title: The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.
abstract: OBJECTIVE
  Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity.
  
  
  METHODS
  The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients.
  
  
  RESULTS
  In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)).
  
  
  CONCLUSIONS
  Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH.
authors.affiliation: Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Serri
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.forename: Julian B S
authors.initials: JB
authors.lastname: Leathart
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Julia
authors.initials: J
authors.lastname: Patch
authors.forename: Anna
authors.initials: A
authors.lastname: Fracanzani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
mesh_terms: D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005190:Family; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease; D020641:Polymorphism, Single Nucleotide; D013482:Superoxide Dismutase / Q000235:genetics*; D000099156:Superoxide Dismutase 2; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D017931:DNA Primers; D008049:Lipase; D008565:Membrane Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent