In this study we analyzed the contribution of genetic variability of the insertion/deletion (I/D) polymorphism of the angiotensin-I converting enzyme (ACE) gene to the predisposition for coronary artery disease (CAD) in a group of patients with type 2 diabetes. The I/D ACE gene polymorphism was tested in 366 Caucasians with type 2 diabetes: 148 cases with CAD and 218 subjects with no history of CAD. We failed to demonstrate that the ACE DD genotype was a risk factor for CAD in Caucasians with type 2 diabetes (OR 2.0, 95 % CI 0.9–4.7; p=0.1). In conclusion, we provide evidence that the ACE deletion/deletion genotype is not a risk factor for CAD in Caucasians with type 2 diabetes

Aleksandra Milutinović

Aleš Pleskovič

Nataša Teran

Rifet Terzić

Ruda Zorc-Pleskovič

English

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Coll. Antropol. 29 (2005) 1: 149–152UDC 577.113:616.127-005.8:616.379-008.64Original scientific paperDeletion/Deletion Genotype of Angiotensin-IConverting Enzyme Gene is not Associatedwith Coronary Artery Disease in Caucasians withType 2 DiabetesRuda Zorc-Pleskovi~1, Nata{a Teran2, Ale{ Pleskovi~1, Rifet Terzi}3,4 and Aleksandra Milutinovi}11 Institute of Histology and Embryology, Medical Faculty, University of Ljubljana2 Department of Ophtalmology, University Medical Centre Ljubljana3 Division of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slovenia4 Department of Biology and Human Genetics, Medical School Tuzla, Bosnia  HerzegovinaA B S T R A C TIn this study we analyzed the contribution of genetic variability of the insertion/deletion (I/D) polymorphism of theangiotensin-I converting enzyme (ACE) gene to the predisposition for coronary artery disease (CAD) in a group of pa-tients with type 2 diabetes. The I/D ACE gene polymorphism was tested in 366 Caucasians with type 2 diabetes: 148cases with CAD and 218 subjects with no history of CAD. We failed to demonstrate that the ACE DD genotype was arisk factor for CAD in Caucasians with type 2 diabetes (OR 2.0, 95 % CI 0.9–4.7; p=0.1). In conclusion, we provide evi-dence that the ACE deletion/deletion genotype is not a risk factor for CAD in Caucasians with type 2 diabetes.Keywords: angiotensin-I converting enzyme, coronary artery disease, diabetes type 2IntroductionThe prevalence of type 2 diabetes has been risingworldwide due to increasing obesity and decreasingphysical activity. In people with type 2 diabetes theleading cause of death is coronary artery disease (CAD)1.It is generally accepted that environmental and gene-tical factors affect the pathogenesis of CAD2,3. In Slove-nia several candidate genes for cardiovascular disordershave been tested in the general population as well as indiabetic patients3–8. Experimental studies and clinicaltrials show that the renin angiotensin system affectsthe pathogenesis of CAD and the prognosis of myocar-dial infarction (MI)9,10.The angiotensin-1 converting enzyme (ACE) dele-tion/deletion (DD) genotype is associated with increasedserum concentrations of ACE, which results in enhan-ced conversion of angiotensin I to II and degradation ofbradykinin11. In 1992 Cambien et al.12 showed that theDD genotype of the ACE gene polymorphism