Antiatherogenic Mitochondrial Genotype in Patients With Type 2 Diabetes

Matsunaga, Hajime; Tanaka, Yasushi; Tanaka, Masashi; Gong, Jian; Zhang, Jin; Nomiyama, Takashi; Ogawa, Osamu; Ogihara, Takeshi; Yamada, Yoshiji; Yagi, Kazuichi; Kawamori, Ryuzo

doi:10.2337/diacare.24.3.500

Cited by 64 publications

(37 citation statements)

References 23 publications

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“…Associations between other candidate polymorphisms and carotid IMT in patients with type 2 diabetes were also recently reported. Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene was associated with advanced carotid atherosclerosis (30), and mitochondrial genotype Mt5178A was shown to be associated with lower carotid IMT values compared with the MT5178C allele (31). We showed in this study that the C807T polymorphism of ␣2 integrin is another candidate polymorphism involved in carotid IMT and carotid plaque.…”

Section: ) Nsmentioning

confidence: 61%

The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

et al. 2002

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Polymorphism of ␣2 integrin (C807T) is shown to be associated with an increased incidence of thrombotic cardiovascular events. However, it is not clear whether this polymorphism is associated with atherosclerotic arterial wall thickening. In this study, we examined the association of C807T polymorphism with arterial wall thickness in 265 control subjects and 272 patients with type 2 diabetes. In all subjects, intima-media thickness of the right carotid artery in the 807TT group (0.649 ؎ 0.028 mm [SE]) was significantly (P ‫؍‬ 0.0228, Scheffe's F test) less than in the 807CC group (0.767 ؎ 0.033). This effect of polymorphism is gene dose dependent (P ‫؍‬ 0.0227, ANOVA). The similar association was also observed in patients with diabetes but not in control subjects. Multiple regression analysis in all subjects revealed that the T allele was inversely (␤ ‫؍‬ ؊0.095, P ‫؍‬ 0.021) associated with intima-media thickness independent of age, HbA 1c , and HDL cholesterol. Finally, an inverse relation between the occurrence of carotid plaque and the T allele was observed in patients with diabetes with an adjusted odds ratio of 0.487 (P ‫؍‬ 0.031) in multiple logistic regression analyses. These results suggest that the number of 807T alleles in ␣2 integrin is protective against atherosclerotic arterial wall thickening and the occurrence of plaque in patients with type 2 diabetes. Diabetes 51:1523-1528, 2002 P rogression of atherosclerosis is known to be related to vascular risk factors such as hypertension, smoking, diabetes, and high cholesterol levels. In addition to these conventional risk factors, genetic predispositions may enhance the risk of cardiovascular events (reviewed in Murata et al. [1]). Initially reported was the relation between a polymorphism of ACE and coronary arterial diseases (2). Other possible genetic risk factors include angiotensin II type I receptor, endothelial nitric oxide synthase, apolipoprotein E, lipoprotein lipase, paraoxonase, methylenetetrahydrofolate reductase, fibrinogen, plasminogen activator inhibitor-1, thrombomodulin, and platelet glycoproteins (GPs; see review [1]).The platelet membrane ␣2␤1 integrin, also known as GP Ia-IIa, serves as a platelet receptor for collagen (3). It mediates platelet primary adhesion to subendothelial tissues and activation (4,5). The gene encoding ␣2 integrin has at least eight polymorphisms, including two silent polymorphisms located within the intron (6). C807T (224Phe) and G873A (246Thr) were reported to be in linkage and associated with the expression density of GP Ia-IIa on the platelet surface (7). T807/A873 is associated with a higher expression of the receptor, and C807/G873 is associated with a lower expression density. The expression density of ␣2 integrin was also shown to be associated with the rate of platelet attachment to type I collagen, even under high shear rates (8).␣2␤1 integrin is also expressed in vascular endothelium (9 -11). In endothelial cells, ␣2␤1 integrin seems to function as a receptor for laminin as well as collagen (12), ...

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Section: ) Nsmentioning

confidence: 61%

The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

et al. 2002

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“…7 In type-II diabetic Japanese, the intima-media thickness in the bilateral carotid arteries is significantly larger in the mt5178C group than in the mt5178A group. 8 Moreover, Wang et al 11 reported that the mean age at onset of diabetes was significantly lower in Japanese patients carrying mt5178C than in those carrying mt5178A. In addition to these metabolic differences, mt5178 A/C polymorphism may partially influence life expectancy by influencing the blood-pressureelevating effects of alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

“…6 In fact, mt5178A was reported to exert antiatherogenic effects. [7][8][9] We reported that serum high-density lipoprotein cholesterol levels were significantly higher in men carrying mt5178A than in men carrying mt5178C, and that triglyceride levels were significantly lower in women carrying mt5178A than in women carrying mt5178C. 7 Blood pressure and serum lipid levels are crucial factors in the pathology of age-related circulatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Longevity-associated mitochondrial DNA 5178 A/C polymorphism and blood pressure in the Japanese population

et al. 2003

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It has been reported that the mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism, also called NADH dehydrogenase subunit 2-237 methionine/ leucine (ND2-237 Met/Leu) polymorphism, may be associated with longevity in Japanese individuals, and that the mt5178A genotype may have an antiatherogenic influence. To determine whether mt5178 A/C polymorphism influences blood pressure, we genotyped 412 healthy Japanese individuals and performed a crosssectional study investigating the relationship between genotype and blood pressure. In women with mt5178A, the mean diastolic blood pressure was higher than in those with mt5178C by 3.2 mmHg (P ¼ 0.040). In men, no statistically significant difference in systolic or diastolic blood pressure was observed between mt5178 A/C genotypes. However, a significant correlation between mt5178 A/C genotypes and the effects of habitual drinking on blood pressure was found. After adjustment for several factors, in men carrying mt5178C, both systolic and diastolic blood pressure were significantly higher in daily drinkers than in occasional (P ¼ 0.002 and 0.002, respectively) as well as nondrinkers (Po0.001 and 0.001, respectively), whereas in men carrying mt5178A, no significant differences in blood pressure were detected, irrespective of alcohol consumption. These results suggest that mt5178 A/C ( ¼ ND2-237 Met/Leu) polymorphism may influence both diastolic blood pressure in Japanese women and the blood-pressureincreasing effect of drinking in Japanese men.

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“…A single nucleotide polymorphism (C5173A), resulting in a leucine to methionine amino acid substitution in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2) gene, has been associated with resistance against T1D in an autoantibody-positive Japanese population (32). In addition to T1D, this allele (mt-Nd2 a ) has been reported to provide resistance against other ROS-mediated pathologies: atherosclerosis (33), myocardial infarction (34,35), and high blood pressure (36)), and correlates with increased longevity (37) and reduced serum lipid levels (38). We hypothesize that decreased mitochondrial ROS production mediated by mt-Nd2 a plays a key role in this allele's protective effects.…”

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mt-Nd2 Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III

Gusdon

Votyakova

Mathews

2008

Journal of Biological Chemistry

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Reactive oxygen species (ROS) play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional ROS-associated conditions. Our previous studies have demonstrated that the adeninecontaining allele (mt-Nd2 a ) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2 c ) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2 c increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase inelectrontransportchain-dependentROSproductionfrom all mt-Nd2 c -encoding strains including ALR.mt NOD , non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR.mt NOD to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2 c elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2 a -encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2 a

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Antiatherogenic Mitochondrial Genotype in Patients With Type 2 Diabetes

Cited by 64 publications

References 23 publications

The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

Longevity-associated mitochondrial DNA 5178 A/C polymorphism and blood pressure in the Japanese population

mt-Nd2 Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III

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