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April 6, 1994, Vol 271, No. 13 >
ARTICLE | April 6, 1994

Lipoprotein(a) Levels and Risk of Coronary Heart Disease in Men: Title and subTitle BreakThe Lipid Research Clinics Coronary Primary Prevention Trial FREE

Ernst J. Schaefer, MD; Stefania Lamon-Fava, MD, PhD; Jennifer L. Jenner, MS; Judith R. McNamara, MT; Jose M. Ordovas, PhD; C. Edward Davis, PhD; Jeffrey M. Abolafia, MA; Kenneth Lippel, PhD; Robert I. Levy, MD
[+] Author Affiliations

Reprint requests to Lipid Metabolism Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111 (Dr Schaefer).


JAMA. 1994;271(13):999-1003. doi:10.1001/jama.1994.03510370051031
Text Size: A A A
Published online
Article
References

Objective.  —To examine the relationship between elevated levels of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) risk in a prospective study.

Design.  —Nested case-control study. The cohort consisted of participants in the Lipid Research Clinics Coronary Primary Prevention Trial.

Setting.  —Lipid research clinics.

Participants.  —The Lipid Research Clinics Coronary Primary Prevention Trial participants (n=3806) were men, aged 35 to 59 years, with plasma cholesterol levels of 6.85 mmol/L (265 mg/dL) or greater, low-density lipoprotein cholesterol levels of 4.91 mmol/L (190 mg/dL) or greater, and triglyceride levels less than 3.39 mmol/L. Subjects were randomly assigned to either cholestyramine or placebo treatment. The Lp(a) levels were measured in plasma samples obtained prior to randomization in 233 cases (participants who developed CHD in the course of the study) and 390 matched CHD-free controls. A total of 96.95% of the subjects were white, 2.25% were black, and 0.80% were of other race.

Main Outcome Measure.  —Coronary heart disease (either fatal or nonfatal) events during a follow-up of 7 to 10 years.

Results.  —The Lp(a) levels were significantly higher (21%) in cases than in controls (23.7 mg/dL [0.59 mmol/L and 19.5 mg/dL [0.49 mmol/L], respectively; P<.02). This difference was still statistically significant (P<.01) after controlling for age, body mass index, cigarette smoking, blood pressure, low-density lipoprotein cholesterol level, and high-density lipoprotein cholesterol level. When subjects were divided by treatment, both cholestyramine-treated and placebo-treated CHD subjects had Lp(a) levels 20% to 22% greater than their matched controls. However, possibly because of smaller sample sizes, these differences were no longer statistically significant.

Conclusions.  —Our data are consistent with the concept that an elevated Lp(a) level is an independent risk factor for CHD in hypercholesterolemic white men.(JAMA. 1994;271:999-1003)

