Given the paucity of data in type 1 diabetes concerning lipoprotein-associated phospholipase A 2 (Lp-PLA2), we examined its prospective relationship with coronary artery disease (CAD), as well as the effect of modification by C-reactive protein (CRP) and haptoglobin genotype, in individuals with type 1 diabetes who are at an increased risk for CAD due to also having macroalbuminuria (n=96). Although Lp-PLA2 activity was univariately predictive of CAD (HR=1.54 per SD, p=0.009), this relationship was not significant after covariate adjustment (p=0.59). There was a significant interaction between Lp-PLA2 and CRP (p=0.02), i.e. those with both markers greater than the median level were more likely to have a CAD event than those persons with low levels of both (HR=2.89, p=0.06). When stratified by haptoglobin genotype, Lp-PLA2 was predictive of CAD in persons with the 2/1 (HR=2.40, p=0.05), but not 2/2 (HR=0.66, p=0.27), genotype. The association between Lp-PLA2 activity and CAD differs by CRP and haptoglobin genotype in this group of persons with type 1 diabetes and macroalbuminuria.
Ross R. ( 1999) Atherosclerosis: an inflammatory disease. N Engl J Med340: 115-126.
2.
McPhee CH , Moores KE, Boyd HF, et al. (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem J338: 479-487.
3.
Snyder F. ( 1995) Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes. Biochim Biophys Acta1254: 231-249.
4.
Häkkinen T., Luoma JS, Hiltunen MO, et al. (1999) Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol19: 2909-2917.
5.
Carpenter KL , Dennis IF, Challis IR, et al. (2001) Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidised LDL on human monocyte-macrophages. FEBS Lett50: 357-363.
6.
Tjoelker LW, Wilder C., Eberhardt C., et al. (1995) Antiinflammatory properties of a platelet-activating factor acetylhydrolase. Nature374: 549-553.
7.
Quarck R., De Geest B., Stengel D., et al. (2001) Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice. Circulation103: 2495-2500.
8.
Noto H., Hara M., Karasawa K., et al. (2003) Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins, conferring protection against oxidative stress. Arterioscler Thromb Vasc Biol23: 829-835.
Packard CJ, O’Reilly DSJ, Caslake MJ, et al. (2000) Lipoprotein-associated phospholipase A2 as an independent predictor of coronary artery disease. N Engl J Med2000; 343: 1148-1154.
11.
Koenig W., Khuseyinova N., Löwel H., Trischler G., Meisinger C. ( 2004) Lipoprotein-associated phospholipase A2 adds to the risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation110: 1903-1908.
12.
Ballantyne CM, Hoovgeveen RC, Bang H., et al. (2004) Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation109: 837-842.
13.
Oei HS, van der Meer IM, Hofman A., et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study . Circulation111: 570-575.
14.
Brilakis ES , McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB (2005) Association of Lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J26: 137-144.
15.
Winkler K., Winkelmann BR, Scharnagl H., et al. Platelet-activating factor acetlyhoydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study . Circulation111: 980-987.
16.
Koenig W., Twardella D., Brenner H., Rothenbacher D. ( 2006) Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol26: 1586-1593.
17.
Kim JY, Hyun YJ, Jang Y., et al. (2008) Lipoprotein-associated phospholipase A2 activity is associated with coronary artery disease and markers of oxidative stress: a case-control study. Am J Clin Nutr88: 360-367.
18.
Deckert T., Poulsen JE, Larsen M. ( 1978) Prognosis of diabetics with diabetes onset before the age of thirty-one. II. Factors influencing the prognosis. Diabetologia14: 371-377.
19.
Christlieb AR , Warram JH, Krolewski AS, et al. (1981) Hypertension: the major risk factor in juvenile-onset insulin-dependent diabetics . Diabetes30: 90-96.
20.
Dorman JS, LaPorte RE, Kuller LH, et al. (1984) The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) Morbidity and Mortality Study: mortality results. Diabetes33: 271-276.
21.
Krolewski AS , Kosinski EJ, Warram JH, et al. (1987) Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol59: 750-755.
22.
Moss SE, Klein R., Klein BE ( 1991) Cause-specific mortality in a population-based study of diabetes. Am J Public Health81: 1158-1162.
23.
Orchard TJ, Olson JC, Erbey JR, et al. (2003) Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes. Diabetes Care26: 1374-1379.
24.
Soedamah-Muthu SS, Chaturvedi N., Toeller M., et al. (2004) The EURODIAB Prospective Complications Study Group: Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study . Diabetes Care27: 530-537.
25.
Pambianco G. , Costacou T., Ellis D., Becker DJ, Klein R., Orchard TJ (2006) The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes55: 1463-1469.
26.
Ridker PM, Hennekens CH, Buring JE, Rifai N. ( 2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med342: 836-843.
27.
Rohde LEP , Hennekens CH, Ridker PM ( 1999) Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol84: 1018-1022.
28.
Strandberg TE, Tiluis RS (2000) C-reactive protein, cardiovascular disease, and mortality in a prospective study in the elderly. Arterioscler Thromb Vasc Biol20: 1057-1060.
29.
Freeman DJ, Norrie J., Caslake MJ, et al. (2002) C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes51: 1596-1600.
