Department of Medicine and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
Montréal Heart Institute, Montréal, QC, Canada.
Sci Rep. 2023 Oct 23;13(1):18084. doi: 10.1038/s41598-023-45102-6.
Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and albuminuria was chosen to enrich for glomerular pathologies. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR > 3 mg/mmol. Controls had neither an ICD code for hematuria nor an uACR > 3 mg/mmol. 2429 cases and 343,509 controls from the UK Biobank were included. eGFR was lower in cases compared to controls, with the exception of the comparison in females using CKD-EPI after age adjustment. Variants at 4 loci met genome-wide significance with the following nearest genes: COL4A4, TRIM27, ETV1 and CUBN. TRIM27 is part of the extended MHC locus. All loci with the exception of ETV1 were replicated in the Geisinger MyCode cohort. The previous GWAS of hematuria reported COL4A3-COL4A4 variants and HLA-B*0801 within MHC, which is in linkage disequilibrium with the TRIM27 variant (D' = 0.59). TRIM27 is highly expressed in the tubules. Additional loci included a coding sequence variant in CUBN (p.Ala2914Val, MAF = 0.014 (A), p = 3.29E-8, OR = 2.09, 95% CI = 1.61-2.72). Overall, GWAS for the composite trait of hematuria and albuminuria identified 4 loci, 2 of which were not previously identified in a GWAS of hematuria.
我们在英国生物库进行的血尿全基因组关联研究鉴定出 6 个位点，其中一些与白蛋白尿的位点重叠，提示存在表型多效性。由于临床综合征通常由多种特征组合定义，因此生成综合表型可以提高检测影响多种特征的基因座的能力。因此，选择血尿和白蛋白尿的复合特征来富集肾小球病变。病例具有通过 ICD 代码定义的血尿和 uACR > 3 mg/mmol 定义的白蛋白尿。对照既没有血尿的 ICD 代码，也没有 uACR > 3 mg/mmol。英国生物库中包括 2429 例病例和 343509 例对照。与对照相比，病例的 eGFR 较低，除了在年龄调整后使用 CKD-EPI 的女性比较。4 个位点的变异达到全基因组显著水平，其最近的基因如下：COL4A4、TRIM27、ETV1 和 CUBN。TRIM27 是扩展 MHC 基因座的一部分。除了 ETV1 之外，所有基因座都在 Geisinger MyCode 队列中得到复制。先前的血尿全基因组关联研究报告了 COL4A3-COL4A4 变体和 MHC 内的 HLA-B*0801，与 TRIM27 变体（D' = 0.59）连锁不平衡。TRIM27 在肾小管中高度表达。其他基因座包括 CUBN 中的编码序列变异（p.Ala2914Val，MAF = 0.014（A），p = 3.29E-8，OR = 2.09，95%CI = 1.61-2.72）。总体而言，血尿和白蛋白尿复合特征的全基因组关联研究鉴定出 4 个基因座，其中 2 个在血尿全基因组关联研究中未被发现。
