Search

Background The association between short stature, undernutrition and the risk to cardiovascular disease has been clinically established. Genetic factor, particularly the variants in cytochrome b-245 alpha chain (CYBA) gene, which alter the formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase level, might affect arterial function. This study aimed to observe the association between single nucleotide variants (SNVs) of the CYBA gene and the arterial function of short stature children to understand the reason why some people with short stature develop cardiovascular disease. Methods A total of 142 genomic deoxyribonucleic acid (DNA) samples have been collected from short stature children in Brebes, Central Java, Indonesia. Four common single-nucleotide polymorphisms (SNPs): C242T (rs4673), A640G (rs1049255), -930A>G (rs9932581) and *49A>G (rs7195830) in the CYBA gene were examined using TaqMan allelic discrimination assay. The arterial function was measured using transthoracic echocardiography and described as aortic stiffness and distensibility index. Statistical analysis was done to find a significant difference in arterial function between genotypes of each SNV. Results A P-value of < 0.05 was considered significant. In rs9932581 (-930A>G) of CYBA gene, the subjects with GG genotype were found to have significantly lower arterial stiffness and higher distensibility compared to AA and AG genotypes. No significant difference was found in the other SNVs. Conclusion The GG genotype in rs9932581 of the CYBA gene might have a protective effect on cardiovascular disease in short stature children.

The invasive infection with Aspergillus fumigatus usually occurs in immunocompromised patients. CNS involvement is extremely rare in children. Usually, the diagnosis is hard, often made after the death of the patient. We describe the first report of a pediatric case of multiple CNS aspergillomas confirmed by a biopsy. We present the case of 3 years old boy who was hospitalized for evolving intracranial hypertension with a cerebellar syndrome. A brain CT showed a left cerebellar mass and early tonsillar commitment and a supra-tentorial lesion in the right occipital lobe. Therefore, a metastatic tumor was suspected and an emergency surgical intervention with cerebral biopsy and ventriculocisternostomy was performed. The cerebral biopsy revealed an Aspergillus fumigatus granuloma and further investigations showed that the patient has chronic granulomatosis due to a homozygous mutation of CYBA gene encoding p22phox. After a favorable evolution in reanimation, he continued the treatment with Voriconazole. At last follow-up, the neurological examination finds no sign of motor focus, no cerebellar syndrome or nystagmus. Walking is difficult with the enlargement of the support base. CNS invasive infection with Aspergillus fumigatus in a child is extremely rare and the presentation might mimic that of a tumor especially with a location of aspergilloma as in our case both supratentorially and infratentorially.

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disease, with approximately 12.5 million affected people worldwide, and it is responsible for over 10% of patients with end-stage renal disease (ESRD) with an important impact on public health. It causes progressive renal failure and other extrarenal manifestations, including endothelial dysfunction and hypertension. These complications are both linked to reduced nitric oxide levels related to excessive Oxidative Stress (OxSt) that different studies confirm occurring in the early stages of ADPKD. This study aims to evaluate ex vivo through a molecular biology approach the OxSt status of ADPKD patients under treatment with tolvaptan (Jinarc) and compare with both a group of untreated young ADPKD subjects with preserved renal function (eGFR> 80 mL/min/1.73m2) and a cohort of healthy subjects as controls. Methods In mononuclear cells of 9 ADPKD patients treated with tolvaptan, 9 untreated ADPKD patients with preserved renal function (eGFR> 80 mL/min/1.73m2) and 9 healthy subjects we evaluated the state of OxSt in terms of protein expression of p22phox, subunit of NADH/NADPH oxidase essential for the production of superoxide; protein expression of Heme oxygenase (HO)-1, protective from OxSt and anti-inflammatory and MYPT-1 phosphorylation, marker of Rho kinase activation, deeply involved in OxSt signaling for the induction of cardiovascular-renal remodeling; Results In patients with tolvaptan treated ADPKD, protein expression of p22phox and phosphorylation state of MYPT-1 were significantly reduced compared to untreated young ADPKD subjects with normal GFR (p=0.01 and p=0.03, respectively). Phosphorylation of MYPT-1 was significantly reduced in patients treated with tolvaptam vs untreated patients and also when compared to healthy controls (p=0.01 for both). HO-1 levels of treated ADPKD patients were significantly higher both vs untreated ADPKD patients with normal GFR (p=0.04) and vs healthy controls (p=0.01) Conclusions Tolvaptan is reported to reduce the rate of GFR deterioration of 1.20 mg/mL/year compared to placebo. Several animal studies have demonstrated the ability of tolvaptan to reduce OxSt and increase HO-1. Our study showed “ex vivo” in humans that in ADPKD patients tolvaptan reduces the OxSt state compared to untreated ADPKD with normal GFR and increases the antioxidant HO-1, in addition to reduce Rho kinase activation, further supporting its renoprotective effect also in terms of OxSt inhibition. This study confirms for the first time in humans that tolvaptan is effective on the reduction of intracellular OxSt and may impair the biochemical/molecular mechanisms that contribute to the worsening of renal function, endothelial damage and hypertension.

