Published Online
on January 20, 2003

A more recent version of this article appeared on February 11, 2003

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Submitted on August 6, 2002
Revised on October 25, 2002
Accepted on October 28, 2002

Association of Polymorphisms of the Apolipoprotein(a) Gene With Lipoprotein(a) Levels and Myocardial Infarction

Stephan R. Holmer MD^*, Christian Hengstenberg MD, Hans-Georg Kraft PhD, Björn Mayer MD, Melanie Pöll , Susanne Kürzinger , Marcus Fischer MD, Hannelore Löwel MD, Gernot Klein MD, Günter A.J. Riegger MD, and Heribert Schunkert MD

From the Klinik und Poliklinik für Innere Medizin II, Universität Regensburg (S.R.H., C.H., B.M., M.P., S.K., M.F., G.A.J.R., H.S.), the GSF Forschungszentrum-Institut für Epidemiologie und Sozialmedizin, Neuherberg (H.L.), the Klinik Höhenried für Herz- und Kreislaufkrankheiten, Bernried (G.K.), and the Institut für Medizinische Biologie und Humangenetik, Universität Innsbruck, Austria (H.-G.K).

^* To whom correspondence should be addressed. E-mail: stephan.holmer{at}klinik.uni-regensburg.de.

Background--Serum lipoprotein(a) [Lp(a)] concentration is largely determined by variability at the apolipoprotein(a) gene locus. Most prominent effects relate to polymorphisms in the promoter (a pentanucleotide [PN] repeat) and coding regions (a kringle IV [K4] repeat), the latter of which also affects Lp(a) particle size. The impact of these polymorphisms on cardiovascular risk is poorly understood.

Methods and Results--We studied both polymorphisms and Lp(a) levels in 834 registry-based myocardial infarction (MI) patients (38% women) and 1548 population-based controls. Lp(a) concentrations were inversely related with the numbers of K4 and PN repeats. However, the effect of the PN polymorphism was restricted to subjects producing small Lp(a) particles (8 PN 66.1 mg/dL versus >8 PN 8.7 mg/dL; P<0.0001). The odds to present with MI were elevated in individuals producing small Lp(a) particles (22 K4 repeats; OR 1.47 for men and 1.69 for women; P<0.002) and in women with 8 PN repeats (OR 1.46, P=0.009). Interestingly, in women, the frequent haplotype with 8 PN and 22 K4 repeats, which is related to high levels of small Lp(a) particles, resulted in an elevated OR for MI (1.79; P=0.01) independently of Lp(a) serum concentration.

Conclusions--The K4 and PN repeat polymorphisms largely explain the high variability of serum Lp(a) levels. A haplotype with 8 PN and 22 K4 repeats is characterized by high concentrations of small Lp(a) particles. Our observation that this haplotype was associated with MI independently of Lp(a) serum levels may suggest that Lp(a) particle size in addition to its concentration may modulate MI risk in women.

Key words: apolipoproteins • polymorphism • myocardial infarction • women • population

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