title: APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis.
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.
  
  
  CONCLUSIONS
  In a dyslipemic population, genetic variants of APOA5 modulate lipoprotein subclass distributions, inducing an atherogenic profile associated with IMT defined subclinical atherosclerosis.
authors.affiliation: 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.
authors.forename: Montse
authors.initials: M
authors.lastname: Guardiola
authors.affiliation: 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.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cofán
authors.affiliation: Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: de Castro-Oros
authors.affiliation: Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cenarro
authors.affiliation: 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.
authors.forename: Núria
authors.initials: N
authors.lastname: Plana
authors.affiliation: Centre of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: 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.
authors.forename: Lluís
authors.initials: L
authors.lastname: Masana
authors.affiliation: 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.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.affiliation: Hospital Universitario Miguel Servet, Instituto Investigación Sanitaria de Aragón, Zaragoza, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.affiliation: 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. Electronic address: josep.ribalta@urv.cat.
authors.forename: Josep
authors.initials: J
authors.lastname: Ribalta
mesh_terms: D000328:Adult; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics*; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D015897:Comorbidity; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000175:diagnosis / Q000453:epidemiology; D010641:Phenotype; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D014280:Triglycerides / Q000097:blood; D055105:Waist Circumference; D055815:Young Adult
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D015415:Biomarkers; D008077:Lipoproteins, LDL; D014280:Triglycerides
keywords: APOA5; Atherogenic dyslipidemia; IMT; NMR; Polymorphisms