Douville Nicholas J, Larach Daniel B, Lewis Adam, Bastarache Lisa, Pandit Anita, He Jing, Heung Michael, Mathis Michael, Wanderer Jonathan P, Kheterpal Sachin, Surakka Ida, Kertai Miklos D
Department of Anesthesiology, University of Michigan Health System, Ann Arbor, MI, United States.
Center for Computational Medicine and Bioinformatics, University of Michigan Health System, Ann Arbor, MI, United States.
Front Genet. 2023 Apr 13;14:1094908. doi: 10.3389/fgene.2023.1094908. eCollection 2023.
The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance ( < 5 × 10) threshold, however, six previously unreported variants exceeded the suggestive threshold ( < 1 × 10). Notable variants detected include: 1) rs74637005, located in the exonic region of and 2) rs17438465, located between and . We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, = 0.005) were significant in the full model. Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors.
近期基因组数据与电子健康记录的整合，使得针对各种围手术期并发症的大规模基因组研究成为可能。然而，关于急性肾损伤的全基因组关联研究规模有限，或因复合结局而产生混淆。全基因组关联研究可用于创建多基因风险评分，然后将其与传统临床风险因素相结合，以更好地预测术后并发症，如急性肾损伤。我们利用来自两个学术生物样本库的整合遗传数据，对心脏手术相关的急性肾损伤进行了全基因组关联研究。接下来，我们开发了一个多基因风险评分，并在控制年龄、性别、主成分、术前血清肌酐以及一系列患者、临床和手术风险因素的回归分析中测试其预测效用。最后，我们使用遗传混合模型估计加性变异遗传力。在范德堡大学医学中心的1014例符合条件的手术中，以及密歇根医学中心的478例手术中，分别有348例（34.3%）和121例（25.3%）发生了急性肾损伤。然而，没有变异超过全基因组显著性（<5×10）阈值，不过，有6个先前未报告的变异超过了提示性阈值（<1×10）。检测到的显著变异包括：1）rs74637005，位于[基因名称]的外显子区域；2）rs17438465，位于[两个基因名称之间]。我们未能重复先前关于术后急性肾损伤的无偏倚研究中的变异。在任何模型中，多基因风险与术后急性肾损伤均无显著关联，然而，手术时长（校正比值比[aOR]=1.002，95%置信区间[CI]1.000 - 1.003，P = 0.013）、糖尿病（aOR = 2.025，95% CI 1.320 - 3.103，P = 0.001）和瓣膜病（aOR = 0.558，95% CI 0.372 - 0.835，P = 0.005）在完整模型中具有显著性。多基因风险评分与心脏手术相关的急性肾损伤无显著关联，且在该人群中急性肾损伤的遗传力可能较低。这些结果表明，易感性仅受基线遗传易感性的轻微影响，而临床风险因素（其中一些是可改变的）在预测这种并发症方面可能发挥更具影响力的作用。与临床风险因素相比，遗传学在心脏手术相关急性肾损伤总体风险中的总体影响可能较小。