Background Physical exercise has been highlighted as an important non-pharmacological therapy for prevention and treatment of several cardiovascular diseases. However, its effects on hearts with minor cardiac remodeling are not clear. Purpose To evaluate the influence of aerobic physical exercise on functional capacity, cardiac structure, left ventricular (LV) function, and gene expression of NADPH oxidase subunits in rats with small-sized myocardial infarction (MI). Methods Three months after MI induction, Wistar rats were divided into three groups: Sham; sedentary MI (MI-SED); and aerobic exercised MI (MI-EA). Rats exercised three times a week for 12 weeks on a treadmill. Echocardiogram was performed before and after experimental period. Infarction size and cardiomyocyte diameters were evaluated by histology. Gene expression was assessed by RT-PCR. Results Only rats with MI size lower than 30% of LV total area were included in the study. Functional capacity was higher in MI-AE than the other groups. Infarction size did not differ between groups. Infarcted rats had increased LV diastolic and systolic diameter, left atrial diameter, and LV mass, with systolic dysfunction. LV diastolic posterior wall thickness was higher in MI-AE than Sham, and relative wall thickness was lower in MI-SED than MI-AE and Sham groups. Cardiomyocyte diameter was smaller in infarcted groups than Sham. Myocardial gene expression of the NADPH oxidase subunits NOX2, NOX4, p22phox, and p47phox did not differ between groups. Conclusion Small-sized myocardial infarction changes cardiac structures and left ventricular systolic function. Late aerobic physical exercise improves functional capacity and cardiac remodeling by preserving left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small myocardial infarction. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): CNPq; CAPES

NAD(P)H oxidases (NOXs) constitute a principal source of cellular reactive oxygen species (ROS) and contribute to exercise-induced ROS production in the skeletal muscle. Here, we aimed to investigate the effect of single-bout exhaustive exercise on redox state biomarkers and oxidative DNA damage based on the C242T polymorphism in the gene encoding NOXs subunit p22phox (CYBA) and aerobic fitness levels. We enrolled 220 healthy adults in their 20s (men, n = 110, women, n = 110), who were divided into CC genotype and T allele groups through the analysis of the CYBA C242T polymorphism. Furthermore, maximum oxygen uptake (VO2max) was evaluated to divide subjects into high fitness (HF, 70th percentile for aerobic fitness) and mid-range fitness (MF, 40&ndash, 60th percentile for aerobic fitness) groups, with a total of 32 subjects assigned to four groups (eight subjects per group): CC genotype and HF group (CC + HF), CC genotype and MF group (CC + MF), T allele and HF group (T + HF), and T allele and MF group (T + MF). All subjects performed treadmill running exercise at 85% of VO2max until exhaustion. Plasma lactate, malondialdehyde (MDA), superoxide dismutase (SOD), and lymphocyte DNA damage (tail DNA percentage [TD], tail length [TL], and the tail moment [TM]) were measured in the blood samples obtained immediately before (IBE), immediately after (IAE), and 30 min after exercise (30 MAE). Plasma lactate levels, SOD activities, and lymphocyte DNA damage markers (TD, TL, and TM) were significantly increased at IAE than that at IBE and significantly decreased at 30 MAE (p &lt, 0.05). All groups displayed increased plasma MDA levels at IAE rather than at IBE, with CC + MF being significantly higher than T + HF (p &lt, 0.05), only the CC + HF and T + HF groups exhibited a significant reduction at 30 MAE (p &lt, 0.05). Moreover, TL at IAE was significantly higher in the CC + MF group than in the T + HF group (p &lt, 0.05), and significantly higher in the CC + MF and CC + HF groups than in the T + HF group at 30 MAE (p &lt, 0.05). TM was significantly higher in the T + MF than in the T + HF group at IAE (p &lt, 0.05) and that of CC + MF was significantly higher than CC + HF and T + HF values at IAE and 30 MAE (p &lt, 0.05). These results suggest that single-bout exhaustive exercise could induce peripheral fatigue and the accumulation of temporary redox imbalance and oxidative DNA damage. Moreover, high aerobic fitness levels combined with the T allele may protect against exercise-induced redox imbalance and DNA damage.

Нарушения редокс-гомеостаза играют ключевую роль в развитии сахарного диабета 2 типа (СД2). Главным эндогенным источником супероксид-радикала является НАДФН-оксидаза, одной из субъединиц которой служит легкая цепь цитохрома b-245, CYBA. Цель исследования - изучить ассоциации полиморфизмов rs7195830 (GA), rs8854 (СT), rs9932581 (CT) и rs4673 (GA) гена CYBA с риском развития СД2. В исследование включено 1024 больных СД2 (средний возраст 61,57,3 года) и 1034 практически здоровых добровольца, сопоставимых по полу и возрасту с группой пациентов. Генотипирование полиморфизмов гена CYBA проводили с использованием технологии iPLEX на геномном времяпролетном масс-спектрометре MassArray Analyzer 4 (Agena Bioscience). Генотип А/А гена CYBA (rs4673, GA) ассоциировался с повышенным риском развития заболевания (OR 1,49, 95CI 1,11-1,99, p0,0074, рецессивная модель). Выявленная ассоциация сохранила значимость и после введения поправки на пол, возраст и индекс массы тела (ORadj 1,51, 95CI 1,09-2,09, padj0,014). При раздельном сравнении больных СД2 мужчин и женщин с контролем оказалось, что установленная ассоциация rs4673 была характерна только для женщин (ORadj 1,60, 95CIadj 1,04-2,46, padj0,032). Больные СД2 имели значимо более высокое содержание перекиси водорода в плазме крови по сравнению с контрольной группой (p0,05) вне зависимости от пола, однако ассоциация генотипа А/А rs4673 с повышением содержания Н2О2 в плазме в среднем на 0,77 мкмоль/л (p0,044) была обнаружена только в подгруппе мужчин. Генотип Т/Т rs9932581 был ассоциирован с повышением уровня гликированного гемоглобина в среднем на 2,71 (р0,042) в общей группе пациентов с СД2, а также с повышением того же показателя в среднем на 4,44 (р0,03) в подгруппе больных СД2 женщин. В подгруппе мужчин отмечена ассоциация генотипа С/Т rs9932581 с увеличением доли HbA1c в среднем на 0,61 (р0,018) и с повышением уровня глюкозы крови в среднем на 1,06 ммоль/л (р0,029). Связь уровня глюкозы натощак была установлена и с генотипом А/А rs7195830, у носителей которого концентрация глюкозы была в среднем на 1,17 ммоль/л выше, чем у гомозигот по референсному аллелю (р0,022). Установленные ассоциации свидетельствуют о наличии полового диморфизма во взаимосвязях полиморфизмов CYBA с биохимическими показателями и статусом болезни., Impairments of redox homeostasis play a key role in the development of type 2 diabetes mellitus (T2D). The main endogenous source of the superoxide radical is NADPH oxidase, one of the subunits of which is the light chain of cytochrome b-245, CYBA. The aim of the study was to study the associations of cytochrome b-245 alpha chain gene polymorphisms rs7195830 (GA), rs8854 (CT), rs9932581 (CT) and rs4673 (GA) with a risk of developing T2D. The study included 1022 patients with T2D (average age 61,1 7,2 years) and 1064 sex-and age-matched healthy volunteers. Genotyping of CYBA gene polymorphisms was performed using iPLEX technology on a MassArray Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience). The CYBA gene A/A genotype (rs4673, GA) was associated with an increased risk of developing the disease (OR 1,49, 95CI 1,11-1,99, P0,0074, recessive model). The identified association remained significant even after the adjustment for gender, age, and body mass index (ORadj 1,51, 95CI 1,09-2,09, padj0,014). Gender-stratified analysis revealed that the established association rs4673 was characteristic only for females (ORadj 1,60, 95 CIadj 1,04-2,46, padj 0,032). Patients with T2D had a significantly higher level of hydrogen peroxide in blood plasma compared with the control group (p0,05), regardless of gender, however, the relationship between the A/A genotype rs4673 with the increase in the content of Н2О2 in plasma by 0,77 mmol/L (p 0,044) was found only in males. The T/T genotype rs9932581 was associated with an increase in glycated hemoglobin level of 2,71 (p 0,042) in the general group of patients with T2D, as well as with an increase in the same indicator by 4,44 (p 0,03) among females. The association of the C/T genotype rs9932581 with an increase in the proportion of HbA1c by 0,61 (p 0,018) and with an increase in blood glucose level by 1,06 mmol/L (p 0,029) was noted exclusively in males. The association of fasting blood glucose level was also established with genotype A/A rs7195830, in which carriers the glucose concentration was 1.17 mmol/L higher than in homozygotes for the reference allele (P 0,022)., №8 (2020)

