Published Online
on February 25, 2002

A more recent version of this article appeared on March 26, 2002

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Submitted on November 20, 2001
Revised on January 18, 2002
Accepted on January 18, 2002

Peroxisome Proliferator-Activated Receptor Gene Variants Influence Progression of Coronary Atherosclerosis and Risk of Coronary Artery Disease

David M. Flavell PhD^*, Yalda Jamshidi PhD, Emma Hawe MSc, Inés Pineda Torra PhD, Marja-Riitta Taskinen MD, M. Heikki Frick MD, Markku S. Nieminen MD, Y. Antero Kesäniemi MD, Amos Pasternack MD, Bart Staels PhD, George Miller MD, Steve E. Humphries PhD, FRCPath, MRCP, Philippa J. Talmud PhD, DSc, FRCPath, and Mikko Syvänne MD

From the Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College of London Medical School, London, UK (D.M.F., Y.J., E.H., S.E.H., P.J.T.); U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, Lille, France (I.P.T., B.S.); the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (M.-R.T., M.H.F., M.S.N., M.S.); the Department of Medicine, University of Oulu, Oulu, Finland (Y.A.K.); the Department of Medicine, Tampere University Hospital, Tampere, Finland (A.P.); and Medical Research Council Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew's Hospital, London, UK (G.M.).

^* To whom correspondence should be addressed. E-mail: d.flavell{at}ucl.ac.uk.

Background—Peroxisome proliferator-activated receptor (PPAR) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD).

Methods and Results—We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPAR gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism

Conclusions—The PPAR gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPAR affects atherosclerotic progression directly in the vessel wall.

Key words: atherosclerosis • genetics • coronary disease

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