SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C.
Journal: 2004/March - Gut
ISSN: 0017-5749
PUBMED: 14960532
Abstract:
OBJECTIVE
The solute carrier family 11 member 1 (SLC11A1) gene (formerly Nramp1) encodes for the protein solute carrier family 11, member 1. It affects susceptibility and clinical outcome of autoimmune and infectious diseases. We investigated the possible role of the functional polymorphism located in the promoter region of SLC11A1 and tumour necrosis factor (TNF) genes in the progression of fibrosis in chronic hepatitis C.
METHODS
A total of 242 Caucasian Spanish patients with biopsy proven chronic hepatitis C and 194 healthy control subjects were genotyped for SLC11A1 and TNF promoter polymorphisms.
RESULTS
No significant differences in the distribution of frequencies among patient and control groups were observed. The SCL11A1 homozygous 2/2 genotype was rarely detected among patients showing advanced fibrosis (2/82; 2.4%) but was highly represented in those with mild fibrosis (29/160; 18.1%; odds ratio (OR) 8.85 (95% confidence interval (CI) 1.9-55.2, p(c) = 0.002). In patients carrying allele 3 of SLC11A1, the presence of -238 TNF A/G was associated with advanced fibrosis (14/26 (53.8%) v 68/216 (31.4%); OR 2.53 (95% CI 1.03-6.23); p = 0.02).
CONCLUSIONS
SLC11A1 gene promoter polymorphism could influence fibrosis progression in chronic hepatitis C in that the homozygous genotype 2/2 exerts a protective effect against cirrhosis development. Also, the combination of TNF -238 A/G and the presence of allele 3 is conducive to progression to pre-cirrhotic or cirrhotic stages of the disease.
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Gut 53(3): 446-450

SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C

+3 authors
Hepatology Unit, Hospital Universitario de Valme, Sevilla, Spain
Immunology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain
Hepatology Section (Digestive Service), Hospital Universitario Virgen del Rocio, Sevilla, Spain
Pathology Unit, Hospital Universitario Virgen del Rocio, Sevilla, Spain
Pathology Unit, Hospital Universitario de Valme, Sevilla, Spain
Correspondence to:
Dr M Romero-Gómez
Hepatology Unit, Hospital Universitario de Valme, Ctra Cádiz s/n, 41014 Sevilla, Spain; se.elbacrepus@goremorm
Correspondence to:
Dr M Romero-Gómez
Hepatology Unit, Hospital Universitario de Valme, Ctra Cádiz s/n, 41014 Sevilla, Spain; se.elbacrepus@goremorm
Accepted 2003 Oct 20.

Abstract

Background and aims: The solute carrier family 11 member 1 (SLC11A1) gene (formerly Nramp1) encodes for the protein solute carrier family 11, member 1. It affects susceptibility and clinical outcome of autoimmune and infectious diseases. We investigated the possible role of the functional polymorphism located in the promoter region of SLC11A1 and tumour necrosis factor (TNF) genes in the progression of fibrosis in chronic hepatitis C.

Methods: A total of 242 Caucasian Spanish patients with biopsy proven chronic hepatitis C and 194 healthy control subjects were genotyped for SLC11A1 and TNF promoter polymorphisms.

Results: No significant differences in the distribution of frequencies among patient and control groups were observed. The SCL11A1 homozygous 2/2 genotype was rarely detected among patients showing advanced fibrosis (2/82; 2.4%) but was highly represented in those with mild fibrosis (29/160; 18.1%; odds ratio (OR) 8.85 (95% confidence interval (CI) 1.9–55.2, pc = 0.002). In patients carrying allele 3 of SLC11A1, the presence of −238 TNF A/G was associated with advanced fibrosis (14/26 (53.8%) v 68/216 (31.4%); OR 2.53 (95% CI 1.03–6.23); p = 0.02).

Conclusions: SLC11A1 gene promoter polymorphism could influence fibrosis progression in chronic hepatitis C in that the homozygous genotype 2/2 exerts a protective effect against cirrhosis development. Also, the combination of TNF −238 A/G and the presence of allele 3 is conducive to progression to pre-cirrhotic or cirrhotic stages of the disease.

Keywords: SCL11A1, host factors, hepatitis C, NRAMP1, cirrhosis, tumour necrosis factor polymorphisms, iron metabolism
Abstract

The pathogenesis of hepatitis C virus (HCV) induced hepatic injury remains unclear but the major role played by the immune response mechanism in the control of viral replication and persistence in HCV induced liver disease has been well documented.1 Recently, several studies seeking candidate genes that may be involved in hepatitis C have been conducted and the results indicate that genes coding for interleukin 10 (IL-10) or tumour growth factor β (TGF-β) are particularly involved in fibrosis progression in chronic hepatitis C.2,3 Solute carrier family 11 member 1 (SLC11A1) protein is located in the late endosomal compartment of resting macrophages, and is recruited to the phagosome by phagocytosis.4 Functional studies with murine SLC11A1 implicate its involvement in macrophage function, including upregulation of chemokine/cytokine genes such as tumour necrosis factor (TNF) and IL-1β, and induction of nitric oxide synthase (iNOS).5 These functions play an important role in the immune response against HCV infection. Several mutations resulting in polymorphic mRNA expression have been identified in the SLC11A1 gene.6 One of them, consisting of a variable number of tandem GT repeats, is located in the promoter region. Four alleles have been found in different populations: allele 1 (GT)5AC(GT)11G, allele 2 (GT)5AC(GT)10G, allele 3 (GT)5AC(GT)9G, and allele 4 (GT)9G (the subscript numbers refer to the number of repeats at the polymorphic site). Functional differences relating to these alleles have been described. For example, in the absence of external stimuli, alleles 1, 2, and 4 are poor promoters whereas allele 3 drives high expression.7 One hypothesis has been that the SLC11A1 protein is an iron transporter that becomes saturated at high circulating iron concentrations8,9 and hence, in circumstances of iron overload (which can occur in chronic hepatitis C infection), the result is fibrosis progression, a characteristic of the disease.10

TNF has been shown to be involved in the immune response to HCV infection and fibrosis progression.11 Conflicting results have been reported with respect to the association of two biallelic polymorphisms located in the promoter region of the TNF gene (at positions −238 TNF A/G and −308 TNF A/G) and cirrhosis development in chronic hepatitis C.3,12,13 Indeed, higher serum concentrations of liver TNF have been shown to impair responses to antiviral therapy.14

The aim of this study was to analyse the possible involvement of known polymorphisms in the promoter regions of the SLC11A1 and TNF genes in the progression of fibrosis in chronic hepatitis C infection.

Acknowledgments

This study was supported in part by grants from Fondo de Investigaciones Sanitarias (FIS 00/0566) and Plan Andaluz de Investigación (PAI, grupos CTS-913, CTS-197 and CTS-102) and a grant (16/01) from Junta de Andalucia and (G03/155) from the Spanish Ministry of Health.

Acknowledgments

Abbreviations

  • SLC11A1, solute carrier family 11 member 1

  • HCV, hepatitis C virus

  • TGF, tumour growth factor

  • IL, interleukin

  • NOS, nitric oxide synthase

  • TNF, tumour necrosis factor

  • HIV, human immunodeficiency virus

  • PCR, polymerase chain reaction

  • OR, odds ratio

  • F, fibrosis

  • AST, aspartate aminotransferase

  • ALT, alanine aminotransferase

  • AP, alkaline phosphatase

  • GGT, gamma glutamyl transpeptidase

Abbreviations

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