A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity.

Abstract

BACKGROUND AND AIMS:

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity.

METHODS:

130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions.

RESULTS:

After adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P < 0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P = 0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P = 1.0 × 10(-4) and 0.048, respectively), steatosis stage (P = 0.029), and higher ALT levels (P = 0.002). Subjects with GRS ≥ 6 showed a significantly increased risk of NASH (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P = 0.219).

CONCLUSION:

NAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals.

• Authors: Paola León-Mimila, Joel Vega-Badillo, Roxana Gutiérrez-Vidal, Hugo Villamil-Ramírez, Teresa Villareal-Molina, Elena Larrieta-Carrasco, Blanca E López-Contreras, Luis R Macías Kauffer, Diana G Maldonado-Pintado, Nahúm Méndez-Sánchez, Armando R Tovar, Rogelio Hernández-Pando, Rafael Velázquez-Cruz, Francisco Campos-Pérez, Carlos A Aguilar-Salinas, Samuel Canizales-Quinteros
• Journal: Experimental and molecular pathology (Exp Mol Pathol) Vol. 98 Issue 2 Pg. 178-83 (Apr 2015) ISSN: 1096-0945 [Electronic] Netherlands
• PMID: 25597287 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Chondroitin Sulfate Proteoglycans
• GCKR protein, human
• Lectins, C-Type
• Membrane Proteins
• Nerve Tissue Proteins
• Neurocan
• Triglycerides
• NCAN protein, human
• Cholesterol
• Lipase
• adiponutrin, human
• Lysophospholipase
• LYPLAL1 protein, human
• PPP1R3B protein, human
• Protein Phosphatase 1

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Cholesterol (analysis, metabolism)
• Chondroitin Sulfate Proteoglycans (genetics)
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Lectins, C-Type (genetics)
• Lipase (genetics)
• Liver (metabolism)
• Lysophospholipase (genetics)
• Male
• Membrane Proteins (genetics)
• Mexico
• Nerve Tissue Proteins (genetics)
• Neurocan
• Non-alcoholic Fatty Liver Disease (genetics, metabolism, pathology)
• Obesity, Morbid (genetics, metabolism, pathology)
• Polymorphism, Single Nucleotide
• Protein Phosphatase 1 (genetics)
• Triglycerides (analysis, metabolism)
• White People (genetics)