Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online July 31, 2007
Diabetes Care 30:2863-2867, 2007
DOI: 10.2337/dc07-0869
© 2007 by the American Diabetes Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0869v1
30/11/2863    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Porchay-Baldérelli, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Porchay-Baldérelli, I.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Epidemiology/Health Services Research
Original Research

The CETP TaqIB Polymorphism Is Associated With the Risk of Sudden Death in Type 2 Diabetic Patients

Isabelle Porchay-Baldérelli, PHD1,2, Franck Péan, MSC1,2, Naïma Bellili, MSC1,2, Riphed Jaziri, PHD1,2, Michel Marre, MD, PHD1,2,3, Frédéric Fumeron, PHD1,2 for the DIABHYCAR Study Group

1 Institut National de la Santé et de la Recherche Médicale, U695, Genetic Determinants for Type 2 Diabetes and Its Vascular Complications, Paris, France
2 University Paris-Diderot, Paris 7, Paris, France
3 Department of Endocrinology, Diabetology, Nutrition and Metabolic Diseases, Assistance Publique-Hôpitaux de Paris, Xavier Bichat Hospital, Paris, France

Address correspondence and reprint requests to F. Fumeron, INSERM, U695, Xavier Bichat Medical School, BP 416, 16 rue Henri Huchard, 75870 Paris cedex 18, France. E-mail: fumeron{at}bichat.inserm.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 APPENDIX--
 References
 
OBJECTIVE—Type 2 diabetic patients have a high risk of coronary heart disease (CHD) and sudden death. This cardiovascular risk can be partly attributed to low levels of HDL cholesterol. The B2 allele of the CETP TaqIB polymorphism has been repeatedly reported to be associated with high HDL cholesterol levels in both healthy and type 2 diabetic subjects, but its association with CHD is unclear. We investigated the association of the CETP TaqIB polymorphism with CHD, and sudden death in particular, in a prospective cohort of type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—The CETP TaqIB polymorphism was genotyped in 3,124 type 2 diabetic subjects with high cardiovascular risk: the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study. We used Cox regression analysis to estimate the impact of the TaqIB single nucleotide polymorphism on the CHD events (myocardial infarction or sudden death) during follow-up.

RESULTS—The incidence of CHD was higher in B1B1 homozygotes than in B2 carriers (P = 0.02). This effect was mainly due to sudden death (hazard ratio [B1B1 vs. B2+] = 1.51 [95% CI = 1.05–2.18]). Although the B1 allele was associated in a dose-dependent fashion with lower HDL cholesterol (P < 0.001), the association with sudden death persisted after adjustment for multiple risk factors, including HDL cholesterol levels.

CONCLUSIONS—In type 2 diabetic patients, the CETP TaqIB polymorphism is a good genetic predictor of cardiac mortality. This association is partly independent of the effect on HDL cholesterol levels.

Abbreviations: CHD, coronary heart disease • CETP, cholesteryl ester transfer protein • CRP, C-reactive protein • DIABHYCAR, Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril • SNP, single nucleotide polymorphism • UAE, urinary albumin excretion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 APPENDIX--
 References
 
Type 2 diabetic patients have a high risk of coronary heart disease (CHD) (1). Sudden death occurs frequently among diabetic patients (2,3). The increased CHD risk is partly due to low HDL cholesterol levels (4,5) that are a common feature of insulin resistance (6). The cholesterol ester transfer protein (CETP) plays a key role in HDL metabolism and reverse cholesterol transport; it exchanges cholesterol ester from HDL for triglycerides from apolipoprotein B–rich particles (7). The CETP gene is localized on chromosome 16q31, and several CETP gene single nucleotide polymorphisms (SNPs) have been described. The most extensively studied CETP SNP is located in the first intron in the gene and disrupts a TaqI restriction site (TaqIB SNP: rs708272). The B2 allele of this SNP is associated with higher HDL cholesterol concentrations and lower CETP levels in both healthy and type 2 diabetic subjects (8,9), probably because of a nearly complete linkage disequilibrium with the –629G>A functional promoter polymorphism modifying the transcriptional activity of the CETP gene (10). Some studies reported that TaqIB SNP was associated with CHD (11–14). Nevertheless, other studies showed no correlation, and some studies supported the hypothesis of a CETP effect independent of HDL levels (15). A recent study of a cohort from the general population reported a higher CHD risk with TaqIB2 and –629A (16). Only a few longitudinal prospective studies have been reported in type 2 diabetes.

