PNPLA3 I148M gene variant and chronic kidney disease in Type 2 diabetic patients with NAFLD: Clinical and experimental findings
PNPLA3 I148M gene variant and chronic kidney disease in Type 2 diabetic patients with NAFLD: Clinical and experimental findings
Background and Aims: Emerging evidence suggests an association between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods: We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) '60 mL/min/1.73 m
2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results: In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m
2, P =.0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P =.028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P '.0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P =.008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions: The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes.
NAFLD, adiponutrin, kidney dysfunction, renal podocytes
1130-1141
Mantovani, Alessandro
19fc8a1f-60fe-403a-b70e-6b6884929e03
Taliento, Alice
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Zusi, Chiara
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Baselli, Guido
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Prati, Daniele
4139a4c7-be7a-4004-a8f7-352612df76cb
Granata, Simona
33ab1813-dcef-4e3e-8b43-315ea2faae10
Zaza, Gianluigi
8f83f913-7e02-4864-b98f-8d05cd68f3a1
Colecchia, Antonio
c7b732f0-98eb-4fd6-be76-17d68ae42858
Maffeis, Claudio
c8f0ad85-e7b9-48a7-9774-7b4c4f363ec1
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Valenti, Luca
714abce4-8745-40de-a8bd-3bee524291f8
Targher, Giovanni
043e0811-b389-4922-974e-22e650212c5f
1 May 2020
Mantovani, Alessandro
19fc8a1f-60fe-403a-b70e-6b6884929e03
Taliento, Alice
f983bcf5-264d-489f-b721-b37037228cc0
Zusi, Chiara
b2fe75f8-ebb9-44e1-82dd-cd791fd2b35f
Baselli, Guido
24d28495-e483-4086-9926-200d65f5ac3c
Prati, Daniele
4139a4c7-be7a-4004-a8f7-352612df76cb
Granata, Simona
33ab1813-dcef-4e3e-8b43-315ea2faae10
Zaza, Gianluigi
8f83f913-7e02-4864-b98f-8d05cd68f3a1
Colecchia, Antonio
c7b732f0-98eb-4fd6-be76-17d68ae42858
Maffeis, Claudio
c8f0ad85-e7b9-48a7-9774-7b4c4f363ec1
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Valenti, Luca
714abce4-8745-40de-a8bd-3bee524291f8
Targher, Giovanni
043e0811-b389-4922-974e-22e650212c5f
Mantovani, Alessandro, Taliento, Alice, Zusi, Chiara, Baselli, Guido, Prati, Daniele, Granata, Simona, Zaza, Gianluigi, Colecchia, Antonio, Maffeis, Claudio, Byrne, Christopher D., Valenti, Luca and Targher, Giovanni
(2020)
PNPLA3 I148M gene variant and chronic kidney disease in Type 2 diabetic patients with NAFLD: Clinical and experimental findings.
Liver International, 40 (5), .
(doi:10.1111/liv.14419).
Abstract
Background and Aims: Emerging evidence suggests an association between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods: We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) '60 mL/min/1.73 m
2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results: In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m
2, P =.0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P =.028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P '.0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P =.008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions: The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes.
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PNPLA3 and eGFR_Liver International_R1
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Figure 1
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Figure 2
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More information
Accepted/In Press date: 19 February 2020
e-pub ahead of print date: 3 March 2020
Published date: 1 May 2020
Additional Information:
Funding Information:
GT is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. CDB is supported in part by grants from the Southampton National Institute for Health Research Biomedical Research Centre. LV was supported by MyFirst Grant AIRC n. 16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS ? ?Liver Investigation: Testing Marker Utility in Steatohepatitis?.
Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Keywords:
NAFLD, adiponutrin, kidney dysfunction, renal podocytes
Identifiers
Local EPrints ID: 438206
URI: http://eprints.soton.ac.uk/id/eprint/438206
ISSN: 1478-3223
PURE UUID: e363d582-5cce-4e13-b528-671b402a167c
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Date deposited: 04 Mar 2020 17:30
Last modified: 17 Mar 2024 05:21
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Contributors
Author:
Alessandro Mantovani
Author:
Alice Taliento
Author:
Chiara Zusi
Author:
Guido Baselli
Author:
Daniele Prati
Author:
Simona Granata
Author:
Gianluigi Zaza
Author:
Antonio Colecchia
Author:
Claudio Maffeis
Author:
Luca Valenti
Author:
Giovanni Targher
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