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

• Published in: Experimental and molecular pathology Vol. 98; no. 2; pp. 178 - 183
• Main Authors: León-Mimila, Paola, Vega-Badillo, Joel, Gutiérrez-Vidal, Roxana, Villamil-Ramírez, Hugo, Villareal-Molina, Teresa, Larrieta-Carrasco, Elena, López-Contreras, Blanca E., Kauffer, Luis R. Macías, Maldonado-Pintado, Diana G., Méndez-Sánchez, Nahúm, Tovar, Armando R., Hernández-Pando, Rogelio, Velázquez-Cruz, Rafael, Campos-Pérez, Francisco, Aguilar-Salinas, Carlos A., Canizales-Quinteros, Samuel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2015
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Cholesterol - analysis; Cholesterol - metabolism; Chondroitin Sulfate Proteoglycans - genetics; European Continental Ancestry Group - genetics; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; GRS; Humans; Lectins, C-Type - genetics; Lipase - genetics; Liver - metabolism; Liver fat content; Lysophospholipase - genetics; Male; Membrane Proteins - genetics; Mexico; NAFLD; NASH; Nerve Tissue Proteins - genetics; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity, Morbid - genetics; Obesity, Morbid - metabolism; Obesity, Morbid - pathology; Polymorphism, Single Nucleotide; Polymorphisms; Protein Phosphatase 1 - genetics; Triglycerides - analysis; Triglycerides - metabolism; GRS; NAFLD; NASH; Polymorphisms; Liver fat content
• ISSN: 0014-4800; 1096-0945; 1096-0945
• DOI: 10.1016/j.yexmp.2015.01.012

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. 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. 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). 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.