30.
Ridker PM, Glynn RJ, Hennekens CH ( 1998) C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction . Circulation97: 2007-2011.
31.
Danesh J., Whincup P., Walker M., et al. (2000) Low grade inflammation and coronary artery disease: prospective study and updated meta-analyses. BMJ321: 199-204.
32.
Ridker PM, Rifai N., Rose L., Burning JE, Cook NR ( 2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events . N Engl J Med1557-1565.
33.
Ridker PM ( 2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation170: 363-369.
34.
Boekholdt SM , Sandhu MS, Day NE, et al. (2006) Physical activity, C-reactive protein levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. Eur J Cardiovasc Prev Rehabil13: 970-976.
35.
Pu LJ, Lu L., Xu XW, et al. (2006) Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes. Cadiovasc Diabetol5: 27.
36.
Hsich MC, Tien KJ, Chang SJ, et al. (2008) High-sensitivity C-reactive protein and silent myocardial ischemia in Chinese with type 2 diabetes mellitus. Metabolism57: 1533-1538.
37.
Colhoun HM, Schalkwijk C., Rubens MB, Stehouwer CD ( 2002) C-reactive protein in type 1 diabetes and its relationship to coronary artery calcification. Diabetes Care25: 1813-1817.
38.
Costacou T. , Zgibor JC, Evans RW, et al. (2005) The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia48: 41-48.
39.
Jenkins AJ, Rothen M., Klein RL, et al. (2008) Cross-sectional associations of C-reactive protein with vascular risk factors and vascular complications in the DCCT/EDIC cohort. J Diabetes Complications22: 153-163.
40.
Levy AP, Hochberg I., Jablonski K., et al. (2002) Strong Heart Study: haptoglobin genotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol40: 1984-1990.
41.
Suleiman M. , Aronson D., Asleh R., et al. (2005) Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes54: 2802-2806.
42.
Roguin A., Koch W., Kastrati A., Aronson D., Schomig A., Levy AP ( 2003) Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes. Diabetes Care26: 2628-2631.
43.
Costacou T. , Ferrell RE, Orchard TJ (2008) Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes. Diabetes57: 1702.
44.
Krolewski AS , Warram JH, Christlieb AR, Busick EJ, Kahn CR (1985) The changing natural history of nephropathy in type I diabetes. Am J Med78: 785-794.
45.
Jensen T., Borch-Johnsen K., Kofoed-Enevoldsen A., Deckert T. ( 1987) Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without nephropathy: incidence and risk factors . Diabetologia30: 144-148.
46.
Tuomilehto J., Borch-Johnsen K., Molarius A., et al. (1998) Incidence of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland. Diabetologia41: 784-790.
47.
Klein BEK , Klein R., McBride PE, et al. (2004) Cardiovascular disease, mortality, and retinal microvascular characteristics in type 1 diabetes: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch Intern Med164: 1917-1924.
48.
Torffvit O. , Lövestam-Adrian M., Agardh E., Agardh C-D. ( 2005) Nephropathy, but not retinopathy, is associated with the development of heart disease in type 1 diabetes: as 12-year observation study of 462 patients. Diabet Med22: 723-729.
49.
Giunti S., Bruno G., Veglio M., et al. (2005) Electrocardiographic left ventricular hypertrophy in type 1 diabetes: prevalence and relation to coronary heart disease and the cardiovascular risk factors: the Eurodiab IDDM Complications Study. Diabetes Care28: 2255-2257.
50.
Koch W., Latz W., Eichinger M., et al. (2002) Genotyping of the common haptoglobin Hp 1/2 polymorphism based on PCR. Clin Chem48: 1377-1382.
51.
Allain CC, Poon LS, Chan CSG, Richmond W., Fu PC ( 1974) Enzymatic determination of total serum cholesterol . Clin Chem20: 470-475.
52.
Bucolo G., David H. ( 1973) Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem19: 476-482.
53.
Warnick GR, Albers JJ ( 1978) Heparin-Mn2 1 quantitation of high-density-lipoprotein cholesterol: an ultrafiltration procedure for lipemic samples. Clin Chem24: 900-904.
54.
National Institutes of Health, Department of Health ( 1975) Lipid Research Clinics Program. Washington, DC: US Government Printing Office, pp 75-628
55.
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem18: 499-502.
56.
Borhani NO, Kass EH, Langford HG, Payne GH, Remington RD, Stamler J. ( 1976) The hypertension detection and follow-up program . Prev Med5: 207-215.
57.
Furberg CD, Nelson JJ, Solomon CS, Cushman M., Swords JN, Psaty BM ( 2008) Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study. J Am Geriatr Soc56: 792-799.
58.
Allison MA, Denenberg JO, Nelson JJ, Natarajan L., Criqui MH ( 2007) The association between lipoprotein-associated phospholipase A2 and cardiovascular disease and total mortality in vascular medicine patients . J Vasc Surg46: 500-506.
59.
Blake GJ, Dada N., Fox JC, Manson JE, Ridker PM ( 2001) A prospective evaluation of lipoprotein-associated phospholipase A2 levels and the risk of future cardiovascular events in women . J Am Coll Cardiol38: 1302-1306.
