Gagliano Taliun Sarah A, Sulem Patrick, Sveinbjornsson Gardar, Gudbjartsson Daniel F, Stefansson Kari, Paterson Andrew D, Barua Moumita
Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada.
Clin J Am Soc Nephrol. 2022 May;17(5):672-683. doi: 10.2215/CJN.13711021. Epub 2022 Apr 26.
Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 (-) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed haplotypes.
In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05-21.33] versus 12.12 mg/g [7.61-19.29]; <0.001; men: 8.85 mg/g [5.66-16.19] versus 7.52 mg/g [5.04-12.39]; <0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m; <0.001; men: 87±15 versus 90±13 ml/min per 1.72 m; <0.001), supporting enrichment of glomerular hematuria. Variants at six loci (, , , , , and ) met genome-wide significance (<5E-8). At chromosome 2, p.Ser969X (rs35138315; minor allele frequency=0.00035; <7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: p.Gly695Arg (rs200287952; minor allele frequency=0.00021; <2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; <2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the haplotypes, (; minor allele frequency=0.14; <4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: , , and ).
Our study identifies six loci associated with hematuria, including independent variants in - and . Additionally, three novel loci are reported, including an association with an intronic variant in expressed in the podocyte.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3.
肾小球性血尿病因多样，但可能有遗传基础，包括阿尔波特综合征和IgA肾病。
设计、地点、参与者及测量方法：我们使用汇总统计数据来识别英国生物银行中英国白人参与者与血尿相关的基因变异。通过排除患有泌尿生殖系统疾病的参与者来富集肾小球性血尿患者。在2号染色体上鉴定出一个强相关位点（-）。使用精准医学跨组学计划对该区域进行重新归因，随后进行多轮区域条件分析，并以前期遗传信号为条件。同样，我们应用条件分析，利用归因单倍型来识别6号染色体上MHC区域的独立变异。
共纳入16,866例血尿病例和391,420例对照。与对照相比，病例的尿白蛋白肌酐比值更高（女性：13.01 mg/g [8.05 - 21.33] 对比12.12 mg/g [7.61 - 19.29]；<0.001；男性：8.85 mg/g [5.66 - 16.19] 对比7.52 mg/g [5.04 - 12.39]；<0.001），估算肾小球滤过率（eGFR）更低（女性：88±14对比90±13 ml/min per 1.72 m；<0.001；男性：87±15对比90±13 ml/min per 1.72 m；<0.001），支持肾小球性血尿的富集。6个位点（，，，，，和）的变异达到全基因组显著性水平（<5E - 8）。在2号染色体上，p.Ser969X（rs35138315；次要等位基因频率 = 0.00035；<7.95E - 35；比值比，87.3；95%置信区间，47.9至159.0）具有最显著的关联，在以该变异为条件进行分析后，该位点的另外两个变异仍与血尿相关：p.Gly695Arg（rs200287952；次要等位基因频率 = 0.00021；<2.16E - 7；比值比，45.5；95%置信区间，11.8至168.0）和一个常见的25号内含子变异（此前未报道；rs58261427；次要等位基因频率 = 0.214；<2.00E - 9；比值比，1.09；95%置信区间，1.06至1.12）。在单倍型中，（；次要等位基因频率 = 0.14；<4.41E - 24；比值比，0.84；95%置信区间，0.82至0.88）显示出最具统计学意义的关联。对于其余位点，我们鉴定出三个新的关联，这些关联在deCODE数据集的试纸法血尿中得到了重复验证（最接近的基因：, , 和）。
我们的研究鉴定出6个与血尿相关的位点，包括 - 和 中的独立变异。此外，还报道了三个新的位点，包括与足细胞中表达的 基因内含子变异的关联。
本文包含一个播客，链接为https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN1371102I.mp
（注：原文中部分基因名称未完整给出，翻译时保留原文形式）
