title: The association between hepatic fat content and liver injury in obese children and adolescents: effects of ethnicity, insulin resistance, and common gene variants.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are highly prevalent in obese youth. Herein, we aimed to study the association between hepatic fat accumulation as assessed by magnetic resonance imaging and circulating levels of cytokeratin-18 (CK-18) fragments, a robust NASH biomarker, and to explore the impact on this association of ethnicity, insulin resistance, and single nucleotide polymorphisms (SNPs) associated with steatosis (rs738409 in the PNPLA3, rs1260326 in the GCKR) or NASH severity (rs2645424 in the FDFT1).
  
  
  METHODS
  Two-hundred twenty-nine obese youths (87 Caucasians, 61 African Americans, and 81 Hispanics; mean age, 12.8 ± 2.9 years; mean BMI, 31.4 ± 7.4) underwent magnetic resonance imaging, oral glucose tolerance test, and CK-18 levels measurement; 12 subjects underwent liver biopsy.
  
  
  RESULTS
  African Americans showed lower CK-18 levels than Hispanics (P < 0.001) and Caucasians (P = 0.004). Hepatic fat content (HFF%) and whole body insulin sensitivity index (WBISI) modulated CK-18 levels in Caucasians and Hispanics (P = 0.02 and P = 0.011), but not in African Americans; in fact, CK-18 was associated with HFF% and WBISI in Caucasians (P = 0.0018 and P < 0.0001) and Hispanics (P < 0.0001 and P = 0.02), but not in African Americans (both P = 0.5). The PNPLA3 SNP showed association in Caucasians (P = 0.02) and Hispanics (P = 0.05), and FDFT1 SNP showed an association in Caucasians (P = 0.05) and Hispanics (P = 0.02), with the same trend in African Americans (P = 0.07).
  
  
  CONCLUSIONS
  African Americans have lower levels of CK-18 than Caucasians and Hispanics irrespective of HFF% and insulin resistance. Moreover, SNPs in the PNPLA3 and FDFT1 may drive the individual predisposition to development of hepatic injury.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.forename: Erik
authors.initials: E
authors.lastname: Enoksson
authors.forename: Bridget
authors.initials: B
authors.lastname: Pierpont
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D002648:Child; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D053538:Keratin-18 / Q000378:metabolism*; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053538:Keratin-18; D008049:Lipase; D008565:Membrane Proteins; C485100:GCKR protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent