Association of NAD(P)H Oxidase p22 phox Gene Variation With Advanced Carotid Atherosclerosis in Japanese Type 2 Diabetes

Abstract

OBJECTIVE -To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects.RESEARCH DESIGN AND METHODS -C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2Јdeoxyguanosine (8-OHdG) as an index of oxidative DNA damage.RESULTS -The diabetic subjects with the TCϩTT genotypes displayed a significantly lower average IMT (1.13 Ϯ 0.31 vs. 1.31 Ϯ 0.34 mm; P ϭ 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors.Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P ϭ 0.0042) and p22 phox CC genotype (P ϭ 0.0151). In nondiabetic subjects, the average IMT of the TCϩTT group was not different from that of the CC group (0.85 Ϯ 0.14 vs. 0.94 Ϯ 0.30 mm, P ϭ 0.417). Fasting plasma insulin concentration (41.4 Ϯ 15.6 vs. 64.2 Ϯ 59.4 pmol/l, P ϭ 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 Ϯ 0.66 vs. 2.60 Ϯ 2.56, P ϭ 0.0066) were significantly lower in the TCϩTT group than in the CC group.CONCLUSIONS -These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects. Diabetes Care 26:458 -463, 2003T he production of vascular reactive oxygen species (ROS) is increased in pathophysiological conditions such as atherosclerosis, hypertension, and diabetes (1-3).NAD(P)H oxidase is a membraneassociated enzyme that catalyzes the 1-electron reduction of oxygen using NAD(P)H as the electron donor. Several studies indicate that NAD(P)H oxidase is the most important source of ROS in intact arteries, rather than arachidonic acid-metabolizing enzymes, xanthine oxidase, or mitochondrial sources (4 -8). It has recently been shown that high glucose stimulates ROS production through the protein kinase C-dependent activation of NAD(P)H oxidase in both vascular smooth muscle cells and endothelial cells (9) and in diabetic vessels (10,11).The p22 phox, cytochrome b 558 of vascular NAD(P)H oxidase, plays an important role in the process of O 2 Ϫ production. Expression of p22 phox was markedly increased in the aorta from OLETF rats compared with that of LETO rats (12). Recently, Guzik et al. (11) showed that the p22 phox was significantly increased in human diabetic veins and arteries. This activation of p22 phox may contribute to the acceleration of atherosclerosis in patients with diabetes.The C2...

The A640G CYBA polymorphism associates with subclinical atherosclerosis in diabetes

“…Similarly, we have detected an increased cIMT in diabetic patients with GG genotype. Our findings are similar to that of HayaishiOkano et al (35) who detected an association of the CYBA C242T polymorphism with cIMT only in diabetic patients but not in controls. This observation in turn exemplifies the importance of the interaction between multiple environmental and genetic factors in complex diseases (34,36).…”

“…Our study shows that, in addition to the biochemical alterations that contribute to atherosclerosis in diabetes, the genetic component may further worsen the clinical profile (34). In agreement with it, Hayaishi-Okano et al (35) showed that another CYBA variant, the C242T associates with cIMT. Therefore, genetic markers like the A640G polymorphism may be useful to identify patients with higher risk.…”

NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

“…However, clinical studies searching for the association of the polymorphism with cardiovascular diseases have provided contradictory results. Although the T allele appeared to confer cardiovascular risk protection in some studies, 16,17,20,[25][26][27] either no protection or increase risk was found in others. 15,17,21,22 In fact, the C242T polymorphism was found associated with coronary artery spasm, 15 coronary artery disease, 21 cerebrovascular disease and with atherothrombotic infarction.…”

Haplotype analysis of NAD(P)H oxidase p22 phox polymorphisms in end-stage renal disease

“…The 242C/ T polymorphism substitutes histidine-72 with tyrosine and is thought to be essential to superoxide production (Guzik et al 2000), whereas the 640A/G polymorphism is located in the 3¢ untranslated region (3¢ UTR). However, significant associations have been observed in a limited number of case-control studies (Gardemann et al 1999;Hayaishi-Okano et al 2003;Inoue et al 1998).…”

“…There are two important polymorphisms in the CYBA gene encoding the p22 phox which have been reported to show associations with coronary artery disease (CAD) (Gardemann et al 1999;Inoue et al 1998) and carotid atherosclerosis (Hayaishi-Okano et al 2003); namely 242C/T and 640A/G polymorphisms. The 242C/ T polymorphism substitutes histidine-72 with tyrosine and is thought to be essential to superoxide production (Guzik et al 2000), whereas the 640A/G polymorphism is located in the 3¢ untranslated region (3¢ UTR).…”