Coal workers' pneumoconiosis (CWP) is caused by long-term exposure to inhaled coal dust; it is likely influenced by the interaction between environmental factors and multiple susceptibility genes, such as the CYBA (cytochrome b-245α polypeptide) gene that has recently been identified to be involved in the genetic susceptibility for several pulmonary diseases. The aim of this case-control study was to explore the association between CYBA gene polymorphisms and the development of CWP in coal miners belonging to the Han ethnic group in China. Single nucleotide polymorphisms (SNPs) rs7195830, rs13306296, rs4673, rs9932581, and rs16966671 of the CYBA gene were analyzed in CWP patients (n = 652) and dust-exposed control subjects (n = 648) using the matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) on the Sequenom MassARRAY® platform (Sequenom, San Diego, CA, USA). Results from the present study showed a strong allele association between CWP patients and the CYBA SNP rs7195830 polymorphism (p .001, OR = 1.550). Using the additive and the dominant model, the CYBA SNP rs7195830 polymorphism also showed significant associations with CWP patients (p .001, OR = 1.621; p = .003, OR = 1.711, respectively). No statistically significant difference was demonstrated in either the allele or genotype frequencies of the other four examined SNPs (rs13306296, rs4673, rs9932581, and rs16966671) between the CWP group and dust-exposed control group (all p .05). The present study is the first to have demonstrated an association between CYBA (rs7195830) polymorphism and the risk of developing CWP in subjects belong to the Han ethnic group in China and provides further clues for research into the pathogenesis of CWP.

Emerging evidence suggests that increased superoxide production is responsible for a significant proportion of endothelial dysfunction. The relationship between variants of the CYBA gene and cardiovascular diseases is currently debated. In the present study, we investigated the influence of CYBA polymorphisms (rs1049255 and rs7195830) on arterial elasticity in a Chinese population. In the 2178 participants enrolled in the GaoYou study, we measured large artery elasticity (C1) and small artery elasticity (C2) non-invasively, genotyped the CYBA polymorphisms and calculated energy expenditure. The AA genotype of the rs1049255 polymorphism was associated with a lower C2 than were the GG/AG genotypes (5.31±0.11 vs. 5.52±0.06 ml mm Hg(-1) × 100; P=0.01). Further analyses revealed an interaction between CYBA polymorphisms and physical activity with respect to C2 (P=0.007 for rs1049255 and P=0.038 for rs7195830). In less physically active participants, the AA genotype of the rs1049255 polymorphism was associated with a significantly lower C2 than the GG/AG genotypes (4.69±0.16 vs. 5.26±0.19 ml mm Hg(-1) × 100; P=0.008). In physically active participants, the GG/AG genotypes of rs7195830 polymorphism were correlated with higher C2 values than the AA genotype (5.84±0.08 vs. 5.08±0.32 ml mm Hg(-1) × 100; P=0.049). Haplotype analyses revealed higher C2 values in rs1049255G-rs7195830G carriers (P=0.0015). In conclusion, the rs1049255 and rs7195830 polymorphisms of the CYBA gene were associated with C2 in a Chinese population; physical activity could modify this genetic effect.

The CYBA gene encodes the p22phox peptide, an essential subunit of vascular NADPH oxidases. The aim of the study was to analyze potential interactions between CYBA gene A640G polymorphism and traditional risk factors of atherosclerosis. We studied 320 subjects: 160 patients with coronary artery disease (CAD) and 160 controls. The results of interactions were interpreted on the basis of synergy index values (SI, SIM). The 640G allele interacted with cigarette smoking (SI = 2.02, SIM = 2.32). Even greater increase of the CAD risk was found whenever the 640G allele interacted with both smoking and hypercholesterolemia (SI = 2.70, SIM = 3.60). The results suggest that the A640G polymorphism may influence individual predispositions to CAD through interactions with smoking and hypercholesterolemia.

