Published online before print March 27, 2003, doi: 10.1161/01.ATV.0000068680.19521.34
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Alanine for Proline Substitution in the Peroxisome Proliferator–Activated Receptor Gamma-2 (PPARG2) Gene and the Risk of Incident Myocardial Infarction
From the Center for Cardiovascular Disease Prevention and the LeDucq Center for Molecular and Genetic Epidemiology (P.M.R., J.P., N.R.C., R.Y.L.Z.), Divisions of Preventive Medicine and Cardiovascular Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Human Genetics (S.C., H.A.E.), Roche Molecular Systems, Alameda, Calif; and the Roche Center for Medical Genomics (K.L.), Basel, Switzerland.
Correspondence to Dr Paul Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston, MA 02215. E-mail pridker{at}partners.org
Objective— Recent studies have implicated the potential importance of peroxisome proliferator–activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction.
Methods and Results— Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024).
Conclusions— In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.
Key Words: genetics • epidemiology • myocardial infarction • risk prediction • polymorphism
This article has been cited by other articles:
 |
|
 |
|
  J. G. Schneider, S. Schiekofer, M. von Eynatten, and K. A. Dugi PPAR{gamma} Variant Influences Angiographic Outcome and 10-Year Cardiovascular Risk in Male Symptomatic Coronary Artery Disease Patients: Response to Regieli et al. Diabetes Care, June 1, 2009; 32(6): e75 - e75. [Full Text] [PDF]
|
|
|
|
|
|
J. J. Regieli, J. W. Jukema, P. A. Doevendans, A. H. Zwinderman, Y. van der Graaf, J. J. Kastelein, and D. E. Grobbee PPAR{gamma} Variant Influences Angiographic Outcome and 10-Year Cardiovascular Risk in Male Symptomatic Coronary Artery Disease Patients Diabetes Care, May 1, 2009; 32(5): 839 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Lehmann and B. B. Lohray A Lesson in Moderation: Applying Pharmacodynamics to Clarify the Relationship Between Thiazolidinediones and Adverse Vascular Outcomes in Type 2 Diabetes J. Clin. Pharmacol., August 1, 2008; 48(8): 999 - 1002. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Z. Duan, M. G. Usher, and R. M. Mortensen Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature Circ. Res., February 15, 2008; 102(3): 283 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A Ruiz-Narvaez, P. Kraft, and H. Campos Ala12 variant of the peroxisome proliferator-activated receptor-{gamma} gene (PPARG) is associated with higher polyunsaturated fat in adipose tissue and attenuates the protective effect of polyunsaturated fat intake on the risk of myocardial infarction Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1238 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Savas, I. W. Taylor, J. L. Wrana, and H. Ozcelik Functional nonsynonymous single nucleotide polymorphisms from the TGF-{beta} protein interaction network Physiol Genomics, April 24, 2007; 29(2): 109 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Morgan, H. M. Krumholz, R. P. Lifton, and J. A. Spertus Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study JAMA, April 11, 2007; 297(14): 1551 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Barlic, Y. Zhang, J. F. Foley, and P. M. Murphy Oxidized Lipid-Driven Chemokine Receptor Switch, CCR2 to CX3CR1, Mediates Adhesion of Human Macrophages to Coronary Artery Smooth Muscle Cells Through a Peroxisome Proliferator-Activated Receptor {gamma}-Dependent Pathway Circulation, August 22, 2006; 114(8): 807 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. I. Freedman, D. W. Bowden, M. M. Sale, C. D. Langefeld, and S. S. Rich Genetic Susceptibility Contributes to Renal and Cardiovascular Complications of Type 2 Diabetes Mellitus Hypertension, July 1, 2006; 48(1): 8 - 13. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Pischon, J. K. Pai, J. E. Manson, F. B. Hu, K. M. Rexrode, D. Hunter, and E. B. Rimm Peroxisome Proliferator-Activated Receptor-{gamma}2 P12A Polymorphism and Risk of Coronary Heart Disease in US Men and Women Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1654 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Ruiz-Narvaez Is the Ala12 variant of the PPARG gene an "unthrifty allele"? J. Med. Genet., July 1, 2005; 42(7): 547 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Knouff and J. Auwerx Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology Endocr. Rev., December 1, 2004; 25(6): 899 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S.F. Doney, B. Fischer, G. Leese, A. D. Morris, and C. N.A. Palmer Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus: A Go-DARTS Study Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2403 - 2407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Florez Phenotypic Consequences of the Peroxisome Proliferator-Activated Receptor-{gamma} Pro12Ala Polymorphism: The Weight of the Evidence in Genetic Association Studies J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4234 - 4237. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Z. Al-Shali, A. A. House, A. J.G. Hanley, H. M.R. Khan, S. B. Harris, B. Zinman, M. Mamakeesick, A. Fenster, J. D. Spence, and R. A. Hegele Genetic Variation in PPARG Encoding Peroxisome Proliferator-Activated Receptor {gamma} Associated With Carotid Atherosclerosis Stroke, September 1, 2004; 35(9): 2036 - 2040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Desvergne, L. Michalik, and W. Wahli Be Fit or Be Sick: Peroxisome Proliferator-Activated Receptors Are Down the Road Mol. Endocrinol., June 1, 2004; 18(6): 1321 - 1332. [Abstract] [Full Text] [PDF]
|
|