title: Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis.
abstract: OBJECTIVE
  To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.
  
  
  METHODS
  A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied, with all subjects having liver biopsy data and DNA available for testing. This study assessed the association of eight single nucleotide polymorphisms (SNPs) in a total of six genes including toll-like receptor 4 (TLR4), transforming growth factor-beta (TGF-β), oxoguanine DNA glycosylase, monocyte chemoattractant protein 1, chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity. Genotyping was performed using high resolution melt analysis and sequencing. The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.
  
  
  RESULTS
  There were significant associations between the cofactors of male gender (P = 0.0001), increasing age (P = 0.006), alcohol consumption (P = 0.0001), steatosis (P = 0.03), hepatic iron concentration (P < 0.0001) and the presence of hepatic fibrosis. Of the candidate gene polymorphisms studied, none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors. We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied. Importantly, in this large, well characterised cohort of patients there was no association between SNPs for TGF-β or TLR4 and the presence of fibrosis, cirrhosis or increasing fibrosis stage in multivariate analysis.
  
  
  CONCLUSIONS
  In our large, well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.
authors.affiliation: Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors.forename: Marnie J
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors.forename: Lawrie W
authors.initials: LW
authors.lastname: Powell
authors.affiliation: Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors.forename: Jeannette L
authors.initials: JL
authors.lastname: Dixon
authors.affiliation: Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.affiliation: Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
mesh_terms: D000328:Adult; D001706:Biopsy; D016009:Chi-Square Distribution; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D055815:Young Adult
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta
keywords: 8-oxoguanine DNA glycosylase; Chemokine (C-C motif) ligand 2; Genetic polymorphism; Haemochromatosis; Interleukin 10; Liver fibrosis; Monocyte chemoattractant protein 1; Toll-like receptor 4; Transforming growth factor beta