Microsatellite polymorphism in the heme oxygenase-1 gene promoter is not associated with alcoholic liver disease severity

Authors

  • Anne Lemaire M.S.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Eric Trépo M.D., Ph.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Romy Ouziel M.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Thierry Gustot M.D., Ph.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Christophe Moreno M.D., Ph.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Delphine Degré M.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Charlotte Minsart M.S.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Eric Quertinmont,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Vincent Vercruysse,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Virginie De Wilde M.D., Ph.D.,

    1. Department of Hematology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Olivier Le Moine M.D., Ph.D.,

    1. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Jacques Devière M.D., Ph.D.,

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Marc Abramowicz M.D., Ph.D.,

    1. Department of Genetics, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. IRIBHM, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Alain Le Moine M.D., Ph.D.,

    1. Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Institute for Medical Immunology (IMI), Université Libre de Bruxelles (ULB), Gosselies, Belgium
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  • Arnaud Lemmers M.D., Ph.D.

    1. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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  • Potential conflict of interest: Nothing to report.

To the Editor:

Induction of heme oxygenase-1 (HO-1) was shown to prevent liver fibrosis[1] and ethanol-induced liver damage in mice.[2, 3] A functional microsatellite (GT)n repeat variant in the HO-1 promoter region is tightly correlated with inducibility of HO-1 protein expression, i.e., short (<26) (GT)n repeat carriers present increased HO-1-expression-derived antiinflammatory and cytoprotective effects.[4] As opposed to cardiac or pulmonary disease, HO-1 gene polymorphisms in human liver disease have been largely unexplored.

We tested the genetic association between the HO-1 promoter (GT)n repeat variant and the presence and severity of alcoholic liver disease (ALD). To this end, we genotyped 487 biopsy-proven ALD Caucasian patients (383 with cirrhosis and 193 with alcoholic hepatitis [AH]; 69% male, median age 54.4 [range, 27-84] years) and 203 healthy Caucasian controls. Analysis of allelic frequency distribution disclosed two peaks at 23 and 30 (GT)n repeats in controls and in ALD patients. The distribution of homozygote long (>29) (GT)n profiles (LL) in controls was no different from that of cirrhosis patients or patients with AH (Table 1). The LL genotype proportion was not significantly higher in patients with alcoholic cirrhosis and AH than in those without AH. Moreover, the length of the (GT)n repeat variant was not correlated with Model for Endstage Liver Disease (MELD) or Child-Pugh scores, nor with the Maddrey score for patients with AH. Populations were in Hardy-Weinberg equilibrium and the size of the cohort corresponded to a power of 82.3%, in light of the 12% allelic frequency difference observed in other diseases.[5] Our cohort had been previously validated for another genetic polymorphism association study (rs738409 C>G PNPLA3/adiponutrin, demonstrated to be associated with increased risk of ALD and alcoholic cirrhosis).[6]

Table 1. Analysis of the Association Between the (GT)n Repeat Variants of the HO-1 Promoter and ALD
 ALD
ControlsCirrhosisAH
OR (CI 95%)
Homozygote LL10.880.77
 (0.60-1.29)a(0.49-1.21)a
 AH 
 Cirrhosis without AHCirrhosis with AH 
  1. a

    P > 0.05. LL, (GT)n repeat homozygote long (>29 repeat); ALD, alcoholic liver disease; AH, alcoholic hepatitis; CI, confidence interval; OR, odds ratio.

Homozygote LL10.76 
  (0.74-1.24)a 

In a representative European Caucasian cohort of ALD patients, microsatellite (GT)n repeat variant polymorphism in the promoter of the HO-1 gene was not associated with the presence of the disease or its severity. However, despite these negative results, the HO-1 pathway plays a major role in inflammatory and fibrosis control in rodents and constitutes an interesting target for new treatments of ALDs.

  • Anne Lemaire, M.S.1

  • Eric Trépo, M.D., Ph.D.1,2

  • Romy Ouziel, M.D.1,2

  • Thierry Gustot, M.D., Ph.D.1,2

  • Christophe Moreno, M.D., Ph.D.1,2

  • Delphine Degré, M.D.1,2

  • Charlotte Minsart, M.S.1

  • Eric Quertinmont1

  • Vincent Vercruysse1

  • Virginie De Wilde, M.D., Ph.D.3

  • Olivier Le Moine, M.D., Ph.D.2

  • Jacques Devière, M.D., Ph.D.1,2

  • Marc Abramowicz, M.D., Ph.D.4,5

  • Alain Le Moine, M.D., Ph.D.6,7

  • Arnaud Lemmers M.D., Ph.D.1,2

  • 1Laboratory of Experimental GastroenterologyUniversité Libre de Bruxelles (ULB), Brussels, Belgium

  • 2Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital

  • Université Libre de Bruxelles (ULB), Brussels, Belgium

  • 3Department of Hematology, Erasme HospitalUniversité Libre de Bruxelles (ULB), Brussels, Belgium

  • 4Department of Genetics, Erasme Hospital

  • Université Libre de Bruxelles (ULB), Brussels, Belgium

  • 5IRIBHM

  • Université Libre de Bruxelles (ULB), Brussels, Belgium

  • 6Department of Nephrology, Erasme Hospital

  • Université Libre de Bruxelles (ULB), Brussels, Belgium

  • 7Institute for Medical Immunology (IMI)

  • Université Libre de Bruxelles (ULB), Gosselies, Belgium

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