We assessed the association of the CETP TaqIB polymorphism with the incidence of CHD and with sudden death in particular in a large cohort of >3,100 French type 2 diabetic patients (the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril [DIABHYCAR] study).


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 APPENDIX--
 References
 
The design and results of the DIABHYCAR study have been reported (17–19). Briefly, DIABHYCAR was a multicentric, random, double-blind, parallel group trial to compare the cardiovascular and renal outcomes of patients taking ramipril (1.25 mg/day) and those taking placebo, in addition to their usual treatment (both groups). The participants were men or women with type 2 diabetes, aged ≥50 years, with serum creatinine ≤150 µmol/l, and elevated urinary albumin excretion (UAE) (≥20 mg/l, two times consecutively). The investigators examined the participants every 6 months for at least 3 years. The mean duration of follow-up was 4 years. The low dose of ramipril was found to be ineffective (19).

For logistical reasons, only French participants (3,124 of the 4,912 participants) were included in this study. Incident myocardial infarction was defined as the first occurrence of a fatal or nonfatal myocardial infarction after the baseline examination. Sudden death was defined as death occurring instantaneously or within 1 h after the onset of new cardiac symptoms (arrhythmia or other cardiovascular causes) or nonwitnessed death, where the body of the deceased was found, and no cause could be discovered. Fatal stroke and myocardial infarction were not included in this group. CHD was defined as the combination of myocardial infarction and sudden death. However, as some people with myocardial infarction died from sudden death, the number of CHD patients is not the sum of myocardial infarction and sudden death groups. An independent adjudication committee without access to the genotyping data evaluated the events (18). The study design was approved by the Angers University Ethics Committee. All participants provided written informed consent.

The CETP TaqIB SNP was genotyped using a PCR molecular beacon technique (20). The PCR was performed in a 96-well microtitration plate. A total of 200 ng of DNA was amplified in a total volume of 25 µl containing 20 pmol of 5' and 3' primers, 0.2 mmol/l dNTPs, 4 mmol/l MgCl2, 10 mmol/l Tris-HCl (pH 8.3), 5 pmol of each allele-specific molecular beacon, and 1 unit of Taq polymerase (gold Taq; Perkin-Elmer, Paris, France). DNA denaturation and Taq activation were performed at 95°C for 10 min in a thermocycler (PTC-200; MJ Research, Watertown, MA) followed by 40 cycles of 20 s at 55°C, 10 s at 72°C, and 10 s at 95°C. After a final denaturation at 95°C for 2 min, hybridization with the probes was performed at 60°C for 1 min. Fluorescence emission was recorded with a plate fluorometer (FLUOstar; BMG Labtech, Offenburg, Germany) using two wavelength systems: 480–520 nm for fluorescein and 520–590 nm for tetramethylrhodamine. The amplifiers and allele-specific probes were synthesized by Eurogentec (Seraing, Belgium). All of the sequences of primers and probes are available from the authors on request.