is a potentrisk factor for MI. Many reports about the role of DD ge-notype in pathogenesis of CAD and MI have been pub-lished since, but only few have so far been performed onpatients with type 2 diabetes13–19. In previous studies onSlovene population the DD genotype was found to be anindependent risk factor for premature MI in generalpopulation20,21.The aim of this study was to determine whether theACE DD genotype is a risk factor for CAD in a group ofCaucasians with type 2 diabetes.Materials and MethodsThe study population of this cross-sectional analysisconsisted of 366 diabetic subjects with type 2 diabetesduration of more than 10 years. In CAD group (148cases) there were 110 cases with a history of MI (the di-agnosis of MI was made according to the criteria ofWorld Health Organization) and 38 cases with anginapectoris confirmed with either abnormal stress testingor abnormal perfusion scan. The control group consistedof 218 diabetics with no history of CAD, no signs of149Received for publication March 4, 2004U:\coll-antropolo\coll-antro-1-2005\zorc.vp17. lipanj 2005 08:14:29Plate: 1 of 4Color profile: DisabledBlack  150 lpi at 45 degreesischemic changes on electrocardiogram and no ischemicchanges during submaximal stress testing. The patientsand control subjects came from independent families.The data and blood samples of age-matched controlswere obtained from general practitioners. The controlsdid not have a history of angina pectoris or MI, and theyhad normal electrocardiogram. All the subjects enrolledin the study were Slovenes. The research protocol wasapproved by the National Medical Ethics Committee.After informed consent was obtained from the patientsand control subjects, a detailed interview was made.The physician interviewed each patient about the coro-nary risk factors (cigarette smoking, arterial hyperten-sion, body weight and height). Smoking habit was de-fined as a daily intake of more than 5 cigarettes. Arte-rial hypertension was defined as binary variable. Arte-rial hypertension was defined as systolic blood pressurehigher than 140 mm Hg, diastolic blood pressure higherthan 90 mm Hg, or both, at repeated measurements, orcurrent use of antihypertensive agents for confirmed di-agnosis of arterial hypertension. Patients were classi-fied as having type 2 diabetes according to current ADAcriteria for the diagnosis and classification of diabetes22.Total cholesterol, low density lipoproteins (LDL),high density lipoproteins (HDL) and triglycerides weredetermined by standard biochemical methods.I/D polymorphism of ACE gene was evaluated as de-scribed previously20. Genotyping was performed by tworesearchers (MG, AM@), blinded to the CAD status ofthe patients.Differences in mean values were analyzed by Stu-dent t-test. Chi-square test was used to compare dis-crete variables. Statistical analysis was performed us-ing the SPSS program for Windows 2000 version 11(SPSS Inc., Illinois). Statistical significance was set atp<0.05. Logistic regression analysis was performed toassess the independent role of the ACE-DD genotypeand other variables, including sex, smoking, duration ofdiabetes, LDL cholesterol level, HDL cholesterol level.ResultsThe