| Title: | Association of Genetically Predicted Skipping of COL4A4 Exon 27 with Hematuria and Albuminuria. |
| Journal: | Journal of the American Society of Nephrology |
| Published: | 27 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39190490/ |
| DOI: | https://doi.org/10.1681/asn.0000000000000480 |
| URL: | https://journals.lww.com/jasn/abstract/9900/association_of_genetically_predicted_skipping_of.408.aspx |
Publication 13078
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Abstract
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.</p>
METHODS: Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from GTEx kidney cortex samples (n = 65) in a transcriptome-wide association study (TWAS) to identify additional potential biological mechanisms influencing hematuria.</p>
RESULTS: The TWAS using kidney cortex identified significant associations for 5 genes in terms of expression and 3 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 NEPTUNE. 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.</p>
CONCLUSIONS: In summary, by integrating multiple data types, we identify a potential splicing event associated with hematuria and albuminuria.</p>
13 Authors
- Frida Lona-Durazo
- Kohei Omachi
- Damian Fermin
- Felix Eichinger
- Jonathan P Troost
- Meei-Hua Lin
- Ian R Dinsmore
- Tooraj Mirshahi
- Alexander R Chang
- Jeffrey H Miner
- Andrew D Paterson
- Moumita Barua
- Sarah A Gagliano Taliun
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