Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.
OBJECTIVE
Peroxisome proliferator activated receptor alpha (PPARalpha) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type II (non-insulin-dependent) diabetes mellitus, suggesting that PPARalpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies.


METHODS
The human PPARalpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays.


RESULTS
We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct.


CONCLUSIONS
Naturally occurring variation alters PPARalpha function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARalpha is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes.
Flavell
D M
DM
Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College London Medical School, The Rayne Institute, UK.
Pineda Torra
I
I
Jamshidi
Y
Y
Evans
D
D
Diamond
J R
JR
Elkeles
R S
RS
Bujac
S R
SR
Miller
G
G
Talmud
P J
PJ
Staels
B
B
Humphries
S E
SE
D016632:Apolipoprotein A-I / Q000097:blood; D001629:Bezafibrate / Q000494:pharmacology; D001665:Binding Sites; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004247:DNA / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006801:Humans; D007438:Introns; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D011446:Prospective Studies; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004247:DNA; D002784:Cholesterol; D001629:Bezafibrate