ACE genotype distributions in cases and con-trols were compatible with Hardy-Weinberg expecta-tions (Table 1; ACE cases: p=0.93, 2=0.007; ACE con-trols: p=0.69, 2=0.15). The characteristics of the casesand control subjects are listed in Table 2 (91.5 % of caseswere males). A higher incidence of cigarette smoking(45.9 % vs. 14.2 %; p0.001) was registered in the CADthan in the control group. The cases had a higher LDLcholesterol level (3.6±1.2 mmol/l vs. 3.2±1.0, p = 0.002),higher BMI (28.9±3.7 vs. 28.0±4.6; p=0.04) and longerduration of diabetes (22.2±6.9 vs. 17.5±8.3; p=0.001)than the controls (Table 2). There were no significantdifferences in the incidence of hypertension, total cho-lesterol level, HDL cholesterol level and triglycerideslevel between the cases and control subjects (Table 2).Univariate analysis (Table 2) demonstrated smokingand male sex to be associated with a 4.9-fold (95%CI=2.9–8.2; p<0.001) and a 2.3-fold risk of CAD (95%CI=1.5–3.6; p<0.001), respectively.Multiple logistic regression analysis of the data (Ta-ble 3) showed that the ACE DD genotype was not an in-dependent risk factor for MI in type 2 diabetes (OR=1.4;95% CI=0.8–2.3; p=0.23).Ruda Zorc-Pleskovi~ et al.: Coronary Disease in Diabetics and ACE, Coll. Antropol. 29 (2005) 1: 149–152150TABLE 1DISTRIBUTION OF ACE I/D GENOTYPES AMONGCAD PATIENTS AND CONTROLS (p=0.3, 2=2.1)Variable CAD patients (%) Controls (%)DD genotype 49 (32.9%) 60 (27.5%)1ID genotype 72 (48.3%) 104 (47.7%)II genotype 28 (18.8%) 54 (24.8%)1 Odds ratio (DD genotype vs. ID genotype + II genotype) =1.3; 95% CI=0.8–2.0; p=0.3)TABLE 3ADJUSTED ODDS RATIOS FOR CARDIOVASCULAR RISKFACTORS IN CAD PATIENTSRisk factors OR (95% CI)1 pDiabetes duration 0.95 (0.9–1.0) 0.07DD genotype2 2.0 (0.9–4.7) 0.1Smoking 1.1 (0.4–3.5) 0.8Male sex 1.1 (0.4–2.6) 0.9HDL cholesterol 1.2 (0.4–4.0) 0.8LDL cholesterol 1.4 (0.9–2.2) 0.21 Odds ratio (95% confidence interval)2ACE insertion/deletion gene polymorphismTABLE 2CHARACTERISTICS OF PATIENTS WITH CAD AND CONTROLSCharacteristicsCADgroup (%)Controlgroup (%)pValueNumber 148 218Age (years) 58.6±11.3 65.4±9.9 <0.001Male sex 97 (65.1) 99 (45.4) <0.001BMI (kg/m2) 28.9±3.7 28.0±4.6 0.04Arterial hypertension 101 (67.8) 141 (64.7) 0.5Smoking habit 68 (45.6) 31 (14.2) <0.001Diabetes duration (years) 22.2±6.9 17.5±8.3 <0.001Total cholesterol (mmol/l) 5.7±1.3 5.5±1.4 0.1HDL cholesterol (mmol/l) 1.1±0.3 1.2±0.3 0.07LDL cholesterol (mmol/l) 3.6±1.2 3.2±1.0 0.002Triglycerides (mmol/l) 2.3±1.3 2.6±1.8 0.2Values are means ± SDU:\coll-antropolo\coll-antro-1-2005\zorc.vp17. lipanj 2005 08:14:29Plate: 2 of 4Color profile: DisabledBlack  150 lpi at 45 degreesDiscussionIn the study we failed to demonstrate that the ACEDD genotype was a risk factor for CAD in Caucasianswith type 2 diabetes.In a mixed population (196 males+170 females) of366 patients with type 2 diabetes we failed to demon-strate an association between the ACE DD genotypeand an increased risk of CAD (OR=1.3; 95% CI=0.8–2.0;p=0.3). A separate analysis by sex showed an associa-tion between the ACE DD genotype and CAD in females(OR=2.6; 95% CI=1.3–5.2; p=0.007), but not in males(OR=0.8; 95% CI=0.4–1.4; p=0.4). In previous study theACE