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Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection

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Abstract

Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation. Our aims were to determine the role of APOE regional polymorphisms on host lipids, IL28B genotype and disease severity in chronic HCV (CHC) patients. The study cohort included 732 CHC patients with available DNA for genotype determination of four polymorphisms in the chromosome 19 region that encompasses the TOMM40, APOE and APOC1 genes. Serum lipid analysis and apolipoproteins levels were measured using an immunoturbidimetric assay. APOE rs7412 polymorphism (capturing the ε2 isoform) was significantly associated with serum ApoE levels in both Caucasians and African-American patients (p = 2.3 × 10−11) and explained 7 % of variance in serum ApoE. Among IL28B-CC patients (n = 196), the rs429358 (defines ε4 isoform) and TOMM40 ‘523’ S polymorphisms were associated with 12 % of variance in ApoB levels. Patients homozygous for the APOE ε3 isoform had a greater than twofold increased odds of F2–F4 fibrosis (p = 1.8 × 10−5), independent of serum lipid and lipoprotein levels. There were no associations between APOE polymorphisms and serum HDL-C, APO-CIII and triglycerides. In CHC patients, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region.

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Authors and Affiliations

  1. Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Ornit Chiba-Falek, Colton Linnertz & Allen D. Roses

  2. Joseph and Kathleen Bryan Alzheimer’s Disease Research Center, Duke University, Durham, NC, 27705, USA

    Ornit Chiba-Falek & Allen D. Roses

  3. Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC, 27710, USA

    Ornit Chiba-Falek & Jeanette J. McCarthy

  4. Division of Endocrinology, Duke University Medical Center, Durham, NC, 27710, USA

    John Guyton

  5. GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA

    Stephen D. Gardner

  6. Zinfandel Pharmaceuticals, Chapel Hill, NC, USA

    Allen D. Roses

  7. Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC, 27710, USA

    Keyur Patel

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  1. Ornit Chiba-Falek
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  2. Colton Linnertz
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  3. John Guyton
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  4. Stephen D. Gardner
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  5. Allen D. Roses
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  6. Jeanette J. McCarthy
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  7. Keyur Patel
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Correspondence to Keyur Patel.

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Chiba-Falek, O., Linnertz, C., Guyton, J. et al. Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection. Hum Genet 131, 1911–1920 (2012). https://doi.org/10.1007/s00439-012-1220-0

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  • DOI: https://doi.org/10.1007/s00439-012-1220-0

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