Quantitative variables are described by means ± SD or geometric means (95% CI) if the distribution was skewed. The association of CETP TaqIB genotypes with baseline characteristics, not including lipids, was tested by ANOVA (continuous variables) or a {chi}2 test (categorical variables) in univariate analysis. The association of CETP TaqIB genotypes with baseline lipid levels was tested by ANCOVA, adjusting for potential confounding variables (age, sex, BMI, A1C, smoking, and alcohol). We defined survival time as the period from the date of entry into the study to the date of the first event (myocardial infarction or sudden death) or the end of the study. Cox regression was used to estimate the hazard ratio; we adjusted for age, sex, prior myocardial infarction, systolic blood pressure, A1C, C-reactive protein (CRP), UAE, serum creatinine, total and HDL cholesterol, smoking, diabetes duration, BMI, and triglyceride levels and for the use of drugs at baseline: different antidiabetes and lipid-lowering treatments, treatments for hypertension, and platelet antiaggregants. We also adjusted for insulin and ACE inhibitor treatments, which could only be introduced during the follow-up (treatments by insulin and/or an ACE inhibitor at entry were exclusion criteria). The distribution of the use of the different drugs did not differ among genotypes. There was no interaction effect between genotype and the use of drugs. No interaction effect was found between sex and genotype, either on lipid levels or on CHD events. Therefore, data are not presented separately according to sex. All calculations were performed using SYSTAT 11 for Windows.


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 APPENDIX--
 References
 
Table 1 provides a summary of features and clinical and lipid profiles at baseline of the DIABHYCAR population as well as the stratified data according to combined CHD incidence (myocardial infarction or cardiovascular death). Subjects with incident CHD during follow-up differed in age; total, LDL, and HDL cholesterol and triglyceride levels; blood pressure; known duration of diabetes; prevalence of prior coronary antecedents (myocardial infarction and angina pectoris); serum CRP; serum creatinine; and UAE. The sex ratio was similar in the two groups. Genotype and allele distributions of the TaqIB SNP are shown in Table 2. The genotype frequencies were in Hardy-Weinberg equilibrium. None of the variables (distribution or levels), including prior coronary events, differed according to CETP Taq1B genotypes (data not shown) except lipid levels (Table 2). The CETP TaqI B1 allele was associated with low levels of HDL cholesterol (P < 0.001), with a gene dose effect (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 1— Baseline characteristics of subjects in the DIABHYCAR study

 

View this table:
[in this window]
[in a new window]

  		Table 2— Association of Taq1B SNP with plasma lipid levels

 
The CHD incidence (myocardial infarction and/or sudden death) according to the CETP genotype is shown in Table 3. There was a higher percentage of B1B1 subjects in the CHD group than in the group without CHD. Cox survival analysis indicated that B1B1 homozygotes had more risk than carriers of the B2 allele, independent of other risk factors, including many variables listed in Table 1 (age, A1C, systolic blood pressure, diabetes duration, prior myocardial infarction, total plasma cholesterol, triglycerides, serum CRP, serum creatinine, and UAE). There was no interaction between genotype and the presence of prior coronary events on the incidence of CHD. Nevertheless, the association was still significant when we excluded subjects with prior myocardial infarction.


View this table:
[in this window]
[in a new window]

  		Table 3— Frequencies of CETP genotypes according to the incidence of coronary events

 
After further adjustment for HDL cholesterol levels, the association remained significant and only slightly lower than that without the adjustment. Sudden death was a major factor in this association (Table 3). The 4-year overall and sudden death–free survival rates were 91 and 95% for B1B1 and B2 carriers, respectively. The B1B1 genotype was also more frequent in the "incident myocardial infarction" group (Table 3), but the association was not significant. This could be due to a lack of power of the study because there were so few cases of incident myocardial infarction.


   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
APPENDIX--
 References
 
We report a prospective study based on a large cohort of French type 2 diabetic patients with micro- or macroalbuminuria and found, for the first time, a strong negative association between the B2 allele and CHD incidence and particularly sudden death. Although the CETP TaqIB polymorphism was associated with HDL cholesterol in these patients, the association with the occurrence of sudden death remained highly significant after adjustment for most potential confounders, including age and HDL cholesterol.

