Hypertension In Carriers Research Articles

Аллельный полиморфизм генов, вовлеченных в продукцию IL-1β, и предрасположенность людей к развитию артериальной гипертензии

Background: The level of IL-1β in blood plasma is determined not only by pro-inflammatory stimuli, but also by allelic polymorphism of the IL1B and NLRP3 genes. Information on the associa-tion of allelic polymorphism of these genes with the risk of arterial hypertension (AH) is scarce and contradictory. The aim of the study: To assess the risk of developing hypertension in carriers of various allelic variants according to the polymorphic markers rs1143634 (c.3953C>T), rs16944 (c.-511T>C), rs1143627 (c.-31C>T) of the IL1B gene and rs35829419 (c.2113C>A) of the NLRP3 gene, as well as to study possible mechanisms for the inclusion of allelic polymorphism of these genes in the etiology and pathogenesis of AH. Materials and methods: 182 DNA samples from healthy people and 180 DNA samples from patients with hypertension (stages I-II) were used for genotyping rs1143634, rs16944, rs1143627 (PCR-RFLP analysis). 215 DNA samples from healthy individuals and 180 hypertensive patients were used to determine alleles and genotypes for rs35829419 of the NLRP3 gene (allele-specific PCR with TaqMan probes). Total RNA obtained from peripheral blood leukocytes (PBL) of 45 healthy people and 50 patients with AH (27 people taking metoprolol or bisoprolol for more than a year and 23 people without antihypertensive thera-py) for assessment of gene expression by real-time PCR was used. The content of pro-inflammatory proteins in the blood plasma of 40 healthy individuals was measured by ELISA. Results: Carriers of the TT genotype for the c.3953C>T marker of the IL1B gene were found to have a 3-fold increased risk of AH (OR=3,239; 95% CI: 1,858-5,649). In healthy individuals with this genotype, the con-tent of IL-1β in blood plasma and the expression of the ICAM1 gene in PBL are higher than in het-erozygotes or homozygotes for the C allele (p=0,029 and p=0,004, respectively). Individuals with the TT genotype for the c.-31C>T marker of the IL1B gene had a reduced risk of АН (OR=0,645; 95% CI: 0,481-0,866). IL1B gene expression and hsCRP levels were lower in healthy individuals with the T allele for rs1143627 (p=0,022, p=0,040, respectively). There were no differences in the distribution of allele and genotype frequencies for markers c.-511T>C of the IL1B gene and c.2113C>A of the NLRP3 gene in the studied groups. Conclusion: Polymorphic markers rs1143634 (c.3953C>T) and rs1143627 (c.-31C>T) of the IL1B gene are probably involved in the predisposi-tion of the inhabitants of Karelia to the development of arterial hypertension.

Selenium as a predictor of metabolic syndrome in middle age women.

Selenium plays an important role in metabolic homeostasis. It has been suggested that it may also affect the expression and activity of PPAR-γ. The aim of study was to analyze the relationships between these variables in the context of the health of women, for whom the risk of MetS increases with age. The study involved 390 women in middle age. The stages of study: a survey-based part; anthropometric measurements; analysis of biological material (blood) in terms of glycemia, triglyceride, HDL, and selenium levels, as well as genetic analysis of the PPAR-γ polymorphisms. It was found that selenium may moderate the effect of the G allele of the PPAR-γ gene on the occurrence of elevated waist circumference (OR=1.030, 95%CI 1.005-1.057, p=0.020); and the effect of the C (OR=1.077, 95%CI 1.009-1.149, p=0.026) and the G alleles (OR=1.052, 95%CI 1.025-1.080, p<0.000) on the odds of elevated blood pressure. Women in whom HDL levels were not significantly reduced, had higher selenium levels (p=0.007). 1. The effect of selenium on MetS and its components has not been demonstrated. 2. The effect of individual alleles of the PPAR-γ gene on MetS and its components was not demonstrated. 3. The concentration of selenium may affect waist circumference in carriers of the G allele, and arterial hypertension in carriers of the C and G alleles by affecting the expression of PPAR-γ. 4. Higher selenium concentrations increased the odds of higher HDL levels in the group of subjects meeting the MetS criteria.

Kinase Activity Is Not Required for G Protein-Coupled Receptor Kinase 4 Restraining mTOR Signaling during Cilia and Kidney Development.

