The Proline 12 Alanine Substitution in the Peroxisome Proliferator–Activated Receptor-γ2 Gene Is Associated With Lower Lipoprotein Lipase Activity in Vivo
- 1Department of Internal Medicine I (Endocrinology, Diabetes and Metabolism), Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany
- 2Department of Internal Medicine III (Cardiology), Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany
Abstract
Lipoprotein lipase (LPL) plays a key role in lipid metabolism by hydrolyzing triglycerides in circulating lipoproteins. Low LPL activity has been linked to coronary artery disease (CAD), but the factors influencing LPL expression are not completely understood. Peroxisome proliferator–activated receptor (PPAR)-γ is a nuclear receptor regulating lipid and glucose metabolism, and a PPAR-responsive element is present in the LPL promoter. We determined the Pro12Ala polymorphism in the PPAR-γ2 gene in 194 male CAD patients because this allele is associated with decreased PPAR activity and reduced LPL promoter activity in vitro. Presence of 12Ala was associated with 20% lower LPL activity in postheparin plasma (141 ± 58 vs. 177 ± 77 nmol · ml−1 · min−1, P < 0.005). Remarkably, the influence of 12Ala on LPL was greater than that of the frequent polymorphisms (HindIII +9%, PvuII ±0%, 447stop +12%) in the LPL gene itself. To confirm these results in a different group of patients, we analyzed 100 diabetic patients in whom the 12Ala allele was also associated with lower LPL activity (12Ala: 132 ± 88 vs. 190 ± 129 nmol · ml−1 · min−1, P < 0.05). Our data demonstrate that the Pro12Ala substitution in PPAR-γ2 is associated with lower LPL activity in vivo and provides a new target for the analysis of genetic influences on LPL activity and CAD risk.
Footnotes
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Address correspondence and reprint requests to Klaus A. Dugi, Department of Internal Medicine I (Endocrinology and Metabolism), University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany. E-mail: klaus_dugi{at}med.uni-heidelberg.de.
Received for publication 28 June 2001 and accepted in revised form 28 November 2001.
CAD, coronary artery disease; LPL, lipoprotein lipase; PPAR, peroxisome proliferator–activated receptor.
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