Jones Alana C, Patki Amit, Srinivasasainagendra Vinodh, Tiwari Hemant K, Armstrong Nicole D, Chaudhary Ninad S, Limdi Nita A, Hidalgo Bertha A, Davis Brittney, Cimino James J, Khan Atlas, Kiryluk Krzysztof, Lange Leslie A, Lange Ethan M, Arnett Donna K, Young Bessie A, Diamantidis Clarissa J, Franceschini Nora, Wassertheil-Smoller Sylvia, Rich Stephen S, Rotter Jerome I, Mychaleckyj Josyf C, Kramer Holly J, Chen Yii-Der I, Psaty Bruce M, Brody Jennifer A, de Boer Ian H, Bansal Nisha, Bis Joshua C, Irvin Marguerite R
Medical Scientist Training Program, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama.
J Am Soc Nephrol. 2024 Nov 1;35(11):1558-1569. doi: 10.1681/ASN.0000000000000437. Epub 2024 Jul 29.
The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits. However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations. Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR.
CKD is a risk factor of cardiovascular disease and early death. Recently, polygenic risk scores (PRSs) have been developed to quantify risk for CKD. However, African ancestry populations are underrepresented in both CKD genetic studies and PRS development overall. Moreover, European ancestry–derived PRSs demonstrate diminished predictive performance in African ancestry populations.
This study aimed to develop a PRS for CKD in Black American populations. We obtained score weights from a meta-analysis of genome-wide association studies for eGFR in the Million Veteran Program and Reasons for Geographic and Racial Differences in Stroke Study to develop an eGFR PRS. We optimized the PRS risk model in a cohort of participants from the Hypertension Genetic Epidemiology Network. Validation was performed in subsets of Black participants of the Trans-Omics in Precision Medicine Consortium and Genetics of Hypertension Associated Treatment Study.
The prevalence of CKD—defined as stage 3 or higher—was associated with the PRS as a continuous predictor (odds ratio [95% confidence interval]: 1.35 [1.08 to 1.68]) and in a threshold-dependent manner. Furthermore, including risk status—a putative variant for CKD with higher prevalence among those of sub-Saharan African descent—improved the score's accuracy. PRS associations were robust to sensitivity analyses accounting for traditional CKD risk factors, as well as CKD classification based on prior eGFR equations. Compared with previously published PRS, the predictive performance of our PRS was comparable with a European ancestry–derived PRS for kidney traits. However, single-ancestry PRSs were less predictive than multi-ancestry–derived PRSs.
In this study, we developed a PRS that was significantly associated with CKD with improved predictive accuracy when including risk status. However, PRS generated from multi-ancestry populations outperformed single-ancestry PRS in our study.
针对肾脏性状，非洲血统特异性多基因风险评分（PRS）的预测性能与欧洲血统来源的PRS相当。然而，在非裔美国人群体中，多血统PRS的表现优于单血统PRS。使用无种族的估算肾小球滤过率（eGFR）可提高PRS对慢性肾脏病（CKD）的预测准确性。
CKD是心血管疾病和过早死亡的风险因素。最近，已开发出多基因风险评分（PRS）来量化CKD风险。然而，在CKD基因研究和整体PRS开发中，非洲血统人群的代表性不足。此外，欧洲血统来源的PRS在非洲血统人群中的预测性能有所下降。
本研究旨在为非裔美国人群体开发CKD的PRS。我们从百万退伍军人计划和中风地理与种族差异原因研究中对eGFR进行全基因组关联研究的荟萃分析中获取评分权重，以开发eGFR PRS。我们在高血压遗传流行病学网络的一组参与者中优化了PRS风险模型。在精准医学跨组学研究联盟和高血压相关治疗遗传学研究的黑人参与者子集中进行了验证。
定义为3期或更高分期的CKD患病率与作为连续预测指标的PRS相关（优势比[95%置信区间]：1.35[1.08至1.68]），且呈阈值依赖方式。此外，纳入风险状态（一种在撒哈拉以南非洲血统人群中患病率较高的CKD假定变异）可提高评分的准确性。PRS关联对考虑传统CKD风险因素以及基于先前eGFR方程的CKD分类的敏感性分析具有稳健性。与先前发表的PRS相比，我们的PRS的预测性能与欧洲血统来源的肾脏性状PRS相当。然而，单血统PRS的预测性低于多血统来源的PRS。
在本研究中，我们开发了一种与CKD显著相关的PRS，纳入风险状态时预测准确性有所提高。然而，在我们的研究中，多血统人群生成的PRS表现优于单血统PRS。
