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Letters to the Editor |
1 Division of Clinical Chemistry, Department of Medicine, University Medical Center, Freiburg, Germany
2 Institute of Transfusion, Medicine and Immunology, Mannheim, Germany
3 LURIC Study nonprofit LLC, Freiburg, Germany
4 Cardiology Group, Frankfurt, Frankfurt-Sachsenhausen, Germany
5 Division of Endocrinology, and Diabetes, Department of Medicine, University Hospital, Ulm, Germany
6 Synlab Centre of Laboratory Diagnostics, Heidelberg, Germany
aAddress correspondence to this author at: Hugstetter Str. 55, D-79106 Freiburg i.Br., Germany. Fax +49-761-2703444, e-mail michael.marcus.hoffmann{at}uniklinik-freiburg.de.
To the Editor:
Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which possess various biological properties with a role in coronary vascular function. Therefore, the cytochrome P450, family 2, subfamily J, polypeptide 2 (CYP2J2) gene, which encodes CYP2J2, the predominant epoxygenase isoform involved in EET formation in the human heart, has been considered a candidate gene for coronary artery disease (CAD) (1). A frequent G-to-T polymorphism at position –50 leads to a 50% reduction in CYP2J2 promoter activity (2)(3). In a cohort of 544 patients, this polymorphism was independently associated with an increased risk of CAD (3).
We investigated whether the –50G>T polymorphism is associated with angiographic CAD, myocardial infarction (MI), or mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, which included white patients hospitalized for coronary angiography between June 1997 and May 2001. The study was approved by the ethics review committee at the Landesärztekammer Rheinland-Pfalz (Mainz, Germany). A detailed description of LURIC has been published (4). In total, the LURIC cohort includes 3243 individuals, 2547 (78.5%) with angiographically proven CAD ("CAD patients") and 696 (21.5%) individuals without CAD ("CAD controls"). Information on vital status was obtained from local registries. Another control group ("blood donor controls") included a cohort of 960 healthy blood donors [male: female 1:1; mean (SD) age 58 (5) years] with an ethnic and geographic origin comparable to that of the LURIC cohort.
Genomic DNA was prepared from EDTA-anticoagulated peripheral blood by salting-out or a commercial system (DNA Blood Mini Kit; Qiagen). The –50G>T polymorphism (rs890293) was genotyped by PCR and AluI restriction fragment-length analysis (3). Associations between categorical variables were examined by 
2 testing or logistic regression analysis, and covariable adjustments were done for age, sex, type 2 diabetes, body mass index, smoking, hypertension, and dyslipidemia. We used the Cox proportional hazards model to calculate hazard ratios and 95% confidence intervals. The criterion for statistical significance was P <0.05. The SPSS statistical package (SPSS Inc. Ver. 11.5) was used.
Genotypes fulfilled Hardy-Weinberg equilibrium in each cohort. There were no significant differences in the frequencies of genotypes for CAD patients, CAD controls, and blood donor controls (Table 1
). None of the logistic regression models revealed a significant association between the CYP2J2 polymorphism and CAD, regardless of whether or not we adjusted for conventional cardiovascular risk factors (data not shown). Very similar results were obtained when we compared the CYP2J2 genotypes in patients with previous MI vs CAD patients without MI (Table 1
). Results were also not significant in any respect when we screened for relationships between CYP2J2 and early manifestations of CAD or MI. Among the 3243 LURIC study participants included in this examination, 496 deaths (15.4%) occurred during a median observation time of 5.45 years. The analysis for cardiovascular mortality included a total of 3229 individuals, of whom 333 (10%) died from cardiovascular causes. No deaths occurred in individuals with the TT genotype. Therefore, Cox models comparing only the GG with the GT genotypes were calculated. Regardless of whether or not we adjusted for age, sex, and conventional risk factors, the CYP2J2 polymorphism showed no association with mortality from all causes or with cardiovascular mortality (data not shown). Because EETs have been reported to inhibit vascular inflammation, we analyzed the relationship between systemic markers of inflammation such as sensitive C-reactive protein, fibrinogen, and leukocyte count and the CYP2J2 genotype. The CAD status was included as main effect, and statistical adjustments were made for age, sex, and cardiovascular risk factors (body mass index, diabetes mellitus, hypertension, and smoking). None of these models revealed any statistically significant relationships between the CYP2J2 genotype and inflammatory markers (data not shown).
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In contrast to a recent study (3), we could not confirm the –50G>T polymorphism as a risk factor for CAD or MI in our large cross-sectional LURIC cohort. In addition, we were not able to detect any relationship of this polymorphism with total mortality or cardiovascular mortality in this cohort at intermediate risk of death. Association studies of genetic polymorphisms often lead to discrepant results, especially if small numbers of cases and controls are examined. Therefore, the validity of genetic association studies using single nucleotide polymorphisms has recently been challenged (5). In many instances, positive associations seen in small studies have not been confirmed in subsequent studies of large cohorts.
Acknowledgments
We thank S. von Karger and A. Schwentek (Freiburg) for technical assistance and the LURIC study team and laboratory staff at the Ludwigshafen General Hospital and the universities of Freiburg and Ulm.
References
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