 eGFR 下降的预测标志物。
