Association of AGT, ACE, NOS3, TNF, MMP9, CYBA polymorphism with subclinical arterial wall changes

Aim Activation of the renin-angiotensin-aldosterone system, decreased nitric oxide production, chronic inflammation, and oxidative stress result in subclinical changes in the arterial wall, which favor the development of cardiovascular diseases (CVD). The effect of allelic gene variants that encode the proteins participating in pathogenetic pathways of age-associated diseases with subclinical changes in the arterial wall [increased pulse wave velocity (PWV), increased intima-media thickness, endothelial dysfunction (ED), presence of atherosclerotic plaques (ASP)] are understudied. This study analyzed the relationship between AGT, ACE, NOS3 TNF, MMP9, and CYBA gene polymorphism and the presence of subclinical changes in the arterial wall, including the dependence on risk factors for CVD, in arbitrarily healthy people of various age.Material and methods The relationship of polymorphisms с.521С>Т of AGT gene, Ins>Del of AСE gene, с.894G>T of NOS3 gene, – 238G>A of TNF gene, – 1562С>T of MMP9 gene, and c.214Т>С of CYBA gene with indexes of changes in the arterial wall and risk factors for CVD was studied in 160 arbitrarily healthy people by building models of multiple logistic regression and also by analyzing frequencies of co-emergence of two signs with the Pearson chi-squared test (χ2) and Fisher exact test.Results The DD-genotype of Ins>Del ACE gene polymorphism was correlated with increased PWV (p=0.006; odds ratio (OR) =3.41, 95 % confidence interval (CI): 1.48–8.67) and ED (p=0.014; OR=2.60, 95 % CI: 1.22–5.68). The GG genotype of с.894G>T NOS3 gene polymorphism was correlated with ED (p=0.0087; OR=2.65, 95 % CI: 1.26–5.72); the ТТ-genotype of с.894G>T NOS3 gene polymorphism was correlated with ASP (p=0.033; OR=0.034, 95 % CI: 0.001–0.549).Conclusion Polymorphic variants of AСE and NOS3 genes correlated with ED, increased arterial wall stiffness, and the presence of subclinical changes in the arterial wall.

POLYMORPHISMS OF ENDOTHELIAL DYSFUNCTION GENES NOS3 AND CYBA IN YAKUT POPULATION

Polymorphisms of different genes can predispose people to various diseases. They can influence the body's physiological response to exogenous risk factors. Polymorphisms of the endothelial dysfunction genes NOS3 and CYBA contribute to the development of socially significant diseases, such as acute coronary syndrome, stroke, as well as diseases accompanied by fibrotic changes (cirrhosis of the liver, pulmonary fibrosis, etc.). Therefore, the study of these genes in the Yakut population seems relevant. The present study involved 124 healthy volunteers, their ethnicity is Yakuts (including Yakuts in the third generation, living in the Republic of Sakha (Yakutia)). Genetic analysis of polymorphisms was performed by the method of polymerase chain reaction of restriction fragment length polymorphisms (PCR-RFLP). The study found that healthy Yakuts have GG homozygote of rs1799983 of the NOS3 gene in 83.87%, GT - 15.32%, TT - 0.81%. The frequency of the G allele was 91.53%, the T allele - 8.47%. The study found that healthy Yakuts have CC homozygote of rs4673 of the CYBA gene in 75.0%, CT - 21.77%, TT - 3.23%. The frequency of C allele was 91.44%, T - 8.56%. These results are consistent with the literature data. Thus, the research of the polymorphism rs1799983 of the NOS3 gene and rs4673 of the CYBA gene in various ethnic groups could have encouraging prospects in the personalized medicine for predicting pathological conditions associated with endothelial dysfunction: liver fibrosis, cardiovascular diseases, obstetric and gynecological pathologies, dysfunctions of various organs and systems.

