Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-08 DOI:10.1172/jci.insight.181238
David Y Zhang, Michael G Levin, Jeffrey T Duda, Latrice G Landry, Walter R Witschey, Scott M Damrauer, Marylyn D Ritchie, Daniel J Rader
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Abstract

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).

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APOL3 蛋白截短变体与 APOL1 风险等位基因的外显关系增加了慢性肾病的风险。
背景:APOL1基因中的两个编码等位基因G1和G2几乎只存在于与西非人群基因相似的个体中,它们对慢性肾脏病(CKD)的发病机制起着重要作用。22号染色体上的APOL基因簇共包含6个APOL基因,它们是基因复制的结果:方法:我们在宾夕法尼亚医学生物库中采用基因组优先方法,在与非洲参考人群基因相似的参与者人群中鉴定了六个 APOL 基因中 62 个小等位基因频率大于 0.1% 的改变蛋白质的变体,并进行了人群特异性全表型关联研究:结果:我们发现rs1108978是APOL3(p.Q58*)中的一个终止-增益变异,即使在APOL1 G1/G2携带者状态的条件下,它也与CKD风险的增加显著相关。这些发现在退伍军人事务百万退伍军人计划和我们所有人研究计划中得到了验证。APOL3 p.Q58*也与许多与慢性肾功能衰竭相关的定量特征有显著关联,包括肾脏体积的减少。这种截短变异在 APOL1 G1/G2 单拷贝患者中导致慢性肾脏病的风险最大,这表明野生型 APOL3 与 APOL1 诱导的肾脏病存在表观相互作用和潜在的保护作用:这项研究表明,即使在基因与疾病关系已得到充分研究的情况下,以基因组优先的方法针对人群特异性变异也是有用的:美国国家心肺血液研究所(F30HL172382、R01HL169378、R01HL169458)、多丽丝-杜克基金会(资助2023-0224)、美国国家生物医学成像和生物工程研究所(P41EB029460)、美国国家转化科学促进中心(UL1-TR-001878)。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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