DD genotype was an independent risk factor forpremature MI in the general population (OR= 2; 95% CI1.1–3.7; p=0.01)20.Only few studies have been performed so far on pa-tients with type 2 diabetes, however, the results wereinconsistent13–16. Several studies including meta-analy-sis published by Samani et al.17 demonstrated an associ-ation between the ACE DD genotype and MI and CHD.However, Agerholm-Larsen et al.11 have recently re-ported a difference in the effect of the ACE DD genotypeon CAD, MI, or ischemic cerebrovascular disease be-tween small and large studies: risk of MI and CAD wasincreased by 47 % and 29 %, respectively, for DD versusID and II genotypes in small studies but not in largestudies11. Case control studies may suffer from severalbiases, which may lead to false positive and false nega-tive results23,24. In association studies the survival biascannot be avoided. It is possible that early mortality inCAD patients with type 2 diabetes is due to the ACEgene and that this could lead to an underestimation ofthe role of the DD genotype in patients with CAD in ourstudy. Furthermore, a higher percentage of women inour study compared to the study of Ruiz et al.16 mightalso be of importance, since CAD mortality associatedwith diabetes is greater for women than for men16,25–27.In our study longer duration of diabetes was demon-strated in the CAD group compared to the control group.Longer duration of diabetes was demonstrated to be animportant predictor of total mortality and the mortalitydue to CAD among women and men with type 2 diabe-tes28,29.In conclusion, the ACE DD genotype is not a risk fac-tor for CAD in Caucasians with type 2 diabetes.AcknowledgementsThe authors thank Ms Mojca Pirc, BA for revisingthe English text.R E F E R E N C E S1. GRUNDY, S. M., I. J. BENJAMIN, G. L. BURKE, Circulation, 100(1999) 1134. — 2. LETONJA, M., D. PETROVI^, Pacing Clin. Electro-physiol., 26 (2003) 2192. — 3. PETROVI^, D., B. PETERLIN, Cardiol-ogy, 99 (2003) 163. — 4. GLOBOCNIK PETROVIC, M., M. HAWLINA,B. PETERLIN, D. PETROVIC, J. Hum. Genet., 48 (2003) 457. — 5.GLOBOCNIK PETROVIC, M., M. HAWLINA, B. PETERLIN, D. PE-TROVIC, Ophthalmologica, 217 (2003) 219. — 6. PETROVIC GLO-BO^NIK, M., K. STEBLOVNIK, B. PETERLIN, D. PETROVIC, Klin.Monatsbl. Augenheilkd., 220 (2003) 873. — 7. PETERLIN, B., M. GLO-BOCNIK PETROVIC, J. MAKUC, M. HAWLINA, D. PETROVIC, J.Hum. Genet., 48 (2003) 646. — 8. PETROVIC, D., M. GLOBOCNIK PE-TROVIC, B. PETERLIN, Cardiology, 100 (2003) 157. — 9. PFEFFER,M. A., E. BRAUNWALD, L. A. MOYE, L. BASTA, E. J. BROWN, T. E.CUDDY, B. R. DAVIS, E. M. GELTMAN, S. GOLDMAN, G. C. FLAKER,N. Engl. J. Med., 327 (1992) 669. — 10. SCHUH, J. R., D. J. BLEHM, G.E. FRIEDLICH, E. G. MCMAHON, E. H. BLAINE, J. Clin. Invest., 91(1993) 1453. — 11. AGERHOLM-LARSEN, B., B. G. NORDESTGAARD,A. TYBJAERG-HANSEN, Arterioscler. Thromb. Vasc. Biol., 20 (2000)484. — 12. CAMBIEN, F., O. POIRIER, L. LACERF, Nature, 359 (1992)641. — 13. ARAZ, M., S. AYNACIOGLU, V. OKAN, I. AKDEMIR, S. AK-TARAN, Acta. Cardiol., 57 (2002) 265. — 14. FUJISAWA, T., H. IKE-GAMI, G. Q. SHEN, E. YAMATO, K. TAKEKAWA, Y. NAKAGAWA, Y.HAMADA, H. UEDA, H. RAKUGI, J. HIGAKI, Diabetes Care, 18 (1995)983. — 