Lipoprotein(a): relation to other risk factors and genetic heritability. Results from a Dutch parent-twin study

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      We measured plasma levels of lipoprotein(a) (Lp(a)) in a sample of 152 Dutch adolescent mono- and dizygotic twin pairs and their parents. The distribution of Lp(a) levels was skewed, with the highest frequencies at low levels and was similar for adult men and women and their children. The relationship of Lp(a) concentrations with other lipoprotein and apolipoprotein risk factors for coronary heart disease and with lathosterol, an indicator of whole-body cholesterol synthesis, was studied dependent on sex and generation. In mothers and children there was a small positive correlation between Lp(a) levels and plasma cholesterol and apolipoprotein (apo) B. In mothers and daughters there also was a correlation between Lp(a)and LDL cholesterol levels. No correlation was found between Lp(a) levels and plasma lathosterol, suggesting that there is no relationship between Lp(a) levels and cholesterol synthesis. Associations among family members, i.e. between monozygotic and dizygotic twins and between parents and offspring were used to study familial transmission of Lp(a) levels. Results showed that almost all of the variance in Lp(a) concentrations was accounted for by genetic heritability. A small, but significant, sex difference in heritability was observed, but heritabilities were the same in parents and offspring. Heritability estimates were 93% for females and 98% for males. No evidence was found for assortative mating or for the influence of a shared family environment. These results indicate that nearly all variance in Lp(a) concentrations that is not accounted for by the apo(a) size polymorphism, is also under genetic control.


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        • Berg K.
        A new serum type system in man — the Lp system.
        Acta Pathol. Microbiol. Immunol. Scand. 1963; 59: 369
        • Utermann G.
        The mysteries of lipoprotein(a).
        Science. 1989; 246: 904
        • Utermann G.
        Lipoprotein(a): A genetic risk factor for premature coronary heart disease.
        Nutr. Metab. Cardiovasc. Dis. 1991; 1: 7
        • Dahlen G.H.
        • Guyton J.R.
        • Attar M.
        • Farmer J.A.
        • Krautz J.A.
        • Gotto A.M.
        Association of levels of lipoprotein Lp(a), plasma lipids and other lipoproteins with coronary artery disease documented by angiography.
        Circulation. 1986; 74: 758
        • Murai A.
        • Miyahara T.
        • Fujimoto N.
        • Matsuda N.
        • Kameyama M.
        Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction.
        Atherosclerosis. 1986; 59: 199
        • Rhoads G.G.
        • Dahlen G.H.
        • Berg K.
        • Morton N.E.
        • Danneberg A.L.
        Lp(a) lipoprotein as a risk factor for myocardial infarction.
        J. Am. Med. Assoc. 1986; 256: 2540
        • Armstrong V.W.
        • Cremer P.
        • Eberle E.
        • Manke A.
        • Schulze F.
        • Wieland H.
        • Kreuzer H.
        • Seidel D.
        The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis, Dependence on serum LDL levels.
        Atherosclerosis. 1986; 62: 249
        • Utermann G.
        • Hoppichler F.
        • Dieplinger H.
        • Seed M.
        • Thompson G.
        • Boerwinkle E.
        Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis.
        in: Proc. Natl. Acad. Sci. USA. 86. 1989: 4171
        • Krempler F.
        • Kostner G.M.
        • Bolzano K.
        • Sandhofer F.
        Turnover of lipoprotein(a) in man.
        J. Clin. Invest. 1980; 65: 1483
        • Bjorkhem I.
        • Miettinen T.A.
        • Riehner E.
        • Ewerth S.
        • Angelin B.
        • Einarsson K.
        Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver.
        J. Lipid Res. 1987; 28: 1137
        • Kempen H.J.M.
        • Glatz J.F.
        • Gevers Leuven J.A.
        • Van der Voort H.A.
        • Katan M.B.
        Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans.
        J. Lipid Res. 1988; 29: 1149
        • Sandholzer C.
        • Hallman D.M.
        • Saha N.
        • Sirgurdsson G.
        • Lackner C.
        • Csaszar A.
        • Boerwinkle E.
        • Utermann G.
        Effects of the apolipoprotein(a) size polymor phism on the lipoprotein(a) concentration in 7 ethnic groups.
        Human Genet. 1991; 86: 607
        • Boerwinkle E.
        • Menzel H.J.
        • Kraft H.G.
        • Utermann G.
