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The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage.
Hepatology 2016; 63(3):787-98Hep

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 <22/20 IU/mL. Besides rs738409 I148M, the rs2294918 G>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.

Authors+Show Affiliations

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy. Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy. Istituto Nazionale Genetica Molecolare (INGM), "Romeo ed Enrica Invernizzi", Bioinformatic Group, Milano, Italy.Hepato-Metabolic Unit, Ospedale Bambin Gesù, Roma, Italy.Department of Gastroenterology, Università di Palermo, Palermo, Italy.UT Southwestern Medical Center, Dallas, TX.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Department of Gastroenterology, Università di Palermo, Palermo, Italy.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.Hepato-Metabolic Unit, Ospedale Bambin Gesù, Roma, Italy.Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26605757

Citation

Donati, Benedetta, et al. "The Rs2294918 E434K Variant Modulates Patatin-like Phospholipase Domain-containing 3 Expression and Liver Damage." Hepatology (Baltimore, Md.), vol. 63, no. 3, 2016, pp. 787-98.
Donati B, Motta BM, Pingitore P, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016;63(3):787-98.
Donati, B., Motta, B. M., Pingitore, P., Meroni, M., Pietrelli, A., Alisi, A., ... Valenti, L. (2016). The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology (Baltimore, Md.), 63(3), pp. 787-98. doi:10.1002/hep.28370.
Donati B, et al. The Rs2294918 E434K Variant Modulates Patatin-like Phospholipase Domain-containing 3 Expression and Liver Damage. Hepatology. 2016;63(3):787-98. PubMed PMID: 26605757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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, Y1 - 2016/01/14/ PY - 2015/05/13/received PY - 2015/11/23/accepted PY - 2015/11/26/entrez PY - 2015/11/26/pubmed PY - 2016/7/5/medline SP - 787 EP - 98 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 63 IS - 3 N2 - UNLABELLED: 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 <22/20 IU/mL. Besides rs738409 I148M, the rs2294918 G>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. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/26605757/The_rs2294918_E434K_variant_modulates_patatin_like_phospholipase_domain_containing_3_expression_and_liver_damage_ L2 - https://doi.org/10.1002/hep.28370 DB - PRIME DP - Unbound Medicine ER -