title: Genetic Determinants of Circulating Lipoproteins in Nonalcoholic Fatty Liver Disease.
abstract: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized.
  
  
  
  We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes.
  
  
  
  In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype.
  
  
  
  PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology.
authors.forename: Zhenghui G
authors.initials: ZG
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, University of Michigan, MI.
authors.forename: Elliot B
authors.initials: EB
authors.lastname: Tapper
authors.affiliation: Department of Medicine, Division of Endocrinology.
authors.forename: Misung
authors.initials: M
authors.lastname: Kim
authors.affiliation: LipoScience, Laboratory Corporation of America Holdings, Raleigh, NC.
authors.forename: Margery A
authors.initials: MA
authors.lastname: Connelly
authors.affiliation: Department of Medicine, Division of Endocrinology.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Krawczyk
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Eric U
authors.initials: EU
authors.lastname: Yee
authors.affiliation: Division of Endocrinology, Duke University Medical Center, Durham, NC.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Herman
authors.affiliation: Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Mukamal
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lai
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent