Department of Urology, Department of Medical Research, Department of Medical Genetics, Million-Person Precision Medicine Initiative, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
Urolithiasis. 2024 Jun 19;52(1):94. doi: 10.1007/s00240-024-01577-0.
Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney stone diseases (CKSD). Previous genome-wide association studies (GWAS) on stone diseases have been reported worldwide; however, these are not focused on calcium-containing stones. We conducted a GWAS to identify germline genetic polymorphisms associated with CKSD in a Medical Center in Taiwan; hence, this study was based primarily on a hospital-based database. CKSD was diagnosed using the chart records. Patients infected with urea-splitting-microorganisms and those with at least two urinary pH value below 5.5 were excluded. None of the patients had cystic stones based on stone analysis. Those over 40 years of age with no history of CKSD and no microscopic hematuria on urinalysis were considered as controls. The DNA isolated from the blood of 14,934 patients (63.7% male and 36.3% female) with CKSD and 29,868 controls (10,830 men and 19,038 women) at a medical center was genotyped for approximately 714,457 single nucleotide polymorphisms (SNPs) with minor allele frequency of ≥ 0.05. We used PLINK 1.9 to calculate the polygenic risk score (PRS) to investigate the association between CKSD and controls. The accuracy of the PRS was verified by dividing it into the training and testing groups. The statistical analyses were calculated with the area under the curve (AUC) using IBM SPSS version 22. We identified 432 susceptibility loci that reached a genome-wide threshold of P < 1.0 × 10. A total of 132 SNPs reached a threshold of P < 5 × 10 using a stricter definition of significance on chromosomes 4, 13, 16, 17, and 18. At the top locus of our study, SNPs in DGKH, PDILT, BCAS3, and ABCG2 have been previously reported. RN7SKP27, HDAC4, PCDH15, AP003068.2, and NFATC1 were novel findings in this study. PRS was adjusted for sex and age, resulting in an AUC of 0.65. The number of patients in the top quartile of PRS was 1.39 folds in the risk of CKSD than patients in the bottom quartile. Our data identified the significance of GWAS for patients with CKSD in a hospital-based study. The PRS also had a high AUC for discriminating patients with CKSD from controls. A total of 132 SNP loci of SNPs significantly associated with the development of CKSD. This first survey, which focused on patients with CKSD, will provide novel insights specific to CKSD and its potential clinical biomarkers.
大约 80%的肾结石疾病含有钙。遗传因素是影响含钙肾结石疾病（CKSD）发展的变量之一。全球已有关于结石病的全基因组关联研究（GWAS）报道；然而，这些研究并不集中在含钙结石上。我们在台湾的一家医学中心进行了 GWAS，以鉴定与 CKSD 相关的种系遗传多态性；因此，这项研究主要基于医院的数据库。CKSD 的诊断使用图表记录。排除感染尿素分解微生物的患者和至少两次尿 pH 值低于 5.5 的患者。根据结石分析，没有患者有囊性结石。那些年龄在 40 岁以上、无 CKSD 病史且尿分析无镜下血尿的患者被视为对照。从 14934 名 CKSD 患者（63.7%为男性，36.3%为女性）和 29868 名对照者（10830 名男性和 19038 名女性）的血液中提取的 DNA 在一个医学中心进行了大约 714457 个单核苷酸多态性（SNP）的基因分型，这些 SNP 的次要等位基因频率≥0.05。我们使用 PLINK 1.9 计算多基因风险评分（PRS），以研究 CKSD 与对照之间的关联。通过将 PRS 分为训练组和测试组来验证其准确性。使用 IBM SPSS 版本 22 计算曲线下面积（AUC）进行统计分析。我们确定了 432 个达到全基因组阈值 P < 1.0 × 10 的易感基因座。在染色体 4、13、16、17 和 18 上使用更严格的显著性定义，共有 132 个 SNP 达到 P < 5 × 10 的阈值。在我们研究的最高基因座，DGKH、PDILT、BCAS3 和 ABCG2 中的 SNP 先前已有报道。RN7SKP27、HDAC4、PCDH15、AP003068.2 和 NFATC1 是本研究中的新发现。PRS 调整了性别和年龄，AUC 为 0.65。PRS 最高四分位的患者患 CKSD 的风险是 PRS 最低四分位的患者的 1.39 倍。我们的数据确定了基于医院的研究中 CKSD 患者 GWAS 的意义。PRS 也具有较高的 AUC，可用于区分 CKSD 患者和对照者。共有 132 个 SNP 与 CKSD 的发展显著相关。这项首次针对 CKSD 患者的调查将提供特定于 CKSD 及其潜在临床生物标志物的新见解。
