Cumulative Effect of Oxidative Stress–Related Gene Polymorphisms on Myocardial Infarction in Type 2 Diabetes
- Naoto Katakami, MD, PHD1,
- Ken'ya Sakamoto, MD, PHD1,
- Hideaki Kaneto, MD, PHD1,
- Munehide Matsuhisa, MD, PHD1,
- Keizo Ohno, MD, PHD2,
- Ikki Shimizu, MD, PHD2,3,
- Fukashi Ishibashi, MD, PHD4,
- Takeshi Osonoi, MD, PHD5,
- Atsunori Kashiwagi, MD, PHD6,
- Ryuzo Kawamori, MD, PHD7 and
- Yoshimitsu Yamasaki, MD, PHD1
- 1Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan;
- 2Ehime Prefectural Central Hospital, Matsuyama City, Japan;
- 3Ehime Prefectural Imabari Hospital, Imabari, Japan;
- 4Ishibashi Clinics, Hiroshima, Japan;
- 5Naka Kinen Clinics, Naka City, Japan;
- 6Department of Medicine, Shiga University of Medical Science, Otsu City, Japan;
- 7Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan.
- Corresponding author: Naoto Katakami, katakami{at}medone.med.osaka-u.ac.jp
It is well-known that oxidative stress plays critical roles in the pathogenesis of atherosclerotic diseases. In this study, we examined the association between four common genetic variants related to oxidative stress (glutamate-cysteine ligase modifier subunit (GCLM) C-588T, myeloperoxidase G-463A, human paraoxonase-1 Gln192Arg, and NADPH oxidase p22phox C242T) and the prevalence of myocardial infarction in type 2 diabetic patients.
All type 2 diabetic patients who periodically attended the outpatient diabetes clinics of five participating hospitals were asked to participate in this study. Subjects who were eligible had type 2 diabetes, diagnosed by diabetologists based on World Health Organization criteria, and were aged ≥50 years. A total of 2,561 type 2 diabetic subjects were included: men, 62%; age, mean ± SD 60.9 ± 9.9 years; duration of diabetes, 7.0 ± 7.3 years; smoking habit, 49%; BMI, 24.0 ± 3.5 kg/m2; A1C, 7.0 ± 1.3%; systolic and diastolic blood pressure, 133 ± 17 and 79 ± 11 mmHg, respectively; serum total cholesterol, 193 ± 34 mg/dl; triglycerides, 131 ± 115 mg/dl; and HDL cholesterol, 57 ± 16 mg/dl. The diagnosis of the occurrence of myocardial infarction was based on clinical records, characteristic electrocardiogram changes, and the findings of a coronary angiography and an echocardiography. The study protocol was approved by the committees on the ethics of human research of Osaka University Graduate School of Medicine. Informed consent was obtained from all subjects.
The genotypes of the four polymorphisms were determined with a fluorescence- or colorimetry-based allele-specific DNA-primer probe assay system (Toyobo Gene Analysis), as previously described (1). The genotype distribution of these polymorphisms was as follows: GCLM C-588T (CC, n = 1,832; CT, n = 655; and TT, n = 74), myeloperoxidase G-463A (GG, n = 2,095; GA, n = 441; and AA, n = 25), human paraoxonase-1 Gln192Arg (GlnGln, n = 87; GlnArg, n = 1,092; and ArgArg, n = 1,182) and NADPH oxidase p22phox C242T (CC, n = 2,102; CT, n = 436; and TT, n = 23). There were no significant associations between each of these four polymorphisms and the prevalence of myocardial infarction.
Next, we assessed the cumulative effect of these polymorphisms on the prevalence of myocardial infarction, based on the working hypothesis that the accumulation of several genetic variations could substantially influence the risk of myocardial infarction. Each polymorphism was determined to be either a pro-oxidant allele or antioxidant allele based on prior evidence of potential functionality in modulating oxidative stress (2–5). A total of four concomitant pro-oxidant alleles (GCLM −588T, myeloperoxidase −463G, paraoxonase-1e 192Gln, and NADPH oxidase p22phox 242C) in each subject theoretically range from 0 (carrying no pro-oxidant alleles) to 8 (carrying all of the pro-oxidant alleles). The prevalence of myocardial infarction was significantly higher in the subjects with ≥5 pro-oxidant alleles (n = 731) than in those with ≤4 pro-oxidant alleles (n = 1,830) (6.8 vs. 4.8%, respectively; P = 0.0406). There was no significant difference with respect to sex, age, duration of diabetes, smoking status, BMI, systolic and diastolic blood pressure, A1C level, and lipid profile. A multiple logistic regression model demonstrated that having ≥5 pro-oxidant alleles is significantly responsible for a high frequency of a history of myocardial infarction (odds ratio 1.50 [95% CI 1.04–2.16]; P = 0.0296). Taken together, the accumulation of pro-oxidant alleles is likely associated with the prevalence of myocardial infarction in type 2 diabetic patients.
Acknowledgments
No potential conflicts of interest relevant to this article were reported.
Footnotes
-
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2009 by the American Diabetes Association.
