Evaluation of genetic associations with clinical phenotypes of kidney stone disease.
Evaluation of genetic associations with clinical phenotypes of kidney stone disease.
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评估遗传与肾结石疾病临床表型的关联。
DOI：
10.1101/2024.01.18.24301501
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Bejan,CosminA
中科院分区：
文献类型：
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作者：
Hsi,RyanS;Zhang,Siwei;Triozzi,JeffersonL;Hung,AdrianaM;Xu,Yaomin;Bejan,CosminA
背景和目的先前的研究已经报道了肾结石风险与基因密切相关。本研究的目的是在一个大规模的电子健康档案系统中识别肾结石疾病的遗传关联。方法我们从5571例患者和83692名对照的基因样本中进行了肾结石的全基因组关联研究。这项分析包括以肾结石为主要研究对象的原发GWASs，以及按结石成分类型分层的GWASs亚组。对于显著的风险变量，我们进行了与结石成分和首次24小时尿液参数的关联分析。为了评估疾病的严重性，我们调查了首次诊断结石的年龄、首次结石相关手术的年龄以及第一次和第二次结石相关手术之间的时间。关键发现和限制初步的GWAS分析确定了10个重要的基因座，都位于UMOD基因编码区的16号染色体上。最强的信号是rs28544423(优势比1.17，95%可信区间1.11-1.23，p=22.7×10-9)。在按肾结石成分6个亚型划分的GWASs亚群中，共检测到19个有意义的基因座，其中2个位于编码区(Brushite、NXPH1、rs79970906和rs4725104)。UMOD单核苷酸多态rs28544423与24小时尿分析物排泄量的差异相关，该微小等位基因与二水草酸钙结石成分呈正相关(p<；P<0.05)。未发现UMOD变异与疾病严重程度之间的关联。局限性包括被忽略的变量偏差和错误分类偏差。结论和临床意义我们在UMOD复制了与肾结石疾病风险相关的胚系变异，并报告了与结石成分相关的新变异。UMOD的遗传变异与24小时尿参数和结石成分的差异有关，但与疾病严重程度无关。患者摘要：我们在电子健康记录(EHR)系统中识别与肾结石疾病相关的遗传变异。这些发现表明，EHR在实现结石疾病的精准医学方法方面发挥了作用。
Background and objectivePrevious studies have reported a strong genetic contribution to kidney stone risk. This study aims to identify genetic associations of kidney stone disease within a large-scale electronic health record system.MethodsWe performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5571 cases and 83 692 controls. This analysis included a primary GWAS focused on nephrolithiasis and subsequent subgroup GWASs stratified by stone composition types. For significant risk variants, we performed association analyses with stone composition and first-time 24-h urine parameters. To assess disease severity, we investigated the associations with age at first stone diagnosis, age at first stone-related procedure, and time between first and second stone-related procedures.Key findings and limitationsThe primary GWAS analysis identified ten significant loci, all located on chromosome 16 within coding regions of theUMODgene. The strongest signal was rs28544423 (odds ratio 1.17, 95% confidence interval 1.11–1.23,p= 2.7 × 10–9). In subgroup GWASs stratified by six kidney stone composition subtypes, 19 significant loci were identified including two loci in coding regions (brushite;NXPH1, rs79970906 and rs4725104). TheUMODsingle nucleotide polymorphism rs28544423 was associated with differences in 24-h excretion of urinary analytes, and the minor allele was positively associated with calcium oxalate dihydrate stone composition(p< 0.05). No associations were found betweenUMODvariants and disease severity. Limitations include an omitted variable bias and a misclassification bias.Conclusions and clinical implicationsWe replicated germline variants associated with kidney stone disease risk atUMODand reported novel variants associated with stone composition.Genetic variants ofUMODare associated with differences in 24-h urine parameters and stone composition, but not disease severity.Patient summaryWe identify genetic variants linked to kidney stone disease within an electronic health record (EHR) system. These findings suggest a role for the EHR to enable a precision-medicine approach for stone disease.