REFERENCES

1 +
Utermann G.  The mysteries of lipoprotein(a). Science . 1989;;246:904-910.
2 +
Scanu AM, Fless GM.  Lipoprotein(a): heterogeneity and biological relevance. J Clin Invest . 1990;; 85:1709-1715.
3 +
Seman LJ, Breckenridge WC.  Isolation and partial characterization of apolipoprotein(a) from human lipoprotein(a). Biochem Cell Biol . 1986;;64:999-1005.
4 +
Berg K.  A new serum type system in man: the Lp system. Acta Pathol Microbiol Scand . 1963;;59: 369-382.
5 +
Morrisett JD, Guyton JR, Gaubatz JW, Gotto AM.  Lipoprotein(a): structure, metabolism, and epidemiology.  In: Gotto AM Jr, ed. Plasma Lipoproteins . Amsterdam, the Netherlands: Elsevier Science Publishers; 1987;:129-152.
6 +
Dahlen GH, Guyton JR, Altar M, Farmer JA, Kautz JA, Gotto AM.  Association of levels of lipoprotein(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation . 1986;;74:758-765.
7 +
HoeflerG, Harnouncourt F, Paschke E, Mitrl W, Pfeiffer KH, Kostner GM.  Lipoprotein(a) Lp(a): a risk factor for myocardial infarction. Arteriosclerosis . 1988;;8:398-401.
8 +
Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G.  Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age. Clin Chem . 1990;;36:20-23.
9 +
Genest J Jr, Jenner JL, McNamara JR, et al.  Prevalence of lipoprotein(a) [Lp(a)] excess in coronary artery disease. Am J Cardiol . 1991;;67:1039-1045.
10 +
Genest JJ Jr, Martin-Munley SS, McNamara JR, et al.  Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation . 1992;;85:2025-2033.
11 +
McLean JW, Tomlinson JE, Kuang WJ, et al.  cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature . 1987;;330:132-137.
12 +
Loscalzo J, Weinfield M, Fless GM, Scanu AM.  Lipoprotein(a), fibrin binding, and plasminogen activation. Arterioscler Thromb . 1990;;10:240-245.
13 +
Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF.  A potential basis for the thrombotic risks associated with lipoprotein(a). Nature . 1989;;339:301-303.
14 +
Hajjar KA, Gavish D, Breslow JL, Nachman RL.  Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature . 1989;;339:303-305.
15 +
Simon DI, Fless GM, Scanu AM, Loscalzo J.  Tissue type plasminogen-activator binds to and is inhibited by surface-bound Lp(a) and LDL. Biochemistry . 1991;;30:6671-6677.
16 +
Naruszewicz M, Selinger E, Davignon J.  Oxidative modification of lipoprotein(a) and the effect of β-carotene. Metabolism . 1992;;41:1215-1224.
17 +
Rader DJ, Brewer HB Jr.  Lipoprotein(a): clinical approach to a unique atherogenic lipoprotein. JAMA . 1992;;267:1109-1112.
18 +
Berg K.  Twin research in coronary heart disease.  In: Gedda L, Parisi P, Nance WE, eds. Twin Research 3: Epidemiological and Clinical Studies . New York, NY: Alan R Liss Inc; 1981;:117-130.
19 +
Lamon-Fava S, Jimenez D, Christian JC, et al.  The NHLBI twin study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis . 1991;;91:97-106.
20 +
Gavish D, Azrolan N, Breslow JL.  Plasma Lp(a) concentration is inversely correlated with ratio of kringle IV/kringle V encoding domains in the apo(a) gene. J Clin Invest . 1989;;84:4171-4174.
21 +
Gaubatz JW, Ghanem HI, Guevara J Jr, Nava ML, Patsch W, Morrisett JD.  Polymorphic forms of human apolipoprotein(a): inheritance and relationship of their molecular weights to plasma levels of lipoprotein(a). J Lipid Res . 1990;;31:603-613.
22 +
Boerwinkle E, Leffert CC, Lackner C, Chiesa G, Hobbs HH.  Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest . 1992;;90: 52-60.
23 +
Sandholtzer C, Hallman DM, Sigurdsson G, et al.  Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet . 1991;;86:607-614.
24 +
Jenner JL, Ordovas JM, Lamon-Fava S, et al.  Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels: the Framingham Offspring Study. Circulation . 1993;;87:1135-1141.
25 +
Rosengren A, Wihelmsen L, Eriksson E, Risberg B, Wedel H.  Lipoprotein(a) and coronary heart disease: a prospective case-control study in the general population sample of middle aged men. BMJ . 1990;;301:1248-1251.
26 +
Jauhiainen M, Koskinen P, Ehnholm C, et al.  Lipoprotein(a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis . 1991;;89:59-67.
27 +
Craig WY, Ledue TB.  The effects of long term storage on serum Lp(a) levels. Atherosclerosis . 1992;; 93:261.
28 +
Ridker PM, Hennekens CH, Stampfer MJ.  A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA . 1993;;270:2195-2199.
29 +
Lipid Research Clinics Program.  The Coronary Primary Prevention Trial: design and implementation. J Chronic Dis . 1979;;32:609-631.
30 +
Lipid Research Clinics Program.  The Lipid Research Clinics Coronary Primary Prevention Trial, I: reduction in incidence of coronary heart disease. JAMA . 1984;;251:351-364.
31 +
Lipid Research Clinics Program.  The Lipid Research Clinics Coronary Primary Prevention Trial, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA . 1984;;251:365-374.
32 +
Breslow NE, Day NE.  Statistical methods in cancer research.  In: The Analysis of Case Control Studies, Volume 1 . Lyon, France: International Agency for Research on Cancer; 1982;.
33 +
Lubin JH, Gail MH.  Biased selection of controls for case-control analyses of cohort studies. Biometrics . 1984;;40:63-75.
34 +
Albers JJ, Adolphson JL, Hazzard WR.  Radioimmunoassay of human plasma Lp(a) lipoprotein. J Lipid Res . 1977;;18:331-338.
35 +
Craig WY, Poulin SE, Forster NR, Neveux LM, Wald NJ, Ledue TB.  The effect of sample storage on the assay of lipoprotein(a) by commercially available radial immunodiffusion and enzymelinked immunosorbent assay kits. Clin Chem . 1992;; 38:550-553.
36 +
Utermann G, Hopplicher F, Dieplinger H, Seed M, Thompson G, Boerwinkle E.  Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of the two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A 1989;;86: 4171-4174.
37 +
Wiklund O, Angelin B, Olofsson S-O, et al.  Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolemia. Lancet . 1990;;335:1360-1363.
38 +
Mbewu AD, Bhatnagar D, Durrington PN, et al.  Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations. Arterioscler Thromb . 1991;;11:940-946.
39 +
Hiraga T, Okubo M, Kobayashi T, Nakanishi K, Sugimoto T, Murase T.  Serum lipoprotein(a) levels differ in different phenotypes of primary hyperlipoproteinemia. Metabolism . 1993;;42:1327-1330.
40 +
Hofman SL, Eaton DL, Brown MS, McConathy WJ, Goldstein JL, Hammer RE.  Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice. J Clin Invest . 1990;;85:1542-1547.
41 +
Brewer HB Jr.  Effectiveness of diet and drugs in the treatment of patients with elevated Lp(a) levels.  In: Scanu AM, ed. Lipoprotein(a) . New York, NY: Academic Press; 1990;:211-220.
42 +
Seed M, Hopplichler F, Reaveley D, et al.  Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med . 1990;;322:1494-1499.
43 +
Meddings NB, Dietschy JM.  Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation . 1986;;74:805-814.
44 +
Rader DJ, Cain W, Zech LA, Usher D, Brewer HB Jr.  Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein(a) isoform is determined by the rate of lipoprotein(a) production. J Clin Invest . 1993;;91:443-447.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Utermann G.  The mysteries of lipoprotein(a). Science . 1989;;246:904-910.
2 +
Scanu AM, Fless GM.  Lipoprotein(a): heterogeneity and biological relevance. J Clin Invest . 1990;; 85:1709-1715.
3 +
Seman LJ, Breckenridge WC.  Isolation and partial characterization of apolipoprotein(a) from human lipoprotein(a). Biochem Cell Biol . 1986;;64:999-1005.
4 +
Berg K.  A new serum type system in man: the Lp system. Acta Pathol Microbiol Scand . 1963;;59: 369-382.
5 +
Morrisett JD, Guyton JR, Gaubatz JW, Gotto AM.  Lipoprotein(a): structure, metabolism, and epidemiology.  In: Gotto AM Jr, ed. Plasma Lipoproteins . Amsterdam, the Netherlands: Elsevier Science Publishers; 1987;:129-152.
6 +
Dahlen GH, Guyton JR, Altar M, Farmer JA, Kautz JA, Gotto AM.  Association of levels of lipoprotein(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation . 1986;;74:758-765.
7 +
HoeflerG, Harnouncourt F, Paschke E, Mitrl W, Pfeiffer KH, Kostner GM.  Lipoprotein(a) Lp(a): a risk factor for myocardial infarction. Arteriosclerosis . 1988;;8:398-401.
8 +
Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G.  Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age. Clin Chem . 1990;;36:20-23.
9 +
Genest J Jr, Jenner JL, McNamara JR, et al.  Prevalence of lipoprotein(a) [Lp(a)] excess in coronary artery disease. Am J Cardiol . 1991;;67:1039-1045.
10 +
Genest JJ Jr, Martin-Munley SS, McNamara JR, et al.  Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation . 1992;;85:2025-2033.
11 +
McLean JW, Tomlinson JE, Kuang WJ, et al.  cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature . 1987;;330:132-137.
12 +
Loscalzo J, Weinfield M, Fless GM, Scanu AM.  Lipoprotein(a), fibrin binding, and plasminogen activation. Arterioscler Thromb . 1990;;10:240-245.
13 +
Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF.  A potential basis for the thrombotic risks associated with lipoprotein(a). Nature . 1989;;339:301-303.
14 +
Hajjar KA, Gavish D, Breslow JL, Nachman RL.  Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature . 1989;;339:303-305.
15 +
Simon DI, Fless GM, Scanu AM, Loscalzo J.  Tissue type plasminogen-activator binds to and is inhibited by surface-bound Lp(a) and LDL. Biochemistry . 1991;;30:6671-6677.
16 +
Naruszewicz M, Selinger E, Davignon J.  Oxidative modification of lipoprotein(a) and the effect of β-carotene. Metabolism . 1992;;41:1215-1224.
