Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known.

We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (n=765,348) and UK Biobank GWAS (90% of the cohort; n=451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data (n=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (n=8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR.

The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen α-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR.

A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

全基因组关联研究 (GWAS) 揭示了许多肾功能 (eGFR) 位点。eGFR 的多基因预测因子、不良肾脏结局事件风险和血浆蛋白质组之间的关系尚不清楚。

我们通过将 LDpred 算法应用于 CKDGen 联盟 GWAS（n = 765,348）和 UK Biobank GWAS（队列的 90%；n =451,508)，然后使用剩余 10% 的英国生物样本库数据 ( n =45,158) 选择最佳参数。然后，我们在社区动脉粥样硬化风险 (ARIC) 研究（ n = 8866）中测试了 PRS与 CKD、ESKD、肾衰竭和 AKI 事件的关联。我们还检查了 PRS 与在中年和成年期测量的 4877 种血浆蛋白之间的关联，并评估了 eGFR 对 PRS 关联的调解。

开发的 PRS 显示与所有结果显着相关。PRS 每降低 1 SD 的风险比范围为 1.06（95% CI，1.01 至 1.11）至 1.33（95% CI，1.28 至 1.37）。PRS 在两个时间点都与 132 种蛋白质显着相关。最强的关联是胱抑素 C、胶原蛋白α -1(XV) 链和 desmocollin-2。大多数蛋白质在较低的肾功能时较高，除了五种蛋白质，包括 testican-2。遗传 PRS 与蛋白质的大多数相关性由 eGFR 介导。

eGFR 的 PRS 现在足够强大，可以捕获一系列肾脏疾病的风险，并广泛影响主要由 eGFR 介导的血浆蛋白质组。