Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized between 2002-2019 in the Million Veteran Program and data from Vanderbilt University Medical Center’s BioVU. AKI was defined as meeting a modified KDIGO Stage1 or more for two or more consecutive days or kidney replacement therapy. Control individuals were required to have one or more qualifying hospitalizations without AKI and no evidence of AKI during any other observed hospitalizations. Genome-wide association studies (GWAS), stratified by race, adjusting for sex, age, baseline estimated glomerular filtration rate (eGFR), and the top ten principal components of ancestry were conducted. Results were meta-analyzed using fixed effects models. In total, there were 54,488 patients with AKI and 138,051 non-AKI individuals included in the study. Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) and rs4859682 near the locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). These loci colocalized with previous studies of kidney function, and genetic correlation indicated significant shared genetic architecture between AKI and eGFR. Notably, the association at the FTO locus was attenuated after adjustment for BMI and diabetes, suggesting that this association may be partially driven by obesity. Both and the loci showed nominal evidence of replication from diagnostic-code-based summary statistics from UK Biobank, FinnGen, and Biobank Japan. Thus, our large GWA meta-analysis found two loci significantly associated with AKI suggesting genetics may explain some risk for AKI.

中文翻译：

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住院患者与急性肾损伤的全基因组关联研究


急性肾损伤（AKI）是一种常见且具有破坏性的住院并发症。在这里，我们确定了 2002 年至 2019 年百万退伍军人计划住院患者中与 AKI 相关的基因位点以及范德比尔特大学医学中心 BioVU 的数据。 AKI 被定义为连续两天或更长时间达到修改后的 KDIGO 第一阶段或以上或肾脏替代治疗。对照个体必须接受一次或多次合格住院治疗，且未出现 AKI，并且在任何其他观察到的住院治疗期间均无 AKI 证据。进行了全基因组关联研究 (GWAS)，按种族分层，调整性别、年龄、基线估计肾小球滤过率 (eGFR) 和血统的十大主要成分。使用固定效应模型对结果进行荟萃分析。该研究总共纳入了 54,488 名 AKI 患者和 138,051 名非 AKI 患者。荟萃分析中两个新位点达到全基因组显着性：rs11642015 靠近 16 号染色体上的位点（肥胖性状）（比值比 1.07（95% 置信区间，1.05-1.09））和 rs4859682 靠近 4 号染色体上的位点（肾小球）过滤屏障完整性）（比值比 0.95（95% 置信区间，0.93-0.96））。这些基因座与之前的肾功能研究共定位，遗传相关性表明 AKI 和 eGFR 之间存在显着的共享遗传结构。值得注意的是，在调整 BMI 和糖尿病后，FTO 位点的关联性减弱，表明这种关联性可能部分是由肥胖驱动的。两个位点都显示了英国生物银行、FinnGen 和日本生物银行基于诊断代码的汇总统计数据的复制证据。 因此，我们的大型 GWA 荟萃分析发现两个与 AKI 显着相关的基因座，表明遗传学可以解释 AKI 的某些风险。