G protein-coupled receptor kinase 4 (GRK4) regulates renal sodium and water reabsorption. Although GRK4 variants with elevated kinase activity have been associated with salt-sensitive or essential hypertension, this association has been inconsistent among different study populations. In addition, studies elucidating how GRK4 may modulate cellular signaling are sparse. In an analysis of how GRK4 affects the developing kidney, the authors found that GRK4 modulates mammalian target of rapamycin (mTOR) signaling. Loss of GRK4 in embryonic zebrafish causes kidney dysfunction and glomerular cysts. Moreover, GRK4 depletion in zebrafish and cellular mammalian models results in elongated cilia. Rescue experiments suggest that hypertension in carriers of GRK4 variants may not be explained solely by kinase hyperactivity; instead, elevated mTOR signaling may be the underlying cause. G protein-coupled receptor kinase 4 (GRK4) is considered a central regulator of blood pressure through phosphorylation of renal dopaminergic receptors and subsequent modulation of sodium excretion. Several nonsynonymous genetic variants of GRK4 have been only partially linked to hypertension, although these variants demonstrate elevated kinase activity. However, some evidence suggests that function of GRK4 variants may involve more than regulation of dopaminergic receptors alone. Little is known about the effects of GRK4 on cellular signaling, and it is also unclear whether or how altered GRK4 function might affect kidney development. To better understand the effect of GRK4 variants on the functionality of GRK4 and GRK4's actions in cellular signaling during kidney development, we studied zebrafish, human cells, and a murine kidney spheroid model. Zebrafish depleted of Grk4 develop impaired glomerular filtration, generalized edema, glomerular cysts, pronephric dilatation, and expansion of kidney cilia. In human fibroblasts and in a kidney spheroid model, GRK4 knockdown produced elongated primary cilia. Reconstitution with human wild-type GRK4 partially rescues these phenotypes. We found that kinase activity is dispensable because kinase-dead GRK4 (altered GRK4 that cannot result in phosphorylation of the targeted protein) prevented cyst formation and restored normal ciliogenesis in all tested models. Hypertension-associated genetic variants of GRK4 fail to rescue any of the observed phenotypes, suggesting a receptor-independent mechanism. Instead, we discovered unrestrained mammalian target of rapamycin signaling as an underlying cause. These findings identify GRK4 as novel regulator of cilia and of kidney development independent of GRK4's kinase function and provide evidence that the GRK4 variants believed to act as hyperactive kinases are dysfunctional for normal ciliogenesis.

Associative role of polymorphism of the gene of &lt;i&gt;MMP-9&lt;/i&gt; (rs11697325) in development of arterial hypertension in patients with the rheumatoid arthritis

Aim. To study a contribution of polymorphism A-8202G (rs11697325) of a gene of matrix metalloproteinase-9 (MMP-9) in development of arterial hypertension (AH) in patients with the rheumatoid arthritis (RA).&#x0D; Materail and methods. 143 patients with RA were examined, among which a group of patients with RA without AH (n=50) and a group of patients with RA in association with AH (n=93) were identified. Healthy volunteers (n=151) were also divided into 2 groups comparable in age, sex and number with the main groups (control group 1 n=54, control group 2 n=97). The work used a range of clinical, laboratory, instrumental methods. A molecular genetic study was also performed. Blood samples were taken from all study participants. DNA isolation was carried out by the standard phenol-chloroform method. Genotyping for the MMP-9 gene was performed by PCR-RFLP analysis (polymerase chain reaction restriction fragment length polymorphism). PCR was carried out with a set of primers to the corresponding regions of the genome. PCR products were analyzed by electrophoresis in 4% polyacrylamide gel followed by staining with ethidium bromide.&#x0D; Results. In the course of a molecular genetic study, a statistically significant predominance of the homozygous AA genotype and the A allele of the MMP-9 (rs11697325) gene polymorphism was observed in the group of patients with RA, both separately and in association with AH, in comparison with the data of control groups. The risk of developing RA estimated by the odds ratio (OR) in carriers of the AA genotype of the MMP-9 gene is 1.8 times higher (95% confidence interval CI 1.1362.950; p=0.02) than in carriers of the GG and GA genotypes; in carriers of the A allele, the risk of developing RA is 1.6 times higher compared to the G allele (95% CI 1.1192.578; p=0.01). The OR risk of developing RA in association with hypertension in carriers of the AA genotype of the MMP-9 gene is 2.8 times higher (95% CI 1.2836.54; p=0.04) compared to GA and GG genotypes, 2.1 times higher in carriers of the A allele (95% CI 1.1134.127; p=0.02) compared to the G allele.&#x0D; Conclusion. Thus, the results of the study indicate that the homozygous AA genotype and the A allele of the MMP-9 (rs11697325) gene polymorphism are the predictors of the development of RA both as a separate nosological unit and in association with AH.

