Autosomal Type IV Collagen Genes Display Sex Differences in Genetic Risk for Hematuria.

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 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 (UKB), with replication results in 2 independent cohorts: the Million Veteran Program (MVP) 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 UKB.

RESULTS

We identified significant sex-differential effects in the UKB (Bonferroni-corrected P < 0.006), corresponding to larger effect sizes in females than in males, but in the same direction of effect, at genetic variants within 2 autosomal type IV collagen genes that encode key structural components of the glomerular basement membrane: COL4A3 and COL4A2.

CONCLUSION

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 than in males, which replicated in an independent cohort. In addition, we identify that COL4A2 is associated with hematuria, also with greater effect size in females than in males, only in the UKB.