title: The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver.
abstract: OBJECTIVE
  The T-455C and C-482T APOC3 promoter region polymorphisms (SNPs) have recently been reported to predispose to dyslipidemia, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) in Indian subjects, but the association with liver damage has not been evaluated so far. The aim was to assess the association between APOC3 SNPs and liver damage in Caucasian patients.
  
  
  METHODS
  We considered 437 Italian patients with histological diagnosis of NAFLD (including 137 children, 120 morbid obese) and 316 healthy controls, 71 Italian family trios, and 321 patients from the UK. APOC3 SNPs were determined by sequencing, allele-specific oligonucleotide probes and PCR-restriction fragment length polymorphism analysis, hepatic APOC3 mRNA levels by real-time PCR.
  
  
  RESULTS
  APOC3 SNPs were not associated with NAFLD in Italian subjects, although a borderline significance for the transmission of the -455T allele was observed in the family study. Homozygosity for the APOC3 wild-type genotype (APOC3 WT) was associated with a more favorable lipid profile in control subjects, and consistently with lower hepatic APOC3 mRNA levels in obese patients without diabetes. However, APOC3 SNPs, alone or in combination, were not associated with insulin resistance, altered lipid levels, liver enzymes, and with liver damage (severity of steatosis, nonalcoholic steatohepatitis, and moderate/severe fibrosis) in Italian as well as in UK patients, and in the whole cohort. Stratification for the I148M PNPLA3 mutation, associated with the susceptibility to NASH, did not alter the results.
  
  
  CONCLUSIONS
  APOC3 genotype is not associated with progressive liver damage in Caucasian patients with NAFLD.
authors.affiliation: Department of Internal Medicine, Università degli Studi Milano, UO Medicina Interna 1B, Ospedale Maggiore Ca' Granda Fondazione Policlinico IRCCS, Milan, Italy. luca.valenti@unimi.it
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Serri
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Julian B S
authors.initials: JB
authors.lastname: Leathart
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zappa
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Anna L
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Arianna
authors.initials: A
authors.lastname: Alterio
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Roviaro
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
mesh_terms: D000293:Adolescent; D000328:Adult; D053305:Apolipoprotein C-III / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D017931:DNA Primers / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007558:Italy; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D006113:United Kingdom; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D053305:Apolipoprotein C-III; D017931:DNA Primers; D008049:Lipase; D008565:Membrane Proteins; D012333:RNA, Messenger; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent