| Title: | Autosomal type IV collagen genes display sex differences in genetic risk for hematuria |
| Journal: | Kidney International Reports |
| Published: | 1 Jun 2026 |
| DOI: | https://doi.org/10.1016/j.ekir.2026.106647 |
Publication 19900
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Abstract
Introduction Hematuria is an understudied condition associated with kidney disease and related outcomes. Sex and gender influence many aspects of human health including kidney traits. However, sex-differential genetic effects, which can be attributed to hormones, gene regulation and other factors, have not yet been comprehensively explored. Methods To identify genetic effects that differ by sex for hematuria, we performed sex-specific genome-wide association analyses in the UK Biobank, with replication results in two independent cohorts: the Million Veteran Program and Geisinger MyCode. Sex-differential genetic effects were evaluated using locus-specific sex-by-genotype interaction analysis. We further performed observational analyses between hematuria and sex hormones (estradiol and testosterone) in the UK Biobank. Results We identified significant sex-differential effects in the UK Biobank (Bonferroni-corrected p-value < 0.006), corresponding to larger effect sizes in females compared to males, but in the same direction of effect, at genetic variants within two autosomal type IV collagen genes that encode key structural components of the glomerular basement membrane: COL4A3 and COL4A2. Conclusions Although males are known to experience more severe kidney disease than females in X-linked Alport syndrome, our findings highlight important sex differential effects in hematuria, where the presence of COL4A3 variation in females results in stronger association effect sizes compared to males, which replicated in an independent cohort. In addition, we identify that COL4A2 is associated with hematuria, also with greater effect size in females compared to males, only in the UK Biobank.</p>
10 Authors
- Frida Lona-Durazo
- Ian R. Dinsmore
- Michelle T. McNulty
- Matthew G. Sampson
- Léonie Forest
- Tooraj Mirshahi
- Alexander R. Chang
- Andrew D. Paterson
- Moumita Barua
- Sarah A. Gagliano Taliun
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