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APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis

  • Montse Guardiola
    Affiliations
    Unitat de Recerca en Lípids i Arteriosclerosi, Hospital Universitari Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

    CIBER Diabetes y Enfermedades Metabólicas (CIBERdem), Instituto de Salud Carlos III (ISCIII), Spain
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  • Montserrat Cofán
    Affiliations
    Lípid Clinic, Endocrinology & Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, Barcelona, Spain

    CIBER Fisioptaologia de la Obesidad y Nutrición (CIBERobn), ISCIII, Spain
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  • Isabel de Castro-Oros
    Affiliations
    Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain
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  • Ana Cenarro
    Affiliations
    Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain
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  • Núria Plana
    Affiliations
    Unitat de Recerca en Lípids i Arteriosclerosi, Hospital Universitari Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

    CIBER Diabetes y Enfermedades Metabólicas (CIBERdem), Instituto de Salud Carlos III (ISCIII), Spain
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  • Philippa J. Talmud
    Affiliations
    Centre of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom
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  • Lluís Masana
    Affiliations
    Unitat de Recerca en Lípids i Arteriosclerosi, Hospital Universitari Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

    CIBER Diabetes y Enfermedades Metabólicas (CIBERdem), Instituto de Salud Carlos III (ISCIII), Spain
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  • Emilio Ros
    Affiliations
    Lípid Clinic, Endocrinology & Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, Barcelona, Spain

    CIBER Fisioptaologia de la Obesidad y Nutrición (CIBERobn), ISCIII, Spain
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  • Fernando Civeira
    Affiliations
    Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain
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  • Josep Ribalta
    Correspondence
    Corresponding author. Unitat de Recerca en Lípids i Arteriosclerosi, Hospital Universitari Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, Sant Llorenç 21, 43201 Reus, Spain.
    Affiliations
    Unitat de Recerca en Lípids i Arteriosclerosi, Hospital Universitari Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

    CIBER Diabetes y Enfermedades Metabólicas (CIBERdem), Instituto de Salud Carlos III (ISCIII), Spain
    Search for articles by this author

      Highlights

      • APOA5 variants predispose to higher TG concentrations and modulate lipoprotein subclass distributions.
      • The atherogenic profile is associated with increased subclinical atherosclerosis.
      • The associations are exacerbated in overweight or patients with large waist circumference (≥90 cm in men and ≥85 cm in women).

      Abstract

      Background

      Triglycerides (TG) are the initiators of the metabolic changes leading to the atherogenic dyslipidemia, which is a major inducer of atherosclerosis as a result of quantitative and qualitative changes in lipoprotein subclass distributions. We hypothesized that variation at the of APOA5 gene locus, encoding apoAV, a key regulator of TG levels, significantly affect lipoprotein subclass distributions toward a more atherogenic pattern in both hyperTG patients and dyslipemic patients.

      Methods

      We recruited four hundred and twenty-two subjects attending a Lipid Clinic, prior to lipid-lowering treatment. We genotyped two APOA5 variants, rs662799 (-1131T>C) and rs3135506 (S19W). Circulating lipoproteins were determined by nuclear magnetic resonance (NMR). Intima-media thickness (IMT) was evaluated using B-mode ultrasound.

      Results

      Carriers of the rare alleles of rs662799 and rs3135506 compared to common allele homozygotes, had a significantly proatherogenic profile of the VLDL and LDL subclasses, resulting in increased concentrations of the proatherogenic subclasses, large VLDLs (+133%, p < 0.001) and small LDLs (+34%, p = 0.014). Significant changes in smaller HDL (+71%, p = 0.032), as well as an 18% decrease in large HDL (p = 0.046), were also been observed. This atherogenic NMR subclass distribution was significantly associated with increased carotid IMT.
      The observed effects were significantly stronger in patients with a BMI ≥ 25 kg/m2 and in male and female patients with a waist circumference ≥90 cm or ≥85 cm, respectively.

      Conclusion

      In a dyslipemic population, genetic variants of APOA5 modulate lipoprotein subclass distributions, inducing an atherogenic profile associated with IMT defined subclinical atherosclerosis.

      Keywords

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