Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin DReceptor (NR 1I1) variants on fibrosis progression rate in HCV patients

Authors

  • Katharina Baur,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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    • These authors contributed equally to the study.
  • Joachim C. Mertens,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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    • These authors contributed equally to the study.
  • Johannes Schmitt,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Rika Iwata,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Bruno Stieger,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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  • Jyrki J. Eloranta,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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  • Pascal Frei,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Felix Stickel,

    1. Institute of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland
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  • Michael T. Dill,

    1. Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
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  • Burkhardt Seifert,

    1. Division of Biostatistics, Institute of Social und Preventive Medicine, University of Zurich, Zurich, Switzerland
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  • Heike A. Bischoff Ferrari,

    1. Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
    2. Department of Rheumatology, University of Zurich, Zurich, Switzerland
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  • Arnold von Eckardstein,

    1. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
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  • Pierre-Yves Bochud,

    1. Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland
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  • Beat Müllhaupt,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
    2. Swiss Hepatopancreatobiliary (HPB)-Centre, University Hospital Zurich, Zurich, Switzerland
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  • Andreas Geier,

    Corresponding author
    1. Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
    2. Swiss Hepatopancreatobiliary (HPB)-Centre, University Hospital Zurich, Zurich, Switzerland
    • Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • the Swiss Hepatitis C Cohort Study Group


Correspondence

Andreas Geier, MD,

Department of Gastroenterology & Hepatology,

University Hospital Zurich, Rämistrasse 100,

CH-8091 Zurich, Switzerland

Tel: ++41 44 255 22 59

Fax: ++41 44 255 4503

e-mail: andreas.geier@usz.ch

Abstract

Background

Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date.

Aims

To analyse combined effects of 25-OH vitamin D plasma levels and vitamin D receptor gene (VDR;NR1I1) polymorphisms on fibrosis progression rate in HCV patients.

Methods

251 HCV patients underwent VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 A and TaqI rs731236 A). Plasma 25-OH vitamin D levels were quantified in a subgroup of 97 patients without advanced fibrosis. The VDR haplotype and genotypes as well as plasma 25-OH vitamin D levels were associated with fibrosis progression.

Results

The bAt[CCA]-haplotype was significantly associated with fibrosis progression >0.101 U/year (P = 0.007; OR = 2.02) and with cirrhosis (P = 0.022; OR = 1.84). Forty-five percent of bAt[CCA]-haplotype patients were rapid fibrosers, 21.1% were cirrhotic. Likewise, ApaI rs7975232 CC genotype was significantly associated with fibrosis progression and cirrhosis. Lower plasma 25-OH vitamin D levels were significantly associated with fibrosis progression >0.101 U/year in F0–2 patients (P = 0.013). Combined analysis of both variables revealed a highly significant additive effect on fibrosis progression with 45.5% rapid fibrosers for bAt[CCA]-haplotype and 25-OH vitamin D < 20 μg/L compared with only 9.1% for the most favourable combination (P = 0.006). In multivariate analysis, the bAt-haplotype was an independent risk factor for fibrosis progression (P = 0.001; OR = 2.83).

Conclusion

Low 25-OH vitamin D plasma levels and the unfavourable VDR bAt[CCA]-haplotype are associated with rapid fibrosis progression in chronic HCV patients. In combination, both variables exert significant additive effects on fibrosis progression.

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