title: The association of genetic variants with hepatic steatosis in patients with genotype 1 chronic hepatitis C infection.
abstract: BACKGROUND
  Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.
  
  
  OBJECTIVE
  We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.
  
  
  METHODS
  A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).
  
  
  RESULTS
  IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.
  
  
  CONCLUSIONS
  IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.
authors.affiliation: Duke Clinical Research Institute, Duke University, PO Box 17969, Durham, NC 27715, USA. drpjclark@gmail.com
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.forename: David M
authors.initials: DM
authors.lastname: Vock
authors.forename: Mingfu
authors.initials: M
authors.lastname: Zhu
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Harrison
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Hans L
authors.initials: HL
authors.lastname: Tillmann
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Kevin
authors.initials: K
authors.lastname: Shianna
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Zachary
authors.initials: Z
authors.lastname: Goodman
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Pedicone
authors.forename: Nezam
authors.initials: N
authors.lastname: Afdhal
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
authors.forename: Janice K
authors.initials: JK
authors.lastname: Albrecht
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
mesh_terms: D000328:Adult; D000368:Aged; D005234:Fatty Liver / Q000235:genetics* / Q000821:virology; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D012044:Regression Analysis; D012307:Risk Factors; D000095022:Interferon Lambda; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D007372:Interferons; D007378:Interleukins; D008049:Lipase; D008565:Membrane Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent