The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage

Benedetta Donati, Benedetta Maria Motta, Piero Pingitore, Marica Meroni, Alessandro Pietrelli, Anna Alisi, Salvatore Petta, Chao Xing, Paola Dongiovanni, Benedetta del Menico, Raffaela Rametta, Rosellina Margherita Mancina, Sara Badiali, Anna Ludovica Fracanzani, Antonio Craxì, Silvia Fargion, Valerio Nobili, Stefano Romeo, Luca Valenti

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P <0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P <0.05). Conclusions: Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - 2016

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Phospholipases
Liver
Fatty Liver
Alleles
Non-alcoholic Fatty Liver Disease
Disease Susceptibility
Transaminases
Lipase
Alanine Transaminase
Introns
Exons
Triglycerides
Fats
Phenotype
Messenger RNA
Serum

ASJC Scopus subject areas

  • Hepatology

Cite this

Donati, B., Motta, B. M., Pingitore, P., Meroni, M., Pietrelli, A., Alisi, A., ... Valenti, L. (Accepted/In press). The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. https://doi.org/10.1002/hep.28370

The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. / Donati, Benedetta; Motta, Benedetta Maria; Pingitore, Piero; Meroni, Marica; Pietrelli, Alessandro; Alisi, Anna; Petta, Salvatore; Xing, Chao; Dongiovanni, Paola; del Menico, Benedetta; Rametta, Raffaela; Mancina, Rosellina Margherita; Badiali, Sara; Fracanzani, Anna Ludovica; Craxì, Antonio; Fargion, Silvia; Nobili, Valerio; Romeo, Stefano; Valenti, Luca.

In: Hepatology, 2016.

Research output: Contribution to journalArticle

Donati, B, Motta, BM, Pingitore, P, Meroni, M, Pietrelli, A, Alisi, A, Petta, S, Xing, C, Dongiovanni, P, del Menico, B, Rametta, R, Mancina, RM, Badiali, S, Fracanzani, AL, Craxì, A, Fargion, S, Nobili, V, Romeo, S & Valenti, L 2016, 'The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage', Hepatology. https://doi.org/10.1002/hep.28370
Donati, Benedetta ; Motta, Benedetta Maria ; Pingitore, Piero ; Meroni, Marica ; Pietrelli, Alessandro ; Alisi, Anna ; Petta, Salvatore ; Xing, Chao ; Dongiovanni, Paola ; del Menico, Benedetta ; Rametta, Raffaela ; Mancina, Rosellina Margherita ; Badiali, Sara ; Fracanzani, Anna Ludovica ; Craxì, Antonio ; Fargion, Silvia ; Nobili, Valerio ; Romeo, Stefano ; Valenti, Luca. / The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. In: Hepatology. 2016.
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title = "The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage",
abstract = "The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P <0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P <0.05). Conclusions: Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases.",
author = "Benedetta Donati and Motta, {Benedetta Maria} and Piero Pingitore and Marica Meroni and Alessandro Pietrelli and Anna Alisi and Salvatore Petta and Chao Xing and Paola Dongiovanni and {del Menico}, Benedetta and Raffaela Rametta and Mancina, {Rosellina Margherita} and Sara Badiali and Fracanzani, {Anna Ludovica} and Antonio Crax{\`i} and Silvia Fargion and Valerio Nobili and Stefano Romeo and Luca Valenti",
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T1 - The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage

AU - Donati, Benedetta

AU - Motta, Benedetta Maria

AU - Pingitore, Piero

AU - Meroni, Marica

AU - Pietrelli, Alessandro

AU - Alisi, Anna

AU - Petta, Salvatore

AU - Xing, Chao

AU - Dongiovanni, Paola

AU - del Menico, Benedetta

AU - Rametta, Raffaela

AU - Mancina, Rosellina Margherita

AU - Badiali, Sara

AU - Fracanzani, Anna Ludovica

AU - Craxì, Antonio

AU - Fargion, Silvia

AU - Nobili, Valerio

AU - Romeo, Stefano

AU - Valenti, Luca

PY - 2016

Y1 - 2016

N2 - The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P <0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P <0.05). Conclusions: Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases.

AB - The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P <0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P <0.05). Conclusions: Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases.

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