Creatinine clearance finds genetic loci that eGFR hides

Design

genome-wide association meta-analysis with sex-specific analyses and in silico functional annotation

Population

58,976 individuals of European ancestry from the Lifelines Cohort Study

Primary outcome

genetic loci associated with measured creatinine clearance

Effect

16 independent loci, 21 lead variants; two novel (rs146465192 near RP1-249F5.3, p=3.38 × 10⁻⁹; rs117014836 near AGPAT4, p=5.42 × 10⁻⁹); two female-specific loci at GPC6 and IGF1R

Every large genetic study of kidney function has used creatinine-based estimated GFR, which is a function of both filtration and muscle mass. That confounding is not a nuisance to be adjusted away — it means eGFR studies have been finding loci for muscle as well as loci for kidney, and missing some of each. This analysis used measured creatinine clearance instead, in 58,976 people of European ancestry from a single cohort, with sex-specific analyses.

Sixteen independent loci reached significance with 21 lead variants. Two had never appeared in kidney function studies: rs146465192 near RP1-249F5.3, associated with plasma IGF2R protein, and rs117014836 near AGPAT4, associated with blood AGPAT4 expression. Both were also associated with eGFR within this cohort but not in previously published eGFR studies — consistent with them having been obscured rather than absent.

Two female-specific loci emerged: rs8002366 at GPC6, linked to GPC6 expression in kidney, and rs12908437 at IGF1R, linked to IGF1R expression in blood. Sex differences in chronic kidney disease progression are well documented and poorly explained, and sex-stratified genetics is one of the few ways to get at them. Both new general loci had effect allele frequencies of 1–2%, so these are uncommon variants with no immediate clinical use.

• Nothing here changes how you estimate GFR in clinic — creatinine clearance requires a timed urine collection and remains impractical for routine use.
• The muscle-mass confounding in eGFR is the clinically relevant reminder: a sarcopenic patient's eGFR overstates their filtration.
• In Indian practice, where lower muscle mass is common and eGFR equations were derived elsewhere, that overestimation is not a theoretical concern.
• Cystatin C-based estimation is the practical alternative when muscle mass is atypical, and is where this reasoning leads clinically.
• Single European-ancestry cohort — these variants have not been tested in South Asian populations.

Why it matters

It names a specific cost to using eGFR as the phenotype for kidney genetics, and demonstrates it with variants that only appear when muscle mass is removed.

Don't overread it

A single cohort of European ancestry with uncommon variants and no external replication — these loci are findings to follow up, not established kidney function genes.

The statistics, in plain English

Genome-wide significance at p=3.38 × 10⁻⁹ and 5.42 × 10⁻⁹ clears the conventional 5 × 10⁻⁸ threshold but not by much, and both variants have effect allele frequencies of 1–2%, where a handful of carriers can drive an association. The key check is replication, and these loci were significant in this cohort's own eGFR data but not in published eGFR studies — which the authors read as eGFR's muscle-mass noise obscuring them, though failure to replicate externally is the other available reading. Sex-specific analyses halve the sample and double the tests.

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