        Genetics of the quantitative Lp(a) lipoprotein trait III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation.
        Human Genet. 1989; 82: 73
        • Utermann G.
        • Duba C.
        • Menzel H.J.
        Genetics of the quantitative Lp(a) lipoprotein trait II. Inheritance of Lp(a) glycoprotein phenotypes.
        Human Genet. 1988; 78: 47
        • Gaubatz J.W.
        • Ghanem K.I.
        • Guevara J.J.
        • Nava M.L.
        • Patsch W.
        • Morrisett J.D.
        Polymorphic forms of human apolipoprotein[a]: inheritance and relationship of their molecular weights to plasma levels of lipoprotein[a].
        J. Lipid Res. 1990; 31: 603
        • Lackner C.
        • Boerwinkle E.
        • Leffert C.C.
        • Rahmig T.
        • Hobbs H.H.
        Molecular basis of apolipoprotein(a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis.
        J. Clin. Invest. 1991; 87: 2153
        • Kamboh M.I.
        • Ferrell R.E.
        • Kottke B.A.
        Expressed hypervariable polymorphism of apolipoprotein(a).
        Am. J. Human Genet. 1991; 49: 1063
        • Jeffreys A.J.
        • Wilson V.
        • Thein S.L.
        Hypervariable “minisatellite” regions in human DNA.
        Nature. 1985; 314: 67
        • Lopes-Virella M.F.
        • Stone P.
        • Ellis S.
        • Calwell J.A.
        Cholesterol determination in high density lipoproteins separated by three different methods.
        Clin. Chem. 1977; 23: 882
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499
        • Rifai N.
        • Warnick G.R.
        • McNamara J.R.
        • Belcher J.D.
        • Grinstead G.F.
        • Frantz I.D.
        Measurement of lowdensity-lipoprotein cholesterol in serum: a status report.
        Clin. Chem. 1992; 38: 150
        • Sandkamp M.
        • Funke H.
        • Schulte H.
        • Köhler E.
        • Assman G.
        Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age.
        Clin. Chem. 1990; 36: 20
        • Kempen H.J.M.
        • de Knijff P.
        • Boomsma D.I.
        • Van der Voort H.A.
        • Gevers Leuven J.A.
        • Havekes L.
        Plasma levels of lathosterol and phytosterols in relation to age, sex, anthropometric parameters, plasma lipids and apolipoprotein E phenotype in 160 Dutch families.
        Metabolism. 1990; 40: 609
        • Albers J.J.
        • Wahl P.W.
        • Cabana V.G.
        • Hazzard W.R.
        • Hoover J.J.
        Quantitation of apolipoprotein A-I of human plasma high density lipoprotein.
        Metabolism. 1976; 25: 633
        • Havekes L.
        • Hemmink J.
        • De Wit E.
        Low-densitylipoprotein apoprotein B in plasma as measured by radial immunodiffusion and rocket immunoelectrophoresis.
        Clin. Chem. 1981; 27: 1829
        • Kaptein A.
        • Roodenburg L.
        • Princen H.M.G.
        Butyrate stimulates the secretion of apolipoprotein A-I and apolipoprotein B100 by the human hepatoma cell line Hep G2. Induction of apo A-I mRNA with no change of apo B100 mRNA.
        Biochem. J. 1991; 278: 557
        • Bos E.S.
        • Van der Doelen A.A.
        • Van Rooij N.
        • Schuurs A.H.W.M.
        3,3′,5,5′-Tetramethylbenzidine as an ames test negative chromogen for horse radish perox idase in enzyme immunoassay.
        J. Immunoassay. 1981; 2: 187
        • Redgrave T.G.
        • Roberts D.C.K.
        • West C.E.
        Separation of plasma lipoproteins by density-gradient ultracentrifugation.
        Anal. Biochem. 1975; 65: 42
        • Labeur C.
        • Michiels G.
        • Bury J.
        • Usher D.C.
        • Rosseneu M.
        Lipoprotein(a) quantified by an enzymelinked immunosorbent assay with monoclonal antibodies.
        Clin. Chem. 1989; 35: 1380
        • Neale M.C.
        • Cardon L.R.
        Methodology for Genetic Studies of Twins and Families.
        Kluwer Academic Publishers B.V, Dordrecht, The Netherlands1992
        • Jöreskog K.G.
        • Sörbom D.
        LISREL VII A Guide to the Program and Applications.
        Spss Inc, Chicago1988
        • Duffy D.L.
        • Martin N.G.
        • Battistutta D.
        • Hopper J.L.
        • Matthews J.D.
        Genetics of asthma and hay fever in Australian twins.
        Am. Rev. Respir. Dis. 1990; 142: 1351
        • Eaves L.J.
        • Last K.A.
        • Young P.A.
        • Martin N.G.
        Model fitting approaches to the analysis of human behavior.
        Heredity. 1978; 41: 249
        • Boomsma D.I.
        • Bree M.B.
        • van den Orlebeke J.F.
        • Molenaar P.C.M.
        Resemblances of parents and twins in sport participation and heart rate.
        Behav. Genet. 1989; : 123
        • Guyton J.R.
        • Dahlen G.H.
        • Patsch W.
        • Kautz J.A.
        • Gotto A.M.
        Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B.
        Arteriosclerosis. 1985; 5: 265
        • Parra H.J.
        • Luyeye I.
        • Bouramoue C.
        • Demarquilly C.
        • Fruchart J.C.
        Black-white differences in serum Lp(a) lipoprotein levels.
        Clin. Chim. Acta. 1987; 168: 27
        • Rath M.
        • Niendorf A.
        • Reblin T.
        • Dietel M.
        • Krebber H.J.
        • Beisiegel U.
        Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.
        Arteriosclerosis. 1989; 9: 579
        • Alessi M.C.
        • Parra H.J.
        • Joly P.
        • Vu-Dac N.
        • Bard J.M.
        • Fruchart J.C.
        • Juhan-Vangue I.
        The increased plasma Lp(a):B lipoprotein particle concentration in angina pectoris is not associated with hypofibrinolysis.
        Clin. Chim. Acta. 1990; 188: 119
        • Kostner G.M.
        • Gries A.
        • Pometta M.
        • Molinari E.
        • Pichler P.
        • Aicher H.
        Immunochemical determination of lipoprotein Lp(a): comparison of Laurell electrophoresis and ELISA.
        Clin. Chim. Acta. 1990; 188: 187
        • Goh E.H.
        • Heimberg M.
        Relationship between activity of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase and secretion of very low-density-lipoprotein cholesterol by the isolated perfused liver and in the intact rat.
        Biochem. J. 1979; 184: 1
        • Kahn B.
        • Wilcox H.G.
        • Heimberg M.
        Cholesterol is required for secretion of very-low-density lipoprotein by rat liver.
        Biochem. J. 1989; 259: 807
        • Arad Y.
        • Ramakrishnan R.
        • Ginsberg H.N.
        Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia by reduc ing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production.
        J. Lipid Res. 1990; 31: 567
        • Thiery J.
        • Armstrong V.W.
        • Schleef J.
        • Creutzfeldt C.
        • Creutzfeldt W.
        • Seidel D.
        Serum lipoprotein Lp(a) concentrations are not influenced by an HMG-CoA reductase inhibitor.
        Klin. Wochenschr. 1988; 66: 462
        • Kostner G.M.
        • Gavish D.
        • Leopold B.
        • Bolzano K.
        • Weintraub M.S.
        • Breslow J.L.
        HMG-CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.
        Circulation. 1989; 80: 1313
        • Wang X.L.
        • Wilcken D.E.L.
        • Dudman N.P.B.
        Early expression of the apolipoprotein(a) gene: Relationships between infants' and their parents' serum apolipoprotein(a) levels.
        Pediatrics. 1992; 89: 401
        • Hasstedt S.J.
        • Williams R.R.
        Three alleles for quantitative Lp(a).
        Genet. Epidemiol. 1986; 3: 53
        • Lamon-Fava S.
        • Jimenez D.
        • Christian J.C.
        • Fabsitz R.R.
        • Reed T.
        • Carmelli D.
        • Castelli W.P.
        • Ordovas J.M.
        • Wilson P.W.F.
        • Schaefer E.J.
        The NHLBI twin study: heritability of apolipoprotein A-1, B and low density lipoprotein subclasses and concordance for lipoprotein(a).
        Atherosclerosis. 1991; 91: 97
        • Boerwinkle E.
        • Leffert C.C.
        • Lin J.
        • Lackner C.
        • Chiesa G.
        • Hobbs H.H.
        Apolipoprotein(a) gene accounts for greater that 90% of the variation in plasma lipoprotein(a) concentrations.
        J. Clin. Invest. 1992; 90: 52