J Korean Diabetes Assoc.  2006 Mar;30(2):122-129. 10.4093/jkda.2006.30.2.122.

The Association of Pro12Ala Polymorphism in PPAR-gamma Gene with Coronary Artery Disease in Korean Subjects

• Kwon CH
• Rhee EJ
• Kim SY
• Kim ER
• Chon CU
• Jung CH
• Yun JH
• Kim BJ
• Sung KC
• Kim BS
• Lee WY
• Oh KW
• Kang JH
• Kim SW
• Lee MH
• Park JR

• KMID: 2063441
• DOI: http://doi.org/10.4093/jkda.2006.30.2.122

Abstract

BACKGROUND
PPAR-gamma, a member of nuclear family, which is involved in the differentiation of adipose tissue, is reported to be associated in the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. We conducted a research to see whether the prevalence of coronary artery disease is associated with Pro12Ala polymorphism in exon B of PPAR-gamma in Korean adults.
METHODS
The study was conducted in 161 subjects (97 males, 64 females, mean age 57 year old) who underwent coronary angiogram due to chest pain. We assessed cardiovascular risk factors in all subjects, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles. Subjects were divided into four groups as normal, 1-vessel, 2-vessel and 3-vessel disease according to the number of stenosed coronary arteries. Genotypings of Pro12Ala polymorphism were done with Real-time polymerase chain reaction.
RESULTS
Allelic frequency for proline was 0.957 and 0.043 for alanine, and they were in compliance with Hardy-Weinberg equilibrium (P = 0.85). 79 subjects (43.5%) had normal coronary artery, 52 subjects (31%), 1-vessel disease, 24 subjects (14.9%), 2-vessel disease and 15 subjects (9.3%), 3-vessel disease. When the cardiovascular risk factors were compared among these four groups, there were no meaningful differences except the age and high-density lipoprotein cholesterol levels, which were lost after adjustment for age and BMI. There were no significant differences in the prevalence or severity of coronary artery diseases according to the different genotypes of Pro12Ala polymorphism.
CONCLUSIONS
There was no significantassociation between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of coronary artery disease in Korean adults. It is considered that further studies on the correlation between Pro12Ala polymorphism and coronary artery disease should be carried out in larger Korean population in the future

Keyword

Coronary angiogram; Coronary heart disease; Pro12Ala polymorphism

MeSH Terms

Adipose Tissue
Adult
Alanine
Atherosclerosis
Blood Glucose
Blood Pressure
Body Mass Index
Chest Pain
Cholesterol
Compliance
Coronary Artery Disease*
Coronary Disease
Coronary Vessels*
Diabetes Mellitus, Type 2
Exons
Fasting
Female
Genotype
Humans
Insulin Resistance
Lipoproteins
Male
Nuclear Family
Prevalence
Proline
Real-Time Polymerase Chain Reaction
Risk Factors
Alanine
Blood Glucose
Cholesterol
Lipoproteins
Proline

Reference

1. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005. 111:3481–3488.

2. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J. 1984. 288:1401–1404.

3. Wilson PW, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA. 1994. 272:1666–1671.

4. Peng DQ, Zhao SP, Nie S, Li J. Gene-Gene interaction of PPARr and ApoE affects coronary heart disease risk. Int J Cardiol. 2003. 92:257–263.

5. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura Y, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000. 20:1595–1599.

6. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999. 100:2473–2476.

7. Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999. 354:141–148.

8. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000. 405:421–424.

9. Desvergne B, Wahli W. Peroxisome proliferators-activated receptors: nuclear control of metabolism. Endocr Rev. 1999. 20:649–688.

10. Rosen ED, Spiegelman BM. PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001. 276:37731–37734.

11. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000. 49:497–505.

12. Marx N, Duez H, Fruchart J-C, Steals B. Peroxisome proliferators-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res. 2004. 94:1168–1178.

13. Staels B. PPARgamma and atherosclerosis. Curr Med Res Opin. 2005. 21:Suppl 1. S13–S20.

14. Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, Colantuoni V. Pro12Ala substitution in the peroxisome proliferators activated receptor-2 is not associated with type 2 diabetes. Diabetes. 1999. 48:1466–1468.

15. Ringel J, Engeli S, Distler A, Sharma AM. Pro12Ala missense mutation of the peroxisome proliferators activated receptor and diabetes mellitus. Biocheml Biophys Res Commun. 1999. 254:450–453.

16. Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, Beamer BA, Charpentier G, Guy-Grand B, Froguel P, Vaisse C. The Pro115Gln and pro12Ala PPAR gene mutations in obesity and type 2 diabetes. Intl J Obes Relat Metab Disord. 2000. 24:391–393.

17. Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki T, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T. The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biocheml Biophys Res Commun. 2000. 271:212–216.

18. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deep SS, Amouyel P. Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord. 2000. 24:195–199.

19. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000. 26:76–80.

20. Memisoglu A, Hu FB, Hankinson SE, Liu S, Meigs JB, Altshuler DM, Hunter DJ, Manson JE. Prospective Study of the Association Between the Proline to Alanine Codon 12 Polymorphism in the PPARgamma Gene and Type 2 Diabetes. Diabetes Care. 2003. 26:2915–2917.

21. Kao WH, Coresh J, Shuldiner AR, Boerwinkle E, Bray MS, Brancati FL. Pro12Ala of the peroxisome proliferator-activated receptor-gamma2 gene is associated with lower serum insulin levels in nonobese African Americans: the Atherosclerosis Risk in Communities Study. Diabetes. 2003. 52:1568–1572.

22. Danawati CW, Nagata M, Moriyama H, Hara K, Yasuda H, Nakayama M, Kotani R, Yamada K, Sakata M, Kurohara M, Wiyono P, Asdie H, Sakaue M, Taniguchi H, Yokono K. A possible association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia. Diabetes Metab Res Rev. 2005. 21:465–469.

23. Oh EY, Min KM, Chung JH, Min YK, Lee MS, Kim KW, Lee MK. Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. J Clin Endocrinol Metab. 2000. 85:1801–1804.

25. Ridker PM, Cook NR, Cheng S, Erlich HA, Lindpaintner K, Plutzky J, Zee RY. Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction. Arterioscler Thromb Vasc Biol. 2003. 23:859–863.

26. Temelkova-Kurktschiev T, Hanefeld M, Chinetti G, Zawadzki C, Haulon S, Kubaszek A, Koehler C, Leonhardt W, Staels B, Laakso M. Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma2 protects against atherosclerosis. J Clin Endocrinol Metab. 2004. 89:4238–4242.

27. Bluher M, Klemm T, Gerike T, Krankenberg H, Schuler G, Paschke R. Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus. Eur J Endocrinol. 2002. 146:545–551.

28. Pischon T, Pai JK, Manson JE, Hu FB, Rexrode KM, Hunter D, Rimm EB. Peroxisome proliferators-activated receptor gamma2 P12A polymorphism and risk of coronary heart disease in US men and women. Arterioscler Thromb Vasc Biol. 2005. 25:1654–1658.

29. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001. 285:2486–2496.

30. Kim KS, Choi SM, Shin SU, Yang HS, Yoon Y. Effects of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism on body fat distribution in female Korean subjects. Metabolism. 2004. 53:1538–1543.

31. Moon MK, Cho YM, Jung HS, Park YJ, Yoon KH, Sung YA, Park BL, Lee HK, Park KS, Shin HD. Genetic polymorphisms in peroxisome proliferator-activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population. Diabet Med. 2005. 22:1161–1166.

32. Yamamoto J, Kageyama S, Nemoto M, Sasaki T, Sakurai T, Ishibashi K, Mimura A, Yokota K, Tajima N. PPARgamma2 pro12Ala polymorphism and insulin resistance in Japanese hypertensive patients. Hypertens Res. 2002. 25:25–29.

33. Yamamoto Y, Hirose H, Miyashita K, Nishikai K, Saito I, Taniyama M, Tomita M, Saruta T. PPAR(gamma)2 gene Pro12Ala polymorphism may influence serum level of an adipocyte-derived protein, adiponectin, in the Japanese population. Metabolism. 2002. 51:1407–1409.

34. Puddu P, Puddu GM, Muscari A. Peroxisome proliferator-activated receptors: are they involved in atherosclerosis progression? Int J Cardiol. 2003. 90:133–140.

35. Hsueh WA, Law R. The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol. 2003. 92:3J–9J.

36. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel P, Dallongeville J, Deeb S, Auwerx J, Amouyel P. A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. Hum Mol Genet. 1998. 7:435–440.

37. Wang XL, Oosterhof J, Duarte N. Peroxisome proliferators-activated receptor gamma C161T polymorphism and coronary artery disease. Cardiovasc Res. 1999. 44:588–594.