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POLYMORPHISMS AND CORONARY DISEASE

Lipoprotein Lipase Gene Polymorphisms and the Risk of Target Vessel Revascularization After Percutaneous Coronary Intervention

Pascalle S. Monraats, MSc^_*,, Jamal S. Rana, MD, Melchior C. Nierman, MD, Nuno M.M. Pires, MSc^_*,, Aeilko H. Zwinderman, PhD^||, John J.P. Kastelein, MD, PhD, Jan Albert Kuivenhoven, PhD, Moniek P.M. de Maat, PhD^¶, Saskia Z.H. Rittersma, MD^#, Abbey Schepers, MD^,**, Pieter A.F. Doevendans, MD, PhD, Robbert J. de Winter, MD, PhD^#, René A. Tio, MD, PhD, Rune R. Frants, PhD, Paul H.A. Quax, PhD^,**, Arnoud van Der Laarse, PhD^_*, Ernst E. van Der Wall, MD, PhD^_* and J. Wouter Jukema, MD, PhD^_*,,_*

^_* Department of Cardiology, Leiden University Medical Center, Leiden
Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht
Department of Vascular Medicine, Academic Medical Center, Amsterdam
Gaubius Laboratory, TNO-Quality of Life, Leiden
^|| Department of Medical Statistics, Academic Medical Center, Amsterdam
^¶ Department of Hematology, Erasmus University Medical Center, Rotterdam
^# Department of Cardiology, Academic Medical Center, Amsterdam
^** Department of Surgery, Leiden University Medical Center, Leiden
Department of Cardiology, University Medical Center, Utrecht
Department of Cardiology, Academic Hospital, Groningen
Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands

Manuscript received April 25, 2005; revised manuscript received May 20, 2005, accepted May 24, 2005.

^_* Reprint requests and correspondence: Dr. J. Wouter Jukema, Leiden University Medical Center, Department of Cardiology, C5-P, P.O. Box 9600, 2300 RC Leiden, the Netherlands (Email: J.W.Jukema{at}lumc.nl).

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.

Abbreviations and Acronyms   CABG = coronary artery bypass graft surgery   HDL = high-density lipoprotein   LDL = low-density lipoprotein   LPL = lipoprotein lipase   NO = nitric oxide   PCI = percutaneous coronary intervention   PCR = polymerase chain reaction   TVR = target vessel revascularization   VLDL = very-low-density lipoprotein

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