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

Alessandro Mantovani1, Serena Pelusi2, Sara Margarita2

  • 1Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.

Alimentary Pharmacology & Therapeutics
|March 22, 2023
PubMed
Abstract

Insights

The PNPLA3 p.I148M variant, a key factor in fatty liver disease, is linked to reduced kidney function and faster decline in estimated glomerular filtration rate (eGFR) among individuals with metabolic dysfunction.

Area of Science:

  • Genetics and Genomics
  • Nephrology
  • Hepatology
  • Metabolic Disorders

Background:

  • The I148M variant of the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is a primary genetic driver of nonalcoholic fatty liver disease (NAFLD).
  • Emerging evidence suggests a link between the PNPLA3 p.I148M variant and kidney damage, but its specific impact on kidney function relative to overall genetic predisposition remains unclear.
  • Therapeutic strategies targeting PNPLA3, such as gene silencing, are under investigation for NAFLD treatment.

Purpose of the Study:

  • To investigate the association between the PNPLA3 p.I148M variant and estimated glomerular filtration rate (eGFR) in middle-aged individuals with metabolic dysfunction.
  • To determine if the PNPLA3 p.I148M variant independently affects kidney function, considering established risk factors and genetic susceptibility to chronic kidney disease (CKD).

Main Methods:

  • Analysis of 1144 middle-aged participants from the Liver-Bible-2022 cohort.
  • Estimation of glomerular filtration rate (eGFR) using the CKD-EPI equation.
  • Statistical modeling using additive genetic models, adjusted for clinical covariates, ethnicity, and a polygenic risk score for CKD (PRS-CKD).
  • Prospective evaluation of eGFR changes in a subset of 144 individuals over a median follow-up of 17 months.

Main Results:

  • The PNPLA3 p.I148M variant was significantly associated with lower eGFR levels (-1.24 mL/min/1.73 m² per allele, P = 0.023), independent of numerous clinical and genetic factors.
  • In prospective analysis, the p.I148M variant was independently linked to a faster decline in eGFR (-3.57 mL/min/1.73 m² per allele, P = 0.037).
  • These associations remained significant after adjusting for age, sex, metabolic parameters, ethnicity, and PRS-CKD.

Conclusions:

  • The PNPLA3 p.I148M variant exerts a detrimental effect on kidney function, evidenced by reduced eGFR levels and accelerated decline in individuals with metabolic dysfunction.
  • This impact is independent of known risk factors for CKD and overall genetic predisposition to kidney disease.
  • Targeting PNPLA3, potentially through silencing strategies, may offer a therapeutic avenue to mitigate kidney damage progression in carriers of the p.I148M variant.
Keywords:
geneticsglomerular filtration ratenonalcoholic fatty liver diseasenonalcoholic steatohepatitispolygenic risk scoreprecision medicine

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