17 +
Rader DJ, Brewer HB Jr.  Lipoprotein(a): clinical approach to a unique atherogenic lipoprotein. JAMA . 1992;;267:1109-1112.
18 +
Berg K.  Twin research in coronary heart disease.  In: Gedda L, Parisi P, Nance WE, eds. Twin Research 3: Epidemiological and Clinical Studies . New York, NY: Alan R Liss Inc; 1981;:117-130.
19 +
Lamon-Fava S, Jimenez D, Christian JC, et al.  The NHLBI twin study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis . 1991;;91:97-106.
20 +
Gavish D, Azrolan N, Breslow JL.  Plasma Lp(a) concentration is inversely correlated with ratio of kringle IV/kringle V encoding domains in the apo(a) gene. J Clin Invest . 1989;;84:4171-4174.
21 +
Gaubatz JW, Ghanem HI, Guevara J Jr, Nava ML, Patsch W, Morrisett JD.  Polymorphic forms of human apolipoprotein(a): inheritance and relationship of their molecular weights to plasma levels of lipoprotein(a). J Lipid Res . 1990;;31:603-613.
22 +
Boerwinkle E, Leffert CC, Lackner C, Chiesa G, Hobbs HH.  Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest . 1992;;90: 52-60.
23 +
Sandholtzer C, Hallman DM, Sigurdsson G, et al.  Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet . 1991;;86:607-614.
24 +
Jenner JL, Ordovas JM, Lamon-Fava S, et al.  Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels: the Framingham Offspring Study. Circulation . 1993;;87:1135-1141.
25 +
Rosengren A, Wihelmsen L, Eriksson E, Risberg B, Wedel H.  Lipoprotein(a) and coronary heart disease: a prospective case-control study in the general population sample of middle aged men. BMJ . 1990;;301:1248-1251.
26 +
Jauhiainen M, Koskinen P, Ehnholm C, et al.  Lipoprotein(a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis . 1991;;89:59-67.
27 +
Craig WY, Ledue TB.  The effects of long term storage on serum Lp(a) levels. Atherosclerosis . 1992;; 93:261.
28 +
Ridker PM, Hennekens CH, Stampfer MJ.  A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA . 1993;;270:2195-2199.
29 +
Lipid Research Clinics Program.  The Coronary Primary Prevention Trial: design and implementation. J Chronic Dis . 1979;;32:609-631.
30 +
Lipid Research Clinics Program.  The Lipid Research Clinics Coronary Primary Prevention Trial, I: reduction in incidence of coronary heart disease. JAMA . 1984;;251:351-364.
31 +
Lipid Research Clinics Program.  The Lipid Research Clinics Coronary Primary Prevention Trial, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA . 1984;;251:365-374.
32 +
Breslow NE, Day NE.  Statistical methods in cancer research.  In: The Analysis of Case Control Studies, Volume 1 . Lyon, France: International Agency for Research on Cancer; 1982;.
33 +
Lubin JH, Gail MH.  Biased selection of controls for case-control analyses of cohort studies. Biometrics . 1984;;40:63-75.
34 +
Albers JJ, Adolphson JL, Hazzard WR.  Radioimmunoassay of human plasma Lp(a) lipoprotein. J Lipid Res . 1977;;18:331-338.
35 +
Craig WY, Poulin SE, Forster NR, Neveux LM, Wald NJ, Ledue TB.  The effect of sample storage on the assay of lipoprotein(a) by commercially available radial immunodiffusion and enzymelinked immunosorbent assay kits. Clin Chem . 1992;; 38:550-553.
36 +
Utermann G, Hopplicher F, Dieplinger H, Seed M, Thompson G, Boerwinkle E.  Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of the two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A 1989;;86: 4171-4174.
37 +
Wiklund O, Angelin B, Olofsson S-O, et al.  Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolemia. Lancet . 1990;;335:1360-1363.
38 +
Mbewu AD, Bhatnagar D, Durrington PN, et al.  Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations. Arterioscler Thromb . 1991;;11:940-946.
39 +
Hiraga T, Okubo M, Kobayashi T, Nakanishi K, Sugimoto T, Murase T.  Serum lipoprotein(a) levels differ in different phenotypes of primary hyperlipoproteinemia. Metabolism . 1993;;42:1327-1330.
40 +
Hofman SL, Eaton DL, Brown MS, McConathy WJ, Goldstein JL, Hammer RE.  Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice. J Clin Invest . 1990;;85:1542-1547.
41 +
Brewer HB Jr.  Effectiveness of diet and drugs in the treatment of patients with elevated Lp(a) levels.  In: Scanu AM, ed. Lipoprotein(a) . New York, NY: Academic Press; 1990;:211-220.
42 +
Seed M, Hopplichler F, Reaveley D, et al.  Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med . 1990;;322:1494-1499.
43 +
Meddings NB, Dietschy JM.  Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation . 1986;;74:805-814.
44 +
Rader DJ, Cain W, Zech LA, Usher D, Brewer HB Jr.  Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein(a) isoform is determined by the rate of lipoprotein(a) production. J Clin Invest . 1993;;91:443-447.

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