Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.
BACKGROUND
Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD).


RESULTS
We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARalpha 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 PPARalpha gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall.
Flavell
David M
DM
Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College of London Medical School, London, UK. d.flavell@ucl.ac.uk
Jamshidi
Yalda
Y
Hawe
Emma
E
Pineda Torra
Inés
I
Taskinen
Marja-Riitta
MR
Frick
M Heikki
MH
Nieminen
Markku S
MS
Kesäniemi
Y Antero
YA
Pasternack
Amos
A
Staels
Bart
B
Miller
George
G
Humphries
Steve E
SE
Talmud
Philippa J
PJ
Syvänne
Mikko
M
D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D001161:Arteriosclerosis / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D015897:Comorbidity; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D018450:Disease Progression; D005387:Finland / Q000453:epidemiology; D015248:Gemfibrozil / Q000627:therapeutic use; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007438:Introns; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018570:Risk Assessment; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
D000960:Hypolipidemic Agents; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015248:Gemfibrozil