out affects collagen IV trimer assembly and secretion. Background Hematuria is an established sign of glomerular disease and can be associated with kidney failure, but there has been limited scientific study of this trait. Methods Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from Genotype Tissue Expression kidney cortex samples (n=65) in a transcriptome-wide association study to identify additional potential biological mechanisms influencing hematuria. Results The transcriptome-wide association study using kidney cortex identified significant associations for five genes in expression and three significant splicing events. Notably, we identified an association between the skipping of COL4A4 exon 27, which is genetically predicted by intronic rs11898094 (minor allele frequency 13%), and hematuria. Association between this variant was also found with urinary albumin excretion. We found independent evidence supporting the same variant predicting this skipping event in glomeruli-derived mRNA transcriptomics data (n=245) from the Nephrotic Syndrome Study Network. The functional significance of loss of exon 27 was demonstrated using the split NanoLuc-based α3α4α5(IV) heterotrimer assay, in which type IV collagen heterotrimer formation was quantified by luminescence. The causal splicing variant for this skipping event is yet to be identified. Conclusions In summary, by integrating multiple data types, we identified a potential splicing event associated with hematuria and albuminuria....

中文翻译：

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遗传预测的 COL4A4 外显子 27 跳跃与血尿和白蛋白尿的相关性


out 影响胶原蛋白 IV 三聚体的组装和分泌。背景 血尿是肾小球疾病的既定体征，可能与肾衰竭有关，但对这一特征的科学研究有限。方法 在这里，我们将来自英国生物样本库的遗传数据与基因型组织表达肾皮层样本 （n=65） 的预测基因表达和剪接相结合，进行转录组范围的关联研究，以确定影响血尿的其他潜在生物学机制。结果 使用肾皮层的转录组范围关联研究确定了 5 个基因表达和 3 个显著剪接事件的显著关联。值得注意的是，我们确定了 COL4A4 外显子 27 的跳跃与血尿之间的关联，这是由内含子 rs11898094 （次要等位基因频率 13%） 遗传预测的。还发现该变体与尿白蛋白排泄之间存在关联。我们在肾病综合征研究网络的肾小球衍生的 mRNA 转录组学数据 （n=245） 中发现了支持预测这种跳跃事件的相同变体的独立证据。使用基于分裂 NanoLuc 的 α3α4α5（IV） 异源三聚体测定法证明了外显子 27 丢失的功能意义，其中 IV 型胶原异源三聚体的形成通过发光进行定量。该跳跃事件的因果剪接变体尚未确定。结论 综上所述，通过整合多种数据类型，我们确定了与血尿和白蛋白尿相关的潜在剪接事件。