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 (<or=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 (<or=22 K4 repeats; OR 1.47 for men and 1.69 for women; P<0.002) and in women with <or=8 PN repeats (OR 1.46, P=0.009). Interestingly, in women, the frequent haplotype with <or=8 PN and <or=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 <or=8 PN and <or=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.
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 (<or=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 (<or=22 K4 repeats; OR 1.47 for men and 1.69 for women; P<0.002) and in women with <or=8 PN repeats (OR 1.46, P=0.009). Interestingly, in women, the frequent haplotype with <or=8 PN and <or=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 <or=8 PN and <or=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.
Authors: Tracie A Seimon; Marissa J Nadolski; Xianghai Liao; Jorge Magallon; Matthew Nguyen; Nicole T Feric; Marlys L Koschinsky; Richard Harkewicz; Joseph L Witztum; Sotirios Tsimikas; Douglas Golenbock; Kathryn J Moore; Ira Tabas Journal: Cell Metab Date: 2010-11-03 Impact factor: 27.287
Authors: David-Alexandre Trégouët; Inke R König; Jeanette Erdmann; Alexandru Munteanu; Peter S Braund; Alistair S Hall; Anika Grosshennig; Patrick Linsel-Nitschke; Claire Perret; Maylis DeSuremain; Thomas Meitinger; Ben J Wright; Michael Preuss; Anthony J Balmforth; Stephen G Ball; Christa Meisinger; Cécile Germain; Alun Evans; Dominique Arveiler; Gérald Luc; Jean-Bernard Ruidavets; Caroline Morrison; Pim van der Harst; Stefan Schreiber; Katharina Neureuther; Arne Schäfer; Peter Bugert; Nour E El Mokhtari; Jürgen Schrezenmeir; Klaus Stark; Diana Rubin; H-Erich Wichmann; Christian Hengstenberg; Willem Ouwehand; Andreas Ziegler; Laurence Tiret; John R Thompson; Francois Cambien; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Sebhat Erqou; Stephen Kaptoge; Philip L Perry; Emanuele Di Angelantonio; Alexander Thompson; Ian R White; Santica M Marcovina; Rory Collins; Simon G Thompson; John Danesh Journal: JAMA Date: 2009-07-22 Impact factor: 56.272