Brief Article
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World J Gastroenterol. Dec 28, 2013; 19(48): 9366-9376
Published online Dec 28, 2013. doi: 10.3748/wjg.v19.i48.9366
Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis
Marnie J Wood, Lawrie W Powell, Jeannette L Dixon, V Nathan Subramaniam, Grant A Ramm
Marnie J Wood, Grant A Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
Marnie J Wood, Lawrie W Powell, V Nathan Subramaniam, Grant A Ramm, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane 4006, Australia
Marnie J Wood, Lawrie W Powell, Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia
Lawrie W Powell, Centre for the Advancement of Clinical Research, Royal Brisbane and Women’s Hospital and the University of Queensland Centre for Clinical Research, Brisbane 4029, Australia
Lawrie W Powell, Jeannette L Dixon, Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
V Nathan Subramaniam, Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
Author contributions: Wood MJ performed the single nucleotide polymorphisms genotyping and analysed data, performed statistical tests and wrote the manuscript; Powell LW recruited subjects, collected clinical data and provided critical review of the manuscript; Dixon JL collected and processed the specimens, maintained the database and provided critical review of the manuscript; Subramaniam VN analysed and interpreted data and provided critical review of the manuscript; Ramm GA designed the research, interpreted data and provided critical review of the manuscript.
Supported by NHMRC Medical Postgraduate Scholarship and the Royal Brisbane and Women’s Hospital Research Foundation to Wood MJ; the National Health and Medical Research Council (NHMRC) to Ramm GA and Powell LW; the recipient of an NHMRC Senior Research Fellowship, 1024672 to Subramaniam VN; an NHMRC Senior Research Fellowship, No. 552409 to Ramm GA
Correspondence to: Grant A Ramm, PhD, Professor, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. grant.ramm@qimr.edu.au
Telephone: +61-7-33620177 Fax: +61-7-33620191
Received: June 12, 2013
Revised: August 23, 2013
Accepted: September 4, 2013
Published online: December 28, 2013
Processing time: 216 Days and 10.8 Hours
Abstract

AIM: 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.

CONCLUSION: In our large, well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.

Keywords: Haemochromatosis; Genetic polymorphism; Liver fibrosis; Toll-like receptor 4; Interleukin 10; Monocyte chemoattractant protein 1; Chemokine (C-C motif) ligand 2; Transforming growth factor beta; 8-oxoguanine DNA glycosylase

Core tip: This study does not support the previously proposed role of mutations in both toll-like receptor 4, transforming growth factor-beta in the progression of hepatic fibrosis associated with hereditary haemochromatosis.