567 A functional polymorphism in the glutathione-S-transferase P1 gene determines the progression to cirrhosis in patients with hereditary hemochromatosis

Stickel, Felix; Oesterreicher, C.; Ferenci, Péter; Datz, C.; Distler, J.; Wrba, Fritz; Hellerbrand, Claus; Schuppan, Detlef

doi:10.1016/s0168-8278(04)90567-3

Cited by 2 publications

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“…Interestingly, the isoenzyme GSTP1 is expressed in biliary epithelial cells and HSCs, and polymorphic variation at base pair 313 (A→G) within the coding region leads to an amino acid substitution (Ile→Val) at codon 105 and threefold decreased capability of GSTP1 to detoxify 4-hydroxynonenal, a highly reactive lipid peroxide promoting fibrogenesis 42. Genotype GSTP1 Val/Val is associated with cirrhosis development in hereditary haemochromatosis, a disease in which oxidative stress is the crucial pathogenic trigger 43. However, the findings of >10 case–control studies investigating GST SNPs in patients with ALD from different ethnicities have remained inconsistent and all positive findings in ‘index studies’ were later challenged by negative results in independent cohorts 26 44…”

Section: The Search For Genetic Risk Factors Of Aldmentioning

confidence: 99%

Genetic determinants of alcoholic liver disease

Stickel

Hampe

2011

Gut

124

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Alcoholic liver disease (ALD) accounts for the majority of chronic liver disease in Western countries. The spectrum of ALD includes steatosis with or without fibrosis in virtually all individuals with an alcohol consumption of >80 g/day, alcoholic steatohepatitis of variable severity in 10-35% and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, there is an annual risk for hepatocellular carcinoma of 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet composition and comedication may modify the natural course of ALD. Twin studies have revealed a substantial contribution of genetic factors to the evolution of ALD, as demonstrated by a threefold higher disease concordance between monozygotic twins and dizygotic twins. With genotyping becoming widely available, a large number of genetic case-control studies evaluating candidate gene variants coding for proteins involved in the degradation of alcohol, mediating antioxidant defence, the evolution and counteraction of necroinflammation and formation and degradation of extracellular matrix have been published with largely unconfirmed, impeached or even disproved associations. Recently, whole genome analyses of large numbers of genetic variants in several chronic liver diseases including gallstone disease, primary sclerosing cholangitis and non-alcoholic fatty liver disease (NAFLD) have identified novel yet unconsidered candidate genes. Regarding the latter, a sequence variation within the gene coding for patatin-like phospholipase encoding 3 (PNPLA3, rs738409) was found to modulate steatosis, necroinflammation and fibrosis in NAFLD. Subsequently, the same variant was repeatedly confirmed as the first robust genetic risk factor for progressive ALD.

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Section: The Search For Genetic Risk Factors Of Aldmentioning

confidence: 99%

Genetic determinants of alcoholic liver disease

Stickel

Hampe

2011

Gut

124

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“…The isoenzyme GSTP1 is expressed in biliary epithelial and pancreatic stellate cells, and its gene reveals a polymorphism which leads to an amino acid substitution (Ile/Val) at codon 105 resulting in a 3-fold decreased capability of GSTP1 to detoxify 1-chloro-2,4-dinitrobenzene (13) and to deactivate 4-hydroxynonenal, a highly reactive product of lipid peroxidation (14). We have recently identified genotype GSTP1 Val/Val as a genetic risk factor for the development of liver cirrhosis in patients with hereditary hemochromatosis, a disease in which oxidative stress is the pivotal trigger of tissue injury (15).…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis

et al. 2007

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Chronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be due to yet unidentified genetic factors. Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione-S-transferase P1 (GSTP1) and manganese-superoxide dismutase (MnSOD) reveal functional polymorphisms that affect the antioxidative capacity and may therefore modulate the development of chronic pancreatitis and long-term complications like endocrine and exocrine pancreatic insufficiency. Two functional polymorphisms of the MnSOD and the GSTP1 gene were assessed by polymerase chain reaction and restriction fragment length polymorphism in 165 patients with chronic alcoholic pancreatitis, 140 alcoholics without evidence of pancreatic disease and 160 healthy control subjects. The distribution of GSTP1 and MnSOD genotypes were in Hardy-Weinberg equilibrium in the total cohort. Genotype and allele frequencies for both genes were not statistically different between the three groups. Although genotype MnSOD Ala/Val was seemingly associated with the presence of exocrine pancreatic insufficiency, this subgroup was too small and the association statistically underpowered. None of the tested genotypes affected the development of endocrine pancreatic insufficiency. Polymorphisms of MnSOD and GSTP1 are not associated with chronic alcoholic pancreatitis. The present data emphasize the need for stringently designed candidate gene association studies with well-characterized cases and controls and sufficient statistical power to exclude chance observations.

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567 A functional polymorphism in the glutathione-S-transferase P1 gene determines the progression to cirrhosis in patients with hereditary hemochromatosis

Cited by 2 publications

References 0 publications

Genetic determinants of alcoholic liver disease

Genetic determinants of alcoholic liver disease

Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis

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