The association of the CETP TaqIB polymorphism and HDL cholesterol levels is widely recognized in many different populations, including type 2 diabetic patients. The B1 allele has also been associated with a higher prevalence of CHD (11–13). Nevertheless, there is a lack of consistent correlation between the CETP genotype and the clinical outcome. This association may depend on gene-gene or gene-environment interactions (21). A recent meta-analysis of large studies (11) showed that CETP TaqIB was associated with cardiovascular risk and that this relationship was mediated by lower HDL cholesterol levels. In contrast, we show that HDL cholesterol modified the risk associated with the TaqIB genotype only slightly. One reason could be the interaction with the diabetic phenotype. Studies of type 2 diabetic populations mostly show an association between CETP and cardiovascular disease (9,12,22,23). HDL cholesterol levels do not greatly modify the relationship between the CETP genotype and the clinical outcome. This finding could be specific to type 2 diabetic subjects in whom HDL cholesterol levels are already lower than those in nondiabetic subjects.

The most striking result from our study is the association with sudden death. There have been only a few prospective studies of CETP TaqIB polymorphisms. Blankenberg et al. (24) investigated the association between the risk of fatal cardiovascular events in 1,211 patients with coronary artery disease and –629C>A, an SNP in near complete positive linkage disequilibrium with the TaqIB polymorphism (10). Mortality was lower for carriers of the minor A allele (4–4.6%) (the one linked to TaqIB2 allele) than for CC homozygotes (10.8%); this was not the case for other cardiovascular outcomes. This allele was also associated with higher HDL cholesterol levels and lower CETP activity, but, similarly to our results, the strong protective effect on future cardiovascular mortality was independent of its effect on HDL cholesterol levels. The TaqIB polymorphism in cases of micro- and macroalbuminuria has been associated with atrial fibrillation (25). This association is very relevant to our findings for type 2 diabetic patients with micro- or macroalbuminuria as atrial fibrillation is associated with an increase in cardiovascular mortality (26,27).

The B2 allele has been associated with lower levels and activity of CETP, which leads to higher HDL cholesterol levels. However, there is evidence that CETP inhibition goes beyond raising HDL cholesterol levels alone for the purpose of prevention of cardiovascular risk (28,29), and our study supports this hypothesis. Nevertheless, the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial with a CETP inhibitor, torcetrapib, was interrupted because of a higher mortality rate in the torcetrapib and atorvastatin group than in the atorvastatin group (30). In another trial (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation [ILLUSTRATE]), there was no significant difference in the atherosclerotic plaque burden in the two study groups (atorvastatin with or without torcetrapib) (31). In both of these trials, the use of torcetrapib was associated with increased blood pressure. In our study, the TaqIB polymorphism was not associated with blood pressure (data not shown). Therefore, our results indirectly suggest that the problem may have been due to an adverse effect of the drug, unrelated to the CETP inhibition, as already suggested (32).

We did not observe associations between the CETP TaqIB SNP and prior myocardial infarction. We think that the prospective design of the DIABHYCAR study allowed us to avoid the biases of cross-sectional/case-control studies, which can lower the power to detect associations, but such biases could explain why we observed only an effect on the CHD incidence but not on the prevalence at entry.

In summary, we have demonstrated that the TaqIB polymorphism of the CETP gene is a good genetic predictor of CHD complications of type 2 diabetes and especially cardiac mortality. This association is not fully explained by the effect of TaqIB SNP on HDL cholesterol levels.


   APPENDIX—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 APPENDIX--
References
 
The DIABHYCAR study group included the following: Principal Investigator: Prof. M. Marre (Bichat Hospital, Paris, France); Steering Committee: F. Alhenc-Gelas, J.P. Boissel, F. Cambien, S. Etienne, A. Girault-Louvel, P. Gueret, M. Lièvre, J. Mann (Vice-Chairman), M. Marre, J. Ménard, P. Passa (Chairman), P.F. Plouin, D. Vasmant, L. Vaur (Secretary), G.C. Viberti, and C. Weisselberg; Central Co-ordinating Center: J.P. Boissel and M. Lièvre; Executive Committee: J.P. Boissel, V. Bost, M. Cambien, Y. Gallois, N. Genes, J. Gillet, M. Hervé, M. Lièvre, M. Marre, L. Martin, A. Perret-Hantzperg, P.F. Plouin, and L. Vaur; Biological Committee: F. Alhenc-Gelas (Chairman), F. Cambien, A. Girault-Louvel (Vice-Chairman), M. Lièvre, M. Marre, and J. Ménard; Central End Point Committee: E. Bonnefoy, G. Chatellier (Chairman), T. Moreau, and L. Pinède; and Independent Data and Safety Committee: E. Eschwege, C.E. Mogensen, N. Victor, and S. Weber.


