This study examined whether African-enriched genetic variants at the GATM locus (encoding the rate-limiting enzyme in creatine biosynthesis) cause systematic bias in creatinine-based eGFR (eGFRCr) estimates, using whole-genome sequencing and phenotypic data from population-based cohorts in Uganda (n=5,760) and South Africa (n=827), with diagnostic validation in African American participants of the Million Veteran Program.
African-enriched GATM variants (allele frequency ~50% in African populations, rare/absent in Europeans) were associated with ~2 ml/min/1.73 m² lower eGFRCr per allele, explained 1.0–1.7% of eGFRCr variance, and increased odds of a CKD diagnosis by eGFRCr thresholds — yet showed **no association** with measured GFR (iohexol) or cystatin C-based eGFR, confirming a biomarker-specific bias rather than true kidney dysfunction.
Study populations were limited to Uganda and South Africa for discovery, which may not represent all African-ancestry groups; the diagnostic analysis in African Americans relied on CKD diagnosis codes rather than directly measured GFR; and end-stage kidney disease was used as a hard outcome proxy, which may miss intermediate renal injury.
In patients of African ancestry, eGFRCr may be systematically underestimated due to common GATM variants that raise serum creatinine without affecting true kidney function — consider cystatin C-based or measured GFR when CKD staging has major clinical implications in this population.
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