Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis

Mantovani, Alessandro; Zusi, Chiara; Csermely, Alessandro; Taverna, Antonio; Cappelli, Davide; Pagani, Micol; Valenti, Luca; Maffeis, Claudio; Targher, Giovanni

doi:10.1016/j.numecd.2023.03.004

Cited by 5 publications

(2 citation statements)

References 18 publications

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“…Similar to the results of our study, these authors also showed that homozygosity for the PNPLA3 p.I148M variant was associated with faster eGFR decline in a small subgroup of subjects followed for a mean period of 5 years 11 . Almost identical results were found in another pilot prospective study of 46 postmenopausal T2D women with preserved kidney function showing that the PNPLA3 p.I148M variant was associated with a faster eGFR decline during a 5‐year follow‐up period, independent of annual changes in common renal risk factors and use of certain glucose‐lowering medications 27 . Finally, in a recent experimental and clinical study, our research group, beside confirming that the p.I148M variant homozygosity was strongly associated with lower eGFR levels, also showed that PNPLA3 mRNA levels were expressed at high levels both in the liver and in the kidney.…”

Section: Discussionsupporting

confidence: 65%

“…11 Almost identical results were found in another pilot prospective study of 46 postmenopausal T2D women with preserved kidney function showing that the PNPLA3 p.I148M variant was associated with a faster eGFR decline during a 5-year follow-up period, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications. 27 Finally, in a recent experimental and clinical study, our research group, beside confirming that the p.I148M variant homozygosity was strongly associated with lower eGFR levels, also showed that PNPLA3 mRNA levels were expressed at high levels both in the liver and in the kidney. In particular, among the cellular types of the kidney, podocytes showed higher PNPLA3 mRNA and protein expression levels than tubular cells.…”

Section: Discussionmentioning

confidence: 53%

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

Mantovani

Pelusi

Margarita

et al. 2023

Aliment Pharmacol Ther

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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 m 2 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 m 2 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.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 53%

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

Mantovani

Pelusi

Margarita

et al. 2023

Aliment Pharmacol Ther

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PNPLA3 variation and kidney disease

Mantovani,

Targher

2024

Liver International

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Accumulating epidemiological evidence shows that the patatin‐like phospholipase domain‐containing protein‐3 (PNPLA3) rs738409 G allele, which is the most robust genetic variant associated with greater susceptibility to metabolic dysfunction‐associated steatotic liver disease (MASLD), is significantly associated with impaired kidney function in both adults and children, regardless of the presence of common renal risk factors, MASLD severity, and other potential confounders. Although some prospective studies have reported a significant association between the PNPLA3 rs738409 G allele and the increased risk of developing chronic kidney disease (CKD), the epidemiological evidence about a possible direct effect of the PNPLA3 rs738409 G allele on the risk of developing CKD is still limited. Experimentally, PNPLA3 is expressed in renal podocytes, pericytes, and proximal tubule cells, thus supporting the notion that the mutant PNPLA3 protein may play a role in developing renal steatosis and fibrosis. However, it cannot be ruled out that a part of the adverse effect of the PNPLA3 rs738409 G allele on kidney function may be driven by a direct impact of this genetic variant on the development and progression of MASLD. It is possible to hypothesize that identifying the PNPLA3 genotype might help identify individuals at higher risk of CKD and those at greater risk of advanced MASLD. In this narrative minireview, we summarize the current epidemiological data about the association between the PNPLA3 rs738409 G allele and the risk of CKD and abnormal albuminuria. We also briefly discuss the putative biological mechanisms underpinning this association and its potential and future clinical implications.

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Impact ofPNPLA3 I148Mon Clinical Outcomes in Patients WithMASLD

Petta,

Armandi,

Bugianesi

2024

Liver International

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Background and AimsMetabolic dysfunction‐associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co‐factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co‐factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long‐term clinical events regardless of, or worsened by, other metabolic risk factors.Methods and ResultsIn this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub‐phenotyping (e.g., ‘lean MASLD’), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non‐invasive tools into polygenic risk scores.

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Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis

Cited by 5 publications

References 18 publications

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

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

PNPLA3 variation and kidney disease

Impact ofPNPLA3 I148Mon Clinical Outcomes in Patients WithMASLD

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