   Acknowledgments
 
This work was supported by a grant from the Association Française des Diabétiques.

Parts of this study were presented as an oral communication at the 66th annual meeting of the American Diabetes Association, Washington, DC, 9–13 June 2006.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 31 July 2007. DOI: 10.2337/dc07-0869.

The design, funding, and interpretation of this genetic association analysis were independent of the sponsor of the DIABHYCAR trial (sanofi-aventis, France).

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication May 4, 2007. Accepted for publication July 21, 2007.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 APPENDIX--
 References
 

  1. Pyorala K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: an epidemiological view. Diabetes Metab Rev 3: 463–524, 1987[Medline]
  2. Balkau B, Jouven X, Ducimetiere P, Eschwege E: Diabetes as a risk factor for sudden death. Lancet 345: 1968–1969, 1999
  3. Curb JD, Rodriguez BL, Burchfiel CM, Abbott RD, Chiu D, Yano K: Sudden death, impaired glucose tolerance, and diabetes in Japanese-American men. Circulation 91: 2591–2595, 1995[Abstract/Free Full Text]
  4. Wilson PW: Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 7: 7S–12S, 1994[Medline]
  5. Suarez GA, Clark VM, Norell JE, Kottke TE, Callahan MJ, O’Brien PC, Low PA, Dyck PJ: Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J Neurol Neurosurg Psychiatry 76: 240–245, 2005[Abstract/Free Full Text]
  6. Dunn FL Hyperlipidemia in diabetes mellitus. Diabetes Metab Rev 6: 47–61, 1990[Medline]
  7. Yamashita S, Hirano K, Sakai N, Matsuzawa Y: Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein. Biochim Biophys Acta 1529: 257–275, 2000[Medline]
  8. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ: The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 338: 86–93, 1998[Abstract/Free Full Text]
  9. Durlach A, Clavel C, Girard-Globa A, Durlach V: Sex-dependent association of a genetic polymorphism of cholesteryl ester transfer protein with high-density lipoprotein cholesterol and macrovascular pathology in type II diabetic patients. J. Clin Endocrinol Metab 84: 3656–3659, 1999[Abstract/Free Full Text]
  10. Dachet C, Poirier O, Cambien F, Luc G, Chapman J, Rouis M: New functional promoter polymorphism, C-629A, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and HDL cholesterol levels: role of Sp1/Sp3 in transcriptional regulation. Arterioscler Thromb Vasc Biol 20: 507–515, 2000[Abstract/Free Full Text]
  11. Boekholdt SM, Sacks FM, Jukema JW, Shepherd J, Freeman DJ, McMahon AD, Cambien F, Nicaud V, de Grooth GJ, Talmud PJ, Humphries SE, Miller GJ, Eiriksdottir G, Gudnason V, Kauma H, Kakko S, Savolainen MJ, Arca M, Montali A, Liu S, Lanz HJ, Zwinderman AH, Kuivenhoven JA, Kastelein JJ: Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13 677 Subjects. Circulation 111: 278–287, 2005[Abstract/Free Full Text]
  12. Kawasaki I, Tahara H, Emoto M, Shoji T, Nishizawa Y: Relationship between TaqIB cholesteryl ester transfer protein gene polymorphism and macrovascular complications in Japanese patients with type 2 diabetes. Diabetes 51: 871–874, 2002[Abstract/Free Full Text]
  13. Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, Lahoz C, Coltell O, Wilson PW, Schaefer EJ: Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study. Arterioscler Thromb Vasc Biol 20: 1323–1329, 2000[Abstract/Free Full Text]
  14. Liu S, Schmitz C, Stampfer MJ, Sacks F, Hennekens CH, Lindpaintner K, Ridker PM, Liu S: A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men. Atherosclerosis 161: 469–474, 2002[Medline]
