title: PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease.
abstract: Single nucleotide polymorphisms (SNPs) near 7 loci have been associated with liver function tests or with liver steatosis by magnetic resonance spectroscopy. In this study we aim to test whether these SNPs influence the risk of histologically-confirmed nonalcoholic fatty liver disease (NAFLD). We tested the association of histologic NAFLD with SNPs at 7 loci in 592 cases of European ancestry from the Nonalcoholic Steatohepatitis Clinical Research Network and 1405 ancestry-matched controls. The G allele of rs738409 in PNPLA3 was associated with increased odds of histologic NAFLD (odds ratio [OR] = 3.26, 95% confidence intervals [CI] = 2.11-7.21; P = 3.6 x 10(-43)). In a case only analysis of G allele of rs738409 in PNPLA3 was associated with a decreased risk of zone 3 centered steatosis (OR = 0.46, 95% CI = 0.36-0.58; P = 5.15 x 10(-11)). We did not observe any association of this variant with body mass index, triglyceride levels, high- and low-density lipoprotein levels, or diabetes (P > 0.05). None of the variants at the other 6 loci were associated with NAFLD.
  
  
  CONCLUSIONS
  Genetic variation at PNPLA3 confers a markedly increased risk of increasingly severe histological features of NAFLD, without a strong effect on metabolic syndrome component traits.
authors.affiliation: Department of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA. espeliotes@partners.org
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.forename: Johannah L
authors.initials: JL
authors.lastname: Butler
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Palmer
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D000328:Adult; D000483:Alleles; D001706:Biopsy; D016022:Case-Control Studies; D018450:Disease Progression; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D044465:White People / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent