title: A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.affiliation: Programa de Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Paola
authors.initials: P
authors.lastname: León-Mimila
authors.affiliation: Programa de Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Joel
authors.initials: J
authors.lastname: Vega-Badillo
authors.affiliation: Programa de Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Roxana
authors.initials: R
authors.lastname: Gutiérrez-Vidal
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Hugo
authors.initials: H
authors.lastname: Villamil-Ramírez
authors.affiliation: Laboratorio de Enfermedades Cardiovasculares y Óseas, INMEGEN, México City 14610, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Villareal-Molina
authors.affiliation: Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" (INCMNSZ), México City 14000, Mexico.
authors.forename: Elena
authors.initials: E
authors.lastname: Larrieta-Carrasco
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: López-Contreras
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico.
authors.forename: Luis R Macías
authors.initials: LR
authors.lastname: Kauffer
authors.affiliation: Clínica de Obesidad, Hospital Rubén Leñero, México City 11340, Mexico.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Maldonado-Pintado
authors.affiliation: Unidad de Investigación de Hígado, Fundación Médica Sur, México City 14050, Mexico.
authors.forename: Nahúm
authors.initials: N
authors.lastname: Méndez-Sánchez
authors.affiliation: Departamento de Fisiología de la Nutrición, INCMNSZ, México City 14000, Mexico.
authors.forename: Armando R
authors.initials: AR
authors.lastname: Tovar
authors.affiliation: Departamento de Patología Experimental, INCMNSZ, México City 14000, Mexico.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
authors.affiliation: Laboratorio de Enfermedades Cardiovasculares y Óseas, INMEGEN, México City 14610, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Velázquez-Cruz
authors.affiliation: Clínica de Obesidad, Hospital Rubén Leñero, México City 11340, Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Campos-Pérez
authors.affiliation: Departamento de Endocrinología y Metabolismo, INCMNSZ, México City 14000, Mexico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, Mexico. Electronic address: cani@unam.mx.
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008245:Lysophospholipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008800:Mexico; D009419:Nerve Tissue Proteins / Q000235:genetics; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D054645:Protein Phosphatase 1 / Q000235:genetics; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism*; D044465:White People / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002784:Cholesterol; D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D008049:Lipase; D008245:Lysophospholipase; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D058580:Neurocan; D054645:Protein Phosphatase 1; D014280:Triglycerides; C485100:GCKR protein, human; C076817:NCAN protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent; C561408:LYPLAL1 protein, human; C586823:PPP1R3B protein, human
keywords: GRS; Liver fat content; NAFLD; NASH; Polymorphisms