  15. Fazio S, Linton MF: Sorting out the complexities of reverse cholesterol transport: CETP polymorphisms, HDL, and coronary disease. J Clin Endocrinol Metab 91: 3273–3275, 2006[Free Full Text]
  16. Borggreve SE, Hillege HL, Wolffenbuttel BH, de Jong PE, Zuurman MW, van der Steege G, van Tol A, Dullaart RP, PREVEND Study Group: An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study. J Clin Endocrinol Metab 91: 3382–3388, 2006[Abstract/Free Full Text]
  17. Passa P, Chatellier G: The DIAB-HYCAR Study. Diabetologia 39: 1662–1667, 1996[Medline]
  18. Lièvre M, Marre M, Chatellier G, Plouin P, Réglier J, Richardson L, Bugnard F, Vasmant D: The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study: design, organization, and patient recruitment: DIABHYCAR Study Group. Control Clin Trials 21: 383–396, 2000[Medline]
  19. Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Menard J: Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 328: 495, 2004[Abstract/Free Full Text]
  20. Hetet G, Elbaz A, Gariepy J, Nicaud V, Arveiler D, Morrison C, Kee F, Evans A, Simon A, Amarenco P, Cambien F, Grandchamp B: Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases. Eur J Clin Invest 31: 382–388, 2001[Medline]
  21. Fumeron F, Betoulle D, Luc G, Behague I, Ricard S, Poirier O, Jemaa R, Evans A, Arveiler D, Marques-Vidal P, Bard JM, Fruchard JC, Ducimetiere P, Apfelbaum M, Cambien F: Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 96: 1664–1671, 1995[Medline]
  22. Meguro S, Takei I, Murata M, Hirose H, Takei N, Mitsuyoshi Y, Ishii K, Oguchi S, Shinohara J, Takeshita E, Watanabe K, Saruta T: Cholesteryl ester transfer protein polymorphism associated with macroangiopathy in Japanese patients with type 2 diabetes. Atherosclerosis 156: 151–156, 2001[Medline]
  23. Relvas WG, Izar MC, Helfenstein T, Fonseca MI, Colovati M, Oliveira A, Ihara SS, Han SW, Las Casas AA, Fonseca FA: Relationship between gene polymorphisms and prevalence of myocardial infarction among diabetic and non-diabetic subjects. Atherosclerosis 178: 101–105, 2005[Medline]
  24. Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L: Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol 41: 1983–1989, 2003[Abstract/Free Full Text]
  25. Asselbergs FW, Moore JH, van den Berg MP, Rimm EB, de Boer RA, Dullaart RP, Navis G, van Gilst WH: A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study. BMC Med Genet 7: 39, 2006[Medline]
  26. Jouven X, Desnos M, Guerot C, Ducimetière P: Idiopathic atrial fibrillation as a risk factor for mortality: the Paris Prospective Study I. Eur Heart J 20: 896–899, 1999[Abstract/Free Full Text]
  27. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98: 946–952, 1998[Abstract/Free Full Text]
  28. Klerkx AH, El Harchaoui K, van der Steeg WA Boekholdt SM, Stroes ES, Kastelein JJ, Kuivenhoven JA: Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis. Arterioscler Thromb Vasc Biol 26: 706–715, 2006[Abstract/Free Full Text]
  29. Barter PJ, Kastelein JJP: Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol 47: 492–499, 2006[Abstract/Free Full Text]
  30. Editorial: Cholesterol: the good, the bad, and the stopped trials. Lancet 368: 2034, 2006[Medline]
  31. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM, ILLUSTRATE Investigators: Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356: 1304–1316, 2007[Abstract/Free Full Text]
  32. Tall AR: CETP inhibitors to increase HDL cholesterol levels: effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356: 1364–1366, 2007[Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0869v1
30/11/2863    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Porchay-Baldérelli, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Porchay-Baldérelli, I.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum