Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk. The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk. Lipoprotein(a) (Lp(a)) was first described by Berg in 1963 (1Berg K. A new serum type system in man: the Lp system.Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Crossref PubMed Scopus (1057) Google Scholar). Lp(a) is a lipoprotein similar in structure to LDL, but differs from LDL in having apo(a), a large glycoprotein, attached to apoB-100 by a disulfide bond (2Utermann G. Weber W. Protein composition of Lp(a) lipoprotein from human plasma.FEBS Lett. 1983; 154: 357-361Crossref PubMed Scopus (190) Google Scholar). Apo(a) shares strong homology with several regions of plasminogen (3McLean J.W. Tomlinson J.E. Kuang W-J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Scopus (1597) Google Scholar), including the protease domain, the kringle 5 domain, and 10 types of the kringle 4 domain. It has been shown that apo(a) is highly polymorphic in size due to different numbers of the kringle 4 type 2 (kringle-42) domain, ranging from a minimum of 3 to greater than 40 (4Marcovina S.M. Hobbs H.H. Albers J.J. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature.Clin. Chem. 1996; 42: 436-439Crossref PubMed Scopus (113) Google Scholar). Plasma levels of Lp(a) are highly heritable (2Utermann G. Weber W. Protein composition of Lp(a) lipoprotein from human plasma.FEBS Lett. 1983; 154: 357-361Crossref PubMed Scopus (190) Google Scholar, 5Utermann G. Menzel H.J. Kraft H.G. Duba H.C. Kemmler H.G. Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.J. Clin. Invest. 1987; 80: 458-465Crossref PubMed Scopus (731) Google Scholar) and are inversely correlated with the apo(a) isoform size, with subjects carrying small isoforms having high plasma Lp(a) levels (5Utermann G. Menzel H.J. Kraft H.G. Duba H.C. Kemmler H.G. Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.J. Clin. Invest. 1987; 80: 458-465Crossref PubMed Scopus (731) Google Scholar). Metabolic studies have shown that the inverse association between plasma Lp(a) levels and apo(a) isoform size is due to differences in the hepatic secretion of apo(a), with subjects carrying small apo(a) isoforms having increased apo(a) secretion (6Rader D.J. Cain W. Ikewaki K. Talley G. Zech L.A. Usher D. Brewer H.B. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.J. Clin. Invest. 1994; 93: 2758-2763Crossref PubMed Scopus (214) Google Scholar, 7Jenner J.L. Seman L.J. Millar J.S. Lamon-Fava S. Welty F.K. Dolnikowski G.G. Marcovina S.M. Lichtenstein A.H. Barrett P.H. deLuca C. The metabolism of apolipoproteins (a) and B-100 within plasma Lipoprotein(a) in human beings.Metabolism. 2005; 54: 361-369Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Boerwinkle et al. (8Boerwinkle E. Leffert C.G. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (831) Google Scholar) indicated that 69% of the variability in plasma Lp(a) levels is accounted for by the number of apo(a) kringle-42 repeats, and an additional 21% of the variation is explained by other sequences within the gene coding for apo(a). Recently, the rs3798220 single-nucleotide polymorphism (SNP) in the apo(a) locus was found to be a strong predictor of Lp(a) levels and coronary heart disease (CHD) risk (9Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S. Parish S. Barlera S. Franzosi M.G. Rust S. Consortium PROCARDIS Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1061) Google Scholar). Plasma Lp(a) levels are associated with CHD risk (10Bennet A. Di Angelantonio E. Erqou S. Eirikdottir G. Sigurdsson G. Woodward M. Rumley A. Lowe G.D. Danesh J. Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease.Arch. Intern. Med. 2008; 168: 598-608Crossref PubMed Scopus (231) Google Scholar, 11Med. Assoc. J. Am. The Emerging Risk Factors Collaboration.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. 2009; 302: 412-423Google Scholar). The mechanisms by which Lp(a) increases CHD risk are not well defined, but may include both a prothrombotic effect due to the similarity of apo(a) to the fibrinolytic pro-enzyme plasminogen (12Ignatescu M. Kostner K. Zorn G. Kneussl M. Maurer G. Lang I.M. Huber K. Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension.Thromb. Haemost. 1998; 80: 231-232Crossref PubMed Scopus (43) Google Scholar, 13Kang C. Dominguez M. Loyau S. Miyata T. Durlach V. Angles-Cano E. Lp(a) particles mold fibrin-binding properties of apo(a) in size-dependent manner: a study with different-length recombinant apo(a), native Lp(a), and monoclonal antibody.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1232-1238Crossref PubMed Scopus (41) Google Scholar), and an atherogenic effect mediated by the preferential binding of oxidized phospholipids by Lp(a) as well as Lp(a) deposition in the arterial wall (14Tsimikas S. Tsironis L.D. Tselepis A.D. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2094-2099Crossref PubMed Google Scholar). The goal of this study was to assess prospectively the risk of CHD associated with elevated plasma Lp(a) levels and the contribution of apo(a) isoform size to this association in the Framingham Offspring Study (FOS). In addition, we have compared the CHD risk prediction associated with elevated Lp(a) levels as assessed by two different immunoassays and by the measurement of Lp(a) cholesterol levels. The FOS is a longitudinal population-based study which started in 1975 and enrolled the children of the participants in the original Framingham Heart Study cohort, and their spouses (15Feinleib M. Kannel W.B. McNamara P.M. Garrison R.J. Castelli W.P. The Framingham Offspring Study: design and preliminary data.Prev. Med. 1975; 4: 518-525Crossref PubMed Scopus (689) Google Scholar). All participants are Caucasian. During the 5th examination cycle (1991–1995), subjects underwent a medical history, physical examination, electrocardiogram (ECG) evaluation, and a blood draw for the assessment of plasma lipid and lipoprotein levels. At cycle 5, there were 1,328 men and 1,562 women who were free of CHD and had their plasma Lp(a) levels measured. These subjects were followed until completion of cycle 8, with a mean follow-up of 12.3 years, for the occurrence of new CHD events. All suspected CHD events were assessed by a panel of three physicians who evaluated the available evidence. CHD was defined as: myocardial infarction diagnosed by ECG, myocardial infarction diagnosed by enzymatic elevations and history, sudden CHD death, and nonsudden CHD death. Blood was drawn after a 12 h overnight fast into 0.1% EDTA tubes. Plasma was separated by centrifugation at 2,500 rpm for 30 min at 4°C and immediately and at Plasma levels of cholesterol and were measured by enzymatic in an enzymatic levels were the levels were of the concentration of lipoprotein cholesterol in of the Chem. PubMed Scopus Google Scholar). Lp(a) levels were measured an as a monoclonal apo(a) that does not the kringle-42 and is independent of apo(a) isoform size S.M. Albers J.J. of the number of apolipoprotein(a) kringle 4 of Chem. PubMed Scopus Google Scholar). Lp(a) levels are in The Lp(a) for this was a serum having and and an of of and Marcovina of and for Lipoprotein(a) for lipoprotein(a) for Chem. Scholar). and of variation were and In only apo(a) isoform is in apo(a) is by both with isoform than the Apo(a) isoforms were measured with described (4Marcovina S.M. Hobbs H.H. Albers J.J. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature.Clin. Chem. 1996; 42: 436-439Crossref PubMed Scopus (113) Google Scholar), in which the size of apo(a) isoforms are agarose The apo(a) isoform size is to the number of kringle-42 repeats (4Marcovina S.M. Hobbs H.H. Albers J.J. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature.Clin. Chem. 1996; 42: 436-439Crossref PubMed Scopus (113) Google Scholar). The apo(a) isoform size was in These were at the and of Lp(a) levels were measured with two other in plasma at examination cycle an from which an that does not with plasminogen and of variation and a which to Lp(a) and the cholesterol content in the and L.J. J.L. McNamara of lipoprotein(a) in plasma by cholesterol in plasma Chem. 1994; PubMed Scopus Google Scholar). available were with two were at the The for the rs3798220 in the apo(a) was to J. J. M. A. M. The structure of in the human 2002; PubMed Scopus Google Scholar). were assessed for and a was to and are for and and are for were by in for subjects who developed new CHD events follow-up subjects who not CHD were compared for and for were to the hazard ratio of CHD associated with high levels of In subjects in the upper tertile of Lp(a) levels tertile of apo(a) isoform were compared with subjects in the tertile of Lp(a) upper tertile of apo(a) isoform were for risk for including and of Plasma Lp(a) concentrations were measured with three different in FOS participants at examination cycle The of Lp(a) concentrations measured with the different is in The Lp(a) by the were highly correlated to the Lp(a) concentrations by the < after of the Lp(a) from to a the size, this a strong apo(a) isoform size-dependent with the that the the Lp(a) in with large apo(a) isoforms and the Lp(a) in with small apo(a) A greater than was in of the The cholesterol content of Lp(a), measured the was correlated with both the Lp(a) and the Lp(a) concentrations < and < a of the Lp(a) cholesterol with the other Lp(a) shown in that the Lp(a) cholesterol may the of Lp(a) cholesterol in with Lp(a) The apo(a) isoform size was significantly and inversely to plasma levels of Lp(a) as assessed with the different < < and < of plasma Lp(a) concentrations in the Framingham Offspring Study Lp(a) Lp(a) Lp(a) Lp(a) participants in plasma Lp(a) levels were measured with three were in men and women in a new participants in plasma Lp(a) levels were measured with three were in men and women who developed new CHD events the 12.3 follow-up were significantly and had a of CHD risk than men who not CHD plasma Lp(a) levels were approximately two-fold in CHD than in subjects for both Lp(a) and The in plasma levels of Lp(a) cholesterol between men with CHD and was significant (P The apo(a) isoform size was significantly in CHD than in (P During only of women developed as to of men. with similar to were significantly and had a of CHD risk than women CHD The in plasma lipid levels and in CHD risk between and was in women than in men. In to plasma Lp(a) Lp(a), Lp(a) cholesterol levels were not significantly different between women CHD and and the apo(a) isoform was in than in (P plasma lipid and Lp(a) levels, and apo(a) isoform size in subjects who developed CHD a mean follow-up of 12.3 years, and in subjects free of after was after was concentration after the of Lp(a) after was after was and women, and after was after was and women, and after was after was blood blood shown as mean with the of and Lp(a), are shown as LDL after was concentration after the of Lp(a) and women, and and women, and in a new shown as mean with the of and Lp(a), are shown as LDL subjects were to of plasma Lp(a) levels, as assessed by the a greater number of CHD relative to were in men in the upper tertile of plasma Lp(a) levels as compared with men in the tertile was not in women of new CHD by of plasma Lp(a) CHD CHD CHD CHD in a new In multivariate the of CHD was greater than in men in the upper tertile of Lp(a) levels than in men in the tertile both with the and the Lp(a) The risk of CHD associated with high Lp(a) levels was not after for several risk for including and plasma levels of and for of and to plasma Lp(a) Apo(a) isoform size is to be a significant of plasma Lp(a) levels, and after for the isoform size, the association between high Lp(a) levels and CHD was significant In multivariate the for CHD was significantly in men in the tertile of apo(a) isoform size than in those in the tertile the of this association was than that for Lp(a) levels, and the was after for plasma Lp(a) levels measured with the the In similar multivariate there was no significantly increased in men in the upper tertile of Lp(a) cholesterol levels than in men in the tertile In women, the risk of CHD associated with high Lp(a) concentrations was not significant after for plasma and of Lp(a) A analysis, the to as in women in this and an of as in men in this that to differences in CHD risk between the and the upper tertile of Lp(a) in women was than for CHD in FOS men by Lp(a) levels tertile apo(a) isoform size tertile upper apo(a) 2 and 3 and 4 and of 5 as in apo(a) isoform as in Lp(a) levels. in a new 2 and 3 and 4 and of 5 as in apo(a) isoform as in Lp(a) levels. The of the rs3798220 was in men and in was associated with plasma Lp(a) levels both in men and women (P < in the multivariate this was not significantly associated with CHD risk in men women Elevated levels of Lp(a) have been to be associated with CHD. In of the and the Framingham Heart we had shown that elevated levels of Lp(a), assessed by were significantly associated with CHD risk Lamon-Fava S. J.L. McNamara K. Lipoprotein(a) levels and risk of coronary heart disease in men. The Am. Med. Assoc. 1994; PubMed Scopus Google Scholar, L.A. J.L. Seman L.J. Castelli W.P. Elevated plasma lipoprotein(a) and coronary heart disease in men and A prospective Am. Med. Assoc. 1996; PubMed Google Scholar, L.A. J.L. Castelli W.P. A prospective of elevated lipoprotein(a) by and cardiovascular disease in The Heart 1994; 90: PubMed Scopus Google Scholar). Recently, there has been a of in Lp(a), with studies in large numbers of subjects an independent association of Lp(a) levels with CHD risk. The Emerging Risk Factors has a significant and association between plasma Lp(a) levels and defined as first CHD death, in participants in different prospective studies Assoc. J. Am. The Emerging Risk Factors Collaboration.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. 2009; 302: 412-423Google Scholar). In this there was no association between plasma Lp(a) levels and nonvascular Assoc. J. Am. The Emerging Risk Factors Collaboration.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. 2009; 302: 412-423Google Scholar). In addition, a of prospective studies in which Lp(a) levels were measured with different indicated an ratio of for CHD in subjects in the upper tertile of Lp(a) levels, relative to subjects in the tertile (10Bennet A. Di Angelantonio E. Erqou S. Eirikdottir G. Sigurdsson G. Woodward M. Rumley A. Lowe G.D. Danesh J. Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease.Arch. Intern. Med. 2008; 168: 598-608Crossref PubMed Scopus (231) Google Scholar). in men in the FOS are with from large men with elevated plasma levels of Lp(a) had a greater than increased risk of relative to men with levels of The for the upper tertile of Lp(a) levels in men was approximately 40 and for the upper tertile of Lp(a) levels was approximately The increased risk of CHD associated with high Lp(a) levels significant after for other lipoprotein levels and other risk for the independent role of Lp(a) in CHD In the association between plasma Lp(a) concentrations and CHD significant after isoform size was into the hazard prediction In addition, the apo(a) isoform size was the for plasma Lp(a) levels the of the isoform both isoform the that plasma Lp(a) levels are than is apo(a) isoform size in risk prediction in the Framingham studies have the role of apo(a) isoform size CHD prediction A. M. Apolipoprotein(a) isoforms and coronary heart disease in a Full Text Full Text PDF PubMed Scopus Google Scholar, J. T. T. and apolipoprotein(a) isoforms as in patients with coronary heart Intern. Med. 2002; PubMed Scopus Google Scholar, H.G. A. S. A. V. D. G. Apolipoprotein(a) kringle number risk for coronary heart disease.Arterioscler. Thromb. Vasc. Biol. 1996; PubMed Scopus Google Scholar, Tsironis L.D. Tselepis A.D. lipoprotein(a) concentrations and apolipoprotein(a) association with the of in patients with coronary heart PubMed Scopus Google Scholar, A. R. elevated lipoprotein(a) and increased risk of myocardial Am. Med. Assoc. 2009; PubMed Scopus Google Scholar, J. P.M. Marcovina S. Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of with of coronary atherosclerosis in The Chem. PubMed Scopus Google Scholar, K. A. J. S. Kraft H.G. G. of the apo(a) size polymorphism in association with Lp(a) concentration and coronary heart Full Text Full Text PDF PubMed Scopus Google Scholar), and of studies have to the prediction relative to isoform size from that of plasma levels of In a small Kraft et al. H.G. A. S. A. V. D. G. Apolipoprotein(a) kringle number risk for coronary heart disease.Arterioscler. Thromb. Vasc. Biol. 1996; PubMed Scopus Google Scholar) have that both Lp(a) levels and isoform size were associated with but both were in the multivariate the of the association was for apo(a) isoform et al. J. P.M. Marcovina S. Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of with of coronary atherosclerosis in The Chem. PubMed Scopus Google Scholar) have found both Lp(a) levels and apo(a) isoform size to be significant of CHD in a small and both were in the multivariate only apo(a) isoform size significantly associated with CHD. In three et al. A. R. elevated lipoprotein(a) and increased risk of myocardial Am. Med. Assoc. 2009; PubMed Scopus Google Scholar) have an increased risk of CHD to in subjects in the of number of apo(a) kringle-42 repeats the In of the three after for Lp(a) levels, the association between the number of kringle-42 repeats was but significant A. R. elevated lipoprotein(a) and increased risk of myocardial Am. Med. Assoc. 2009; PubMed Scopus Google Scholar). It has been that the association between apo(a) isoform and CHD be explained by a greater of Lp(a) particles with number of repeats A. R. elevated lipoprotein(a) and increased risk of myocardial Am. Med. Assoc. 2009; PubMed Scopus Google Scholar, J. P.M. Marcovina S. Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of with of coronary atherosclerosis in The Chem. PubMed Scopus Google Scholar). in two Lp(a) levels were associated with CHD risk of apo(a) isoform size K. A. J. S. Kraft H.G. G. of the apo(a) size polymorphism in association with Lp(a) concentration and coronary heart Full Text Full Text PDF PubMed Scopus Google Scholar). In prospective the multivariate including Lp(a) and apo(a) isoform size in the that the of the increased risk of CHD by Lp(a) in men is to the concentration of the lipoprotein and that isoform size to a The contribution of isoform size to risk prediction be explained by isoform size but not the of plasma Lp(a) levels (8Boerwinkle E. Leffert C.G. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (831) Google Scholar). Genetic at the apo(a) locus other than kringle-42 repeats have been shown to be associated with plasma Lp(a) levels (9Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S. Parish S. Barlera S. Franzosi M.G. Rust S. Consortium PROCARDIS Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1061) Google Scholar, K. K. Lawn R.M. regions of the apolipoprotein(a) gene and of the plasminogen gene 90: PubMed Scopus Google Scholar, D. D. J. J.J. A polymorphism in the of apolipoprotein(a) is associated with coronary disease.Arterioscler. Thromb. Vasc. Biol. 2007; 27: PubMed Scopus Google Scholar). Genetic studies the between plasma Lp(a) levels and CHD. The PROCARDIS Consortium Study has shown a significant CHD risk prediction associated with two in the apo(a) gene rs3798220 and (9Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S. Parish S. Barlera S. Franzosi M.G. Rust S. Consortium PROCARDIS Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1061) Google Scholar). These variants were both associated with plasma Lp(a) levels, and the association between gene variants and CHD was plasma Lp(a) levels were into the In the rs3798220 was significantly associated with Lp(a) levels, was not a significant predictor of CHD. is due to the that this is only of the several of Lp(a) levels, and the that Lp(a) concentrations are associated with CHD risk. of different Lp(a) that the two had similar CHD prediction be that the Lp(a) concentrations as measured by the were to in subjects with large apo(a) isoform and to in subjects with small isoform the other the cholesterol content of Lp(a) was not significantly associated with CHD in multivariate may that the cholesterol content of the which is by the metabolism of the similar to the cholesterol content in LDL, does not for the of Lp(a), that the for Lp(a) cholesterol assessment is not and other the between elevated Lp(a) and the for the of Lp(a) is not Lp(a) has been shown to as a of oxidized phospholipids (14Tsimikas S. Tsironis L.D. Tselepis A.D. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2094-2099Crossref PubMed Google Scholar, S. J. M. M. S. J.L. lipoprotein-associated phospholipase A2 and cardiovascular from the Thromb. Vasc. Biol. 2007; 27: PubMed Scopus Google Scholar), and this may be for and of due to the high of homology between apo(a) and plasminogen (3McLean J.W. Tomlinson J.E. Kuang W-J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Scopus (1597) Google Scholar), has been that Lp(a) with the fibrinolytic and may be Marcovina S.M. Lipoprotein(a) as a risk for atherosclerosis and insights from PubMed Scopus Google Scholar). of of Lp(a) are to the apo(a) In women, we not a significant association between CHD and Lp(a) levels. is in to other large prospective and studies a similar association between high Lp(a) levels and CHD risk in men and women (9Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S. Parish S. Barlera S. Franzosi M.G. Rust S. Consortium PROCARDIS Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1061) Google Scholar, 11Med. Assoc. J. Am. The Emerging Risk Factors Collaboration.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. 2009; 302: 412-423Google Scholar). indicated that both a and a greater number of participants have been to a significant association between Lp(a) levels and CHD risk in women in the study a significant and independent role of Lp(a) cardiovascular disease in men. coronary heart disease of variation electrocardiogram Framingham Offspring Study hazard ratio Lipoprotein(a) single-nucleotide polymorphism cholesterol