Association of NCF2, NCF4, and CYBA Gene Polymorphisms with Rheumatoid Arthritis in a Chinese Population

Objective. Recent studies have focused on the special roles of NADPH-oxidase in multiple autoimmune diseases. Nevertheless, the association of genetic variation in NADPH-oxidase genes with rheumatoid arthritis (RA) was not extensively studied in a Chinese population. We performed this study to examine the association of NCF2, NCF4, and CYBA gene polymorphisms with RA susceptibility in a Chinese population. Methods. Six single nucleotide polymorphisms (SNPs) (NCF2 rs10911363, NCF4 rs1883112, rs4821544, rs729749, CYBA rs3794624, and rs4673) were genotyped in a cohort composed of 593 RA patients and 596 normal controls. Improved multiple ligase detection reaction (iMLDR) was used for genotyping. Results. We observed that NCF4 rs4821544 CT genotype and C allele frequencies in RA patients were significantly decreased when compared to controls (CT vs. TT: P = 0.043 ; C vs. T: P = 0.031 ), and rs4821544 polymorphism was significantly associated with an increased RA risk under the dominant model (TT vs. CT+CC: P = 0.031 ). Our results also indicated that rs729749 CT genotype frequency was significantly lower in RA patients than that in controls (CT vs. CC: P = 0.033 ). Moreover, the rs729749 CT genotype frequency was also significantly decreased in RA patients in males (CT vs. CC: P = 0.024 ). No significant association between NCF2 and CYBA gene polymorphisms and RA susceptibility was observed. There were significant associations between rs4821544 TT genotype and T allele frequencies and anti-CCP in male RA patients. Conclusions. In summary, NCF4 rs4821544 and rs729749 polymorphisms might contribute to RA susceptibility, while NCF2 and CYBA gene polymorphisms were not associated with RA susceptibility.

Role of cyba gene polymorphisms in pathogenesis of type 2 diabetes mellitus

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 (G>A), rs8854 (С>T), rs9932581 (C>T) и rs4673 (G>A) гена CYBA с риском развития СД2. В исследование включено 1024 больных СД2 (средний возраст 61,5±7,3 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, G>A) ассоциировался с повышенным риском развития заболевания (OR 1,49, 95%CI 1,11-1,99, p=0,0074, рецессивная модель). Выявленная ассоциация сохранила значимость и после введения поправки на пол, возраст и индекс массы тела (ORadj 1,51, 95%CI 1,09-2,09, padj=0,014). При раздельном сравнении больных СД2 мужчин и женщин с контролем оказалось, что установленная ассоциация rs4673 была характерна только для женщин (ORadj 1,60, 95%CIadj 1,04-2,46, padj=0,032). Больные СД2 имели значимо более высокое содержание перекиси водорода в плазме крови по сравнению с контрольной группой (p<0,05) вне зависимости от пола, однако ассоциация генотипа А/А rs4673 с повышением содержания Н2О2 в плазме в среднем на 0,77 мкмоль/л (p=0,044) была обнаружена только в подгруппе мужчин. Генотип Т/Т rs9932581 был ассоциирован с повышением уровня гликированного гемоглобина в среднем на 2,71% (р=0,042) в общей группе пациентов с СД2, а также с повышением того же показателя в среднем на 4,44% (р=0,03) в подгруппе больных СД2 женщин. В подгруппе мужчин отмечена ассоциация генотипа С/Т rs9932581 с увеличением доли HbA1c в среднем на 0,61% (р=0,018) и с повышением уровня глюкозы крови в среднем на 1,06 ммоль/л (р=0,029). 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 (р=0,022). 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 (G>A), rs8854 (C>T), rs9932581 (C>T) and rs4673 (G>A) 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, G>A) was associated with an increased risk of developing the disease (OR 1,49, 95%CI 1,11-1,99, P=0,0074, recessive model). The identified association remained significant even after the adjustment for gender, age, and body mass index (ORadj 1,51, 95%CI 1,09-2,09, padj=0,014). 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 (p<0,05), 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).