Adverse effect of PNPLA3 p.I148M genetic variant on kidney function in middle-aged individuals with metabolic dysfunction

Background: The PNPLA3 p.I148M variant is the main genetic determinant of nonalcoholic fatty liver disease, and PNPLA3 silencing is being evaluated to treat this liver condition. Data suggest that the p.I148M variant predisposes to kidney damage, but the relative contribution to kidney function, compared to overall genetic susceptibility, is not defined.

Aims: We aimed to assess the effect of PNPLA3 p.I148M on the estimated glomerular filtration rate (eGFR) in individuals with metabolic dysfunction.

Methods: We included 1144 middle-aged individuals from the Liver-Bible-2022 cohort. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. The effect of PNPLA3 p.I148M on eGFR_CKD-EPI levels was tested under additive genetic models adjusted for clinical predictors, ethnicity and a polygenic risk score of chronic kidney disease (PRS-CKD). In a subset of 144 individuals, we examined the effect of PNPLA3 p.I148M on eGFR_CKD-EPI over a median follow-up of 17 months.

Results: The p.I148M variant was associated with lower eGFR_CKD-EPI levels (-1.24 mL/min/1.73 m² per allele, 95% CI: -2.32 to -0.17; p = 0.023), independent of age, sex, height, waist circumference, systolic blood pressure, LDL-cholesterol, transaminases, fasting insulin, albuminuria, lipid-lowering drugs, ethnicity and PRS-CKD score. In the prospective evaluation, the p.I148M variant was independently associated with faster eGFR_CKD-EPI decline (ΔeGFR_CKD-EPI -3.57 mL/min/1.73 m² per allele, 95% CI: -6.94 to -0.21; p = 0.037).

Conclusions: We found a detrimental impact of the PNPLA3 p.I148M variant on eGFR_CKD-EPI levels in middle-aged individuals with metabolic dysfunction. This association was independent of established risk factors, ethnicity and genetic predisposition to CKD. PNPLA3 p.I148M silencing may protect against kidney damage progression in carriers.