TY - JOUR
T1 - Lipoprotein lipase gene polymorphisms and the risk of target vessel revascularization after percutaneous coronary intervention
AU - Monraats, Pascalle S
AU - Rana, Jamal S
AU - Nierman, Melchior C
AU - Pires, Nuno M M
AU - Zwinderman, Aeilko H
AU - Kastelein, John J P
AU - Kuivenhoven, Jan Albert
AU - de Maat, Moniek P M
AU - Rittersma, Saskia Z H
AU - Schepers, Abbey
AU - Doevendans, Pieter A F
AU - de Winter, Robbert J
AU - Tio, René A
AU - Frants, Rune R
AU - Quax, Paul H A
AU - van der Laarse, Arnoud
AU - van der Wall, Ernst E
AU - Jukema, J Wouter
N1 - J rticle
PY - 2005/9/20
Y1 - 2005/9/20
N2 - OBJECTIVES: We sought to identify polymorphisms in genes that predispose to restenosis.BACKGROUND: Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis.METHODS: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process.RESULTS: Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement.CONCLUSIONS: The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.
AB - OBJECTIVES: We sought to identify polymorphisms in genes that predispose to restenosis.BACKGROUND: Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis.METHODS: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process.RESULTS: Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement.CONCLUSIONS: The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.
KW - ARTERY-DISEASE
KW - HDL CHOLESTEROL
KW - HEART-DISEASE
KW - NITRIC-OXIDE
KW - PLASMA TRIGLYCERIDES
KW - MONOCYTE ADHESION
KW - STENT ERA
KW - RESTENOSIS
KW - ATHEROSCLEROSIS
KW - EXPRESSION
U2 - 10.1016/j.jacc.2005.05.071
DO - 10.1016/j.jacc.2005.05.071
M3 - Article
C2 - 16168296
SN - 0735-1097
VL - 46
SP - 1093
EP - 1100
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 6
ER -