15. KEAVNEY, B. D., C. R. DUDLEY, I. M. STRATTON, R. R.HOLMAN, D. R. MATTHEWS, P. J. RATCLIFFE, R. C. TURNER, Dia-betologia, 38 (1995) 948. — 16. RUIZ, J., H. BLANCHE, N. COHEN,Proc. Natl. Acad. Sci. USA, 91 (1994) 3662. — 17. SAMANI, N. J., J. R.THOMPSON, L. O’TOOLE, K. CHANCER, K. L. WOODS, Circulation,94 (1996) 708. — 18. TARNOW, L., F. CAMBIEN, P. ROSSING, F. S.NIELSEN, B. V. HANSEN, L. LECERF, O. POIRIER, S. DANILOV, S.BOELSKIFTE, K. BORCH-JOHNSEN, Diabetologia, 38 (1995) 798. —19. WONG, T. Y., C. C. SZETO, K. M. CHOW, J. C. CHAN, P. K. LI, Am.J. Kidney Dis., 38 (2001) 9. — 20. PETROVIC, D., M. ZORC, V. KANIC,B. PETERLIN, Angiology, 52 (2001) 247. — 21. PETROVI^, D., I. KE-BER, M. ZORC, B. PETERLIN, Pflugers Arch., 431 Suppl. (1996) 197.— 22. The Expert Committee on the Diagnosis and Classification of Dia-betes Mellitus: Report of the Expert Committee on the Diagnosis andClassification of Diabetes Mellitus, Diabetes Care, 20 (1997) 1183. — 23.COX, N. J., G. I. BELL, Diabetes, 38 (1989) 947. — 24. PETROVIC, D.,M. BIDOVEC, B. PETERLIN, Folia. Biol. (Krakow), 50 (2002) 53. — 25.BARRETT-CONNOR, E. L., B. A. COHN, D. L. WINGARD, S. L. EDEL-STEIN, JAMA, 265 (1991) 627. — 26. ROSENGREN, A., L. WELIN, A.TSIPOGIANNI, L. WILHELMSEN, BMJ, 299 (1989) 1127. — 27. PE-TROVIC, D., M. ZORC, B. PETERLIN, Folia. Biol. (Praha), 46 (2000)181. — 28. CHO, E., E. B. RIMM, M. J. STAMPFER, W. C. WILLETT, F.B. HU, J. Am. Coll. Cardiol., 40 (2002) 954. — 29. KUUSISTO, J., L.MYKKANEN, K. PYORALA, M. LAAKSO, Diabetes, 43 (1994) 960.A. Milutinovi}Institute of Histology and Embryology, Medical Faculty, University of LjubljanaRuda Zorc-Pleskovi~ et al.: Coronary Disease in Diabetics and ACE, Coll. Antropol. 29 (2005) 1: 149–152151U:\coll-antropolo\coll-antro-1-2005\zorc.vp17. lipanj 2005 08:14:30Plate: 3 of 4Color profile: DisabledBlack  150 lpi at 45 degreesDELECIJA/DELECIJA GENOTIP ZA ANGIOTENZIN I KONVERTAZU NIJE POVEZANS KORONARNOM BOLESTI SRCA KOD BIJELACA S DIJABETESOM TIPA 2S A @ E T A KU ovoj studiji analiziran je doprinos genetske varijabilnosti insercije/delecije polimorfizma gena za angiotenzin-Ikonvertazu na predispoziciju za koronarnu bolest srca u grupi pacijenata s dijabetesom tipa 2. Varijabilnost insercije/delecije gena za angiotenzin-I konvertazu je testirana na 366 bijelaca s dijabetesom tipa 2: 148 ih je imalo koronarnubolest srca, dok ih 218 nije imalo koronarnu bolest srca. Nije dokazano da je delecija/delecija genotip za angiotenzin-Ikonvertazu rizi~ni faktor za koronarnu bolest srca kod bijelaca s dijabetesom tipa 2 (OR 2.0, 95% CI 0,9–4,7; p=0,1).Kao zaklju~ak, pru`amo dokaz da delecija/delecija genotip za angiotenzin-I konvertazu nije rizi~ni faktor za koro-narnu bolest srca kod bijelaca s dijabetesom tipa 2.Ruda Zorc-Pleskovi~ et al.: Coronary Disease in Diabetics and ACE, Coll. Antropol. 29 (2005) 1: 149–152152U:\coll-antropolo\coll-antro-1-2005\zorc.vp17. lipanj 2005 08:14:30Plate: 4 of 4Color profile: DisabledBlack  150 lpi at 45 degrees

Deletion/Deletion Genotype of Angiotensin-I Converting Enzyme Gene is not Associated with Coronary Artery Disease in Caucasians with Type 2 Diabetes

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