Genome-wide Association Study for AKI.
Genome-wide Association Study for AKI.
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DOI：
10.34067/kid.0000000000000175
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发表时间：
2023-07-01
期刊：
影响因子：
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通讯作者：
Wurfel MM
中科院分区：
文献类型：
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作者：
Bhatraju PK;Stanaway IB;Palmer MR;Menon R;Schaub JA;Menez S;Srivastava A;Wilson FP;Kiryluk K;Palevsky PM;Naik AS;Sakr SS;Jarvik GP;Parikh CR;Ware LB;Ikizler TA;Siew ED;Chinchilli VM;Coca SG;Garg AX;Go AS;Kaufman JS;Kimmel PL;Himmelfarb J;Wurfel MM
DISP1-TLR5基因座中的两种遗传变异与AKI风险相关。DISP1和TLR5在AKI患者的肾活检组织中与无AKI患者相比差异调节。虽然CKD的常见遗传风险已得到很好的确定，但对影响住院患者AKI风险的遗传因素了解甚少。我们在AKI研究的评估、系列评价和后续后遗症中对1369名参与者进行了一项全基因组关联研究;有和无AKI的住院参与者的多种族人群在住院前的人口统计学、合并症和肾功能方面相匹配。然后，我们使用来自肾脏精准医学项目的12名AKI患者和18名健康活体供体的肾脏活检单细胞RNA测序数据，完成了AKI表现最佳变体的功能注释。在AKI的评估、系列评估和后续后遗症中，未发现全基因组与AKI风险的显著相关性（P <5 × 10 − 8）。与AKI相关性最强的前两个变体定位于分派的耐药-增殖-分裂（RND）转运蛋白家族成员1（DISP1）基因和toll样受体5（TLR5）基因位点，rs17538288（比值比，1.55; 95%置信区间，1.32~182; P = 9.47 × 10 − 8）和rs7546189（比值比，1.53; 95%置信区间，1.30~1.81; P = 4.60 × 10 − 7）。与健康活体供者的肾组织相比，AKI患者的肾活检显示，DISP1在近端肾小管上皮细胞（校正P = 3.9 × 10 − 2）和Henle袢粗升支（校正P = 8.7 × 10 − 3）中表达差异，TLR5基因在Henle袢粗升支（校正P = 4.9 × 10 − 30）中表达差异。AKI是一种异质性临床综合征，具有各种潜在风险因素、病因学和病理生理学，可能限制遗传变异的识别。虽然没有变异达到全基因组意义，我们报告了DISP1和TLR5之间的基因间区域的两个变异，表明该区域是AKI易感性的新风险。
Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI. Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood. We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project. No genome-wide significant associations with AKI risk were found in Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (P < 5×10−8). The top two variants with the strongest association with AKI mapped to the dispatched resistance-nodulation-division (RND) transporter family member 1 (DISP1) gene and toll-like receptor 5 (TLR5) gene locus, rs17538288 (odds ratio, 1.55; 95% confidence interval, 1.32 to 182; P = 9.47×10−8) and rs7546189 (odds ratio, 1.53; 95% confidence interval, 1.30 to 1.81; P = 4.60×10−7). In comparison with kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential DISP1 expression in proximal tubular epithelial cells (adjusted P = 3.9×10−2) and thick ascending limb of the loop of Henle (adjusted P = 8.7×10−3) and differential TLR5 gene expression in thick ascending limb of the loop of Henle (adjusted P = 4.9×10−30). AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies, and pathophysiology that may limit the identification of genetic variants. Although no variants reached genome-wide significance, we report two variants in the intergenic region between DISP1 and TLR5, suggesting this region as a novel risk for AKI susceptibility.