The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

Rosellina Margherita Mancina, Paola Dongiovanni, Salvatore Petta, Piero Pingitore, Marica Meroni, Raffaela Rametta, Jan Borén, Tiziana Montalcini, Arturo Pujia, Olov Wiklund, George Hindy, Rocco Spagnuolo, Benedetta Maria Motta, Rosaria Maria Pipitone, Antonio Craxì, Silvia Fargion, Valerio Nobili, Pirjo Käkelä, Vesa Kärjä, Ville MännistöJussi Pihlajamäki, Dermot F. Reilly, Jose Castro-Perez, Julia Kozlitina, Luca Valenti, Stefano Romeo

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

Original languageEnglish (US)
Pages (from-to)1219-1230e6
JournalGastroenterology
Volume150
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Liver
Genes
Phosphatidylinositols
Biopsy
Fibrosis
Non-alcoholic Fatty Liver Disease
Acyltransferases
Sampling Studies
Genome-Wide Association Study
Liver Diseases
Triglycerides
Fats
Alleles
Genotype
Alcohols
Membranes
DNA
Population
Proteins

Keywords

  • Arachidonic Acid
  • NASH
  • PNPLA3
  • TM6SF2

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Mancina, R. M., Dongiovanni, P., Petta, S., Pingitore, P., Meroni, M., Rametta, R., ... Romeo, S. (2016). The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology, 150(5), 1219-1230e6. https://doi.org/10.1053/j.gastro.2016.01.032

The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. / Mancina, Rosellina Margherita; Dongiovanni, Paola; Petta, Salvatore; Pingitore, Piero; Meroni, Marica; Rametta, Raffaela; Borén, Jan; Montalcini, Tiziana; Pujia, Arturo; Wiklund, Olov; Hindy, George; Spagnuolo, Rocco; Motta, Benedetta Maria; Pipitone, Rosaria Maria; Craxì, Antonio; Fargion, Silvia; Nobili, Valerio; Käkelä, Pirjo; Kärjä, Vesa; Männistö, Ville; Pihlajamäki, Jussi; Reilly, Dermot F.; Castro-Perez, Jose; Kozlitina, Julia; Valenti, Luca; Romeo, Stefano.

In: Gastroenterology, Vol. 150, No. 5, 01.05.2016, p. 1219-1230e6.

Research output: Contribution to journalArticle

Mancina, RM, Dongiovanni, P, Petta, S, Pingitore, P, Meroni, M, Rametta, R, Borén, J, Montalcini, T, Pujia, A, Wiklund, O, Hindy, G, Spagnuolo, R, Motta, BM, Pipitone, RM, Craxì, A, Fargion, S, Nobili, V, Käkelä, P, Kärjä, V, Männistö, V, Pihlajamäki, J, Reilly, DF, Castro-Perez, J, Kozlitina, J, Valenti, L & Romeo, S 2016, 'The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent', Gastroenterology, vol. 150, no. 5, pp. 1219-1230e6. https://doi.org/10.1053/j.gastro.2016.01.032
Mancina, Rosellina Margherita ; Dongiovanni, Paola ; Petta, Salvatore ; Pingitore, Piero ; Meroni, Marica ; Rametta, Raffaela ; Borén, Jan ; Montalcini, Tiziana ; Pujia, Arturo ; Wiklund, Olov ; Hindy, George ; Spagnuolo, Rocco ; Motta, Benedetta Maria ; Pipitone, Rosaria Maria ; Craxì, Antonio ; Fargion, Silvia ; Nobili, Valerio ; Käkelä, Pirjo ; Kärjä, Vesa ; Männistö, Ville ; Pihlajamäki, Jussi ; Reilly, Dermot F. ; Castro-Perez, Jose ; Kozlitina, Julia ; Valenti, Luca ; Romeo, Stefano. / The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. In: Gastroenterology. 2016 ; Vol. 150, No. 5. pp. 1219-1230e6.
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abstract = "Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.",
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T1 - The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

AU - Mancina, Rosellina Margherita

AU - Dongiovanni, Paola

AU - Petta, Salvatore

AU - Pingitore, Piero

AU - Meroni, Marica

AU - Rametta, Raffaela

AU - Borén, Jan

AU - Montalcini, Tiziana

AU - Pujia, Arturo

AU - Wiklund, Olov

AU - Hindy, George

AU - Spagnuolo, Rocco

AU - Motta, Benedetta Maria

AU - Pipitone, Rosaria Maria

AU - Craxì, Antonio

AU - Fargion, Silvia

AU - Nobili, Valerio

AU - Käkelä, Pirjo

AU - Kärjä, Vesa

AU - Männistö, Ville

AU - Pihlajamäki, Jussi

AU - Reilly, Dermot F.

AU - Castro-Perez, Jose

AU - Kozlitina, Julia

AU - Valenti, Luca

AU - Romeo, Stefano

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

AB - Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

KW - Arachidonic Acid

KW - NASH

KW - PNPLA3

KW - TM6SF2

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