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD., Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. Amutation in one of the 4 genes encoding the components p22phox, p47phox, p67phox, and p40phox of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. Amutation in the CYBB gene encoding gp91phox leads to X-linked recessive CGD. Objective The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. Methods We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. Results Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A220, A670 or X910 phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47phox-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index≥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. Conclusion Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A220 and A670 subtypes manifests as severe as the X910 subtype.

Background and purpose Reactive oxygen species play an important role in the physiology and pathology of cerebral arteries, including ischaemic stroke. The cytochrome b-245 alpha gene ( CYBA ) encodes cytochrome b-245 alpha light chain (p22phox peptide), a critical element of NAD(P)H oxidases, the most important source of superoxide anion in the cerebral arteries. To search for genetic factors associated with paediatric ischaemic stroke, the possible association between CYBA gene C242T polymorphism and the disease was evaluated. Material and methods The study group consisted of 238 individuals: children with ischaemic stroke ( n = 70), their biological parents ( n = 118) and children without any symptoms of stroke ( n = 50). The C242T polymorphism was genotyped using polymerase chain reaction – restriction fragment length methodology. To evaluate the possible association between polymorphism and stroke, the transmission disequilibrium test and the case-control method were applied. Results The C242 allele was transmitted more frequently than 242T (62.2% vs. 37.8%) but observed frequencies did not differ significantly from expected ( p = 0.10). There were also no significant differences in allele and genotype distribution between patients and control subjects (patients: CC – 50.0%, CT – 38.6%, TT – 11.4% vs. controls: CC – 52.0%, CT – 36.0%, TT – 12.0%). Conclusions The study did not show that the C242T polymorphism of the CYBA gene is a risk factor of ischaemic stroke in children.

BACKGROUND Smoking-induced damage to the cardiovascular system has been shown in many studies; however, the degree of damage varies from individual to individual. We hypothesized that the -930A/G CYBA gene polymorphism in the NADPH oxidase influences the association between cigarette smoking and carotid intima-media thickness (IMT) in young healthy adults. METHODS Cross-sectional data obtained in 2001 for the Cardiovascular Risk in Young Finns Study were used. IMT was measured with ultrasound. The genotyping was performed using a 5'-nuclease assay. A linear regression model was used to test whether the interaction between smoking and the genotypes was associated with IMT. The magnitude of the interaction effect was further examined by performing a stratified analysis according to smoking habits. RESULTS In the entire population, the mean and maxima IMT were higher in smokers than nonsmokers (P = 0.005 and 0.008, respectively). The differences were most significant in subjects with the GG genotype, borderline significant for the GA genotype, and nonsignificant for the AA genotype. The interaction of genotypes with smoking was associated with mean and maximal IMT (P = 0.042 and 0.022). Among smokers, subjects with the GG genotype had a higher mean and maximal IMT compared with carriers of the A allele (P = 0.021 and 0.012). In contrast, the mean and maximal IMT were lower for G allele carriers than subjects with the AA genotype among nonsmokers (P = 0.022 and 0.026). All results had been adjusted for potential risk factors related to IMT. CONCLUSION The -930A/G polymorphism modifies the association between cigarette smoking and IMT in young healthy adults.

BackgroundObservational and experimental studies have thus far been unable to resolve whether the CYBA C242T polymorphism is associated with coronary artery disease (CAD). Therefore, we undertook a comprehensive meta-analysis to more precisely evaluate the influence of this polymorphism on CAD and potential biases.MethodsWe screened MEDLINE, Embase, CNKI, Wanfang and CBM up to January 2013 and extracted data from 22 studies with 9,279 CAD patients and 9,349 controls. A random-effects model was exploited to synthesize the inconsistent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.ResultsThe CYBA C242T polymorphism conformed to Hard-Weinberg Equilibrium for all studies (P>0.05). Overall comparison of the T allele with the C allele produced a non-significant risk estimate for CAD but with striking heterogeneity (T versus C: P = 0.87, OR = 0.99, 95%CI 0.89-1.11, P(heterogeneity)ConclusionTaken together, our results suggested the CYBA C242T polymorphism might be a risk-conferring factor on developing CAD and BMI and study design were probable sources of between-study heterogeneity.