Triglycerides, hypertension, and smoking predict cardiovascular disease in dysbetalipoproteinemia

  • Martine Paquette
    Lipids, Nutrition and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Québec, Canada
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  • Sophie Bernard
    Lipids, Nutrition and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Québec, Canada

    Division of Endocrinology, Department of Medicine, Université de Montreal, Québec, Canada
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  • Guillaume Paré
    Genetic Molecular Epidemiology Lab, Population Health Research Institute, Ontario, Canada
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  • Alexis Baass
    Corresponding author. Alexis Baass, Lipids, Nutrition and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, 110 avenue des Pins Ouest, Montreal, Québec H2W 1R7, Canada.
    Lipids, Nutrition and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Québec, Canada

    Divisions of Experimental Medicine and Medical Biochemistry, Department of Medicine, McGill University, Québec, Canada
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Published:December 24, 2019DOI:


      • Dysbetalipoproteinemia (DBL) is a rare autosomal recessive lipid disorder.
      • DBL is associated with an increased cardiovascular disease (CVD) risk.
      • Triglycerides, hypertension, and smoking are independent predictors of CVD in DBL.


      Dysbetalipoproteinemia (DBL) is an autosomal recessive lipid disorder associated with a reduced clearance of remnant lipoproteins and is associated with an increased cardiovascular disease (CVD) risk. The genetic cause of DBL is apoE2 homozygosity in 90% of cases. However, a second metabolic hit must be present to precipitate the disease. However, no study has investigated the predictors of CVD, peripheral artery disease and coronary artery disease in a large cohort of patients with DBL.


      The objectives of this study were to describe the clinical characteristics of a DBL cohort and to identify the predictors of CVD, peripheral artery disease, and coronary artery disease in this population.


      The inclusion criteria included age ≥ 18 years, apoE2/E2, triglycerides (TG) > 135 mg/dL and VLDL-C/plasma TG ratio > 0.30.


      We studied 221 adult DBL patients, of which 51 (23%) had a history of CVD. We identified 3 independent predictors of CVD, namely hypertension (OR 5.68, 95% CI 2.13–15.16, P = .001), pack year of smoking (OR 1.03, 95% CI 1.01–1.05, P = .01) and TG tertile (OR 1.82, 95% CI 1.09–3.05, P = .02). The CVD prevalence was 51% in patients with hypertension and 18% in those without hypertension (P = .00001), and 30% in the highest TG tertile vs 15% in the lowest tertile (P = .04). Similarly, the CVD prevalence was higher in heavy smokers compared with nonsmokers (36% vs 13%, P = .006).


      Hypertension, smoking, and TG are independently associated with CVD risk in patients with DBL. Aggressive treatment should be initiated in patients with DBL because of the increased risk of CVD.


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        • Koopal C.
        • Marais A.D.
        • Visseren F.L.
        Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder.
        Curr Opin Endocrinol Diabetes Obes. 2017; 24: 133-139
        • Blum C.B.
        Type III Hyperlipoproteinemia: still worth considering?.
        Prog Cardiovasc Dis. 2016; 59: 119-124
        • Genest J.
        Lipoprotein disorders and cardiovascular risk.
        J Inherit Metab Dis. 2003; 26: 267-287
        • Smelt A.H.
        • de Beer F.
        Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects.
        Semin Vasc Med. 2004; 4: 249-257
        • Morise A.P.
        • Hegele R.A.
        Atypical familial dysbetalipoproteinemia associated with high polygenic cholesterol and triglyceride scores treated with ezetimibe and evolocumab.
        J Clin Lipidol. 2019; 13: 411-414
        • Mahley R.W.
        • Rall Jr., S.C.
        Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.
        in: Scriver C.R. Beaudet A.L. Sly W.S. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, NY2001: 2835-2862
        • Rall Jr., S.C.
        • Weisgraber K.H.
        • Innerarity T.L.
        • Mahley R.W.
        Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects.
        Proc Natl Acad Sci U S A. 1982; 79: 4696-4700
        • Morganroth J.
        • Levy R.I.
        • Fredrickson D.S.
        The biochemical, clinical, and genetic features of type III hyperlipoproteinemia.
        Ann Intern Med. 1975; 82: 158-174
        • Henneman P.
        • van der Sman-de Beer F.
        • Moghaddam P.H.
        • et al.
        The expression of type III hyperlipoproteinemia: involvement of lipolysis genes.
        Eur J Hum Genet. 2009; 17: 620-628
        • Fredrickson D.S.
        • Morganroth J.
        • Levy R.I.
        Type III hyperlipoproteinemia: an analysis of two contemporary definitions.
        Ann Intern Med. 1975; 82: 150-157
        • Hopkins P.N.
        • Brinton E.A.
        • Nanjee M.N.
        Hyperlipoproteinemia type 3: the forgotten phenotype.
        Curr Atheroscler Rep. 2014; 16: 440
        • Sniderman A.
        • Tremblay A.
        • Bergeron J.
        • Gagné C.
        • Couture P.
        Diagnosis of type III hyperlipoproteinemia from plasma total cholesterol, triglyceride, and apolipoprotein B.
        J Clin Lipidol. 2007; 1: 256-263
        • Civeira F.
        • Cenarro A.
        • Ferrando J.
        • et al.
        Comparison of the hypolipidemic effect of gemfibrozil versus simvastatin in patients with type III hyperlipoproteinemia.
        Am Heart J. 1999; 138: 156-162
        • Jones P.H.
        • Davidson M.H.
        Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin.
        Am J Cardiol. 2005; 95: 120-122
        • Kei A.
        • Miltiadous G.
        • Bairaktari E.
        • Hadjivassiliou M.
        • Cariolou M.
        • Elisaf M.
        Dysbetalipoproteinemia: two cases report and a diagnostic algorithm.
        World J Clin Cases. 2015; 3: 371-376
        • Hopkins P.N.
        • Wu L.L.
        • Hunt S.C.
        • Brinton E.A.
        Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease.
        J Am Coll Cardiol. 2005; 45: 1003-1012
        • Koopal C.
        • Retterstøl K.
        • Sjouke B.
        • et al.
        Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: a European cross-sectional study.
        Atherosclerosis. 2015; 240: 90-97
        • de Beer F.
        • Stalenhoef A.F.
        • Hoogerbrugge N.
        • et al.
        Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158--> Cys) homozygotes is associated with hyperinsulinemia.
        Arterioscler Thromb Vasc Biol. 2002; 22: 294-299
        • Selvin E.
        • Erlinger T.P.
        Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.
        Circulation. 2004; 110: 738-743
        • Koopal C.
        • Geerlings M.I.
        • Muller M.
        • et al.
        The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease.
        Atherosclerosis. 2016; 246: 187-192
        • Sniderman A.D.
        Type III Hyperlipoproteinemia: the forgotten, disregarded, neglected, overlooked, ignored but highly atherogenic, and highly treatable dyslipoproteinemia.
        Clin Chem. 2018; 65: 225-227
        • Bouthillier D.
        • Sing C.F.
        • Davignon J.
        Apolipoprotein E phenotyping with a single gel method: application to the study of informative matings.
        J Lipid Res. 1983; 24: 1060-1069
        • Hixson J.E.
        • Vernier D.T.
        Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
        J Lipid Res. 1990; 31: 545-548
        • Bernelot Moens S.J.
        • Verweij S.L.
        • Schnitzler J.G.
        • et al.
        Remnant cholesterol elicits arterial wall inflammation and a multilevel cellular immune response in humans.
        Arterioscler Thromb Vasc Biol. 2017; 37: 969-975
        • Varbo A.
        • Benn M.
        • Nordestgaard B.G.
        Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
        Pharmacol Ther. 2014; 141: 358-367
        • Sniderman A.D.
        • de Graaf J.
        • Thanassoulis G.
        • Tremblay A.J.
        • Martin S.S.
        • Couture P.
        The spectrum of type III hyperlipoproteinemia.
        J Clin Lipidol. 2018; 12: 1383-1389
        • Davignon J.
        • Dufour R.
        Primary Hyperlipidemias: An Atlas of Investigation and Diagnosis.
        Clinical Publishing, Oxford, UK2007: 156
        • Feussner G.
        • Wagner A.
        • Ziegler R.
        Relation of cardiovascular risk factors to atherosclerosis in type III hyperlipoproteinemia.
        Hum Genet. 1993; 92: 122-126
        • Stein E.A.
        • Raal F.J.
        Targeting LDL: is lower better and is it safe?.
        Best Pract Res Clin Endocrinol Metab. 2014; 28: 309-324
        • Schaefer J.R.
        Unraveling hyperlipidemia type III (dysbetalipoproteinemia), slowly.
        Eur J Hum Genet. 2009; 17: 541-542