Identifying Interactions between Dietary Sodium, Potassium, Sodium-Potassium Ratios, and FGF5 rs16998073 Variants and Their Associated Risk for Hypertension in Korean Adults.

Hypertension is affected by both genetic and dietary factors. This study aimed to examine the interaction between dietary sodium/potassium intake, sodium–potassium ratios, and FGF5 rs16998073 and link these with increased risk for developing hypertension. Using data from the Health Examinee (HEXA) Study of the Korean Genome and Epidemiologic Study (KoGES), we were able to identify a total of 17,736 middle-aged Korean adults who could be included in our genome-wide association study (GWAS) to confirm any associations between hypertension and the FGF5 rs16998073 variant. GWAS analysis revealed that the FGF5 rs16698073 variant demonstrated the strongest association with hypertension in this population. Multivariable logistic regression was used to examine the relationship between dietary intake of sodium, potassium, and sodium–potassium ratios and the FGF5 rs16998073 genotypes (AA, AT, TT) and any increased risk of hypertension. Carriers with at least one minor T allele for FGF5 rs16998073 were shown to be at significantly higher risk for developing hypertension. Male TT carriers with a daily sodium intake ≥2000 mg also demonstrated an increased risk for developing hypertension compared to the male AA carriers with daily sodium intake <2000 mg (adjusted odds ratio (AOR) = 2.41, 95% confidence intervals (CIs) = 1.84–3.15, p-interaction < 0.0001). Female AA carriers with a daily potassium intake ≥3500 mg showed a reduced risk for hypertension when compared to female AA carriers with a daily potassium intake <3500 mg (AOR = 0.75. 95% CIs = 0.58–0.95, p-interaction < 0.0001). Male TT carriers in the mid-tertile for sodium–potassium ratio values showed the highest odds ratio for hypertension when compared to male AA carriers in the lowest-tertile for sodium–potassium ratio values (AOR = 3.03, 95% CIs = 2.14–4.29, p-interaction < 0.0001). This study confirmed that FGF5 rs16998073 variants do place their carriers (men and women) at increased risk for developing hypertension. In addition, we showed that high daily intake of sodium exerted a synergistic effect for hypertension when combined with FGF5 rs16998073 variants in both genders and that dietary sodium, potassium, and sodium–potassium ratios all interact with FGF5 rs16998073 and alter the risk of developing hypertension in carriers of either gender among Koreans.

Lack of association of the HSD11B1 gene polymorphisms with obesity and other traits of metabolic syndrome in children and adolescents

Introduction. Obesity and its related disorders, clustered into metabolic syndrome (MetS), are increasingly diagnosed in children and adolescents. Clinical features, which define MetS are also encountered in patients with glucocorticoid excess. Since no evident hypercortisolaemia was detected in obesity and MetS, investigations turned to the local modulators of cortisol action. 11b-hydroxysteroid dehydrogenase type 1, encoded by HSD11B1 gene, controls tissue availability of cortisol by its regeneration from inert cortisone. Changes in HSD11B1 expression and enzyme activity may be influenced by its sequence variants and seem implicated in MetS pathogenesis. Our study was designed to evaluate plausible association of the HSD11B1 polymorphisms with early-onset obesity and features of MetS in Polish children and adolescents. Material and methods. The study comprised of 258 obese children (136 females), aged 12.3 ± 3.6 years, with excessive body mass lasting 7.1 ± 3.8 years. Anthropometric and blood pressure measurements, baseline biochemical analyses and oral glucose tolerance test were performed in all participants. Genotyp­ing of the HSD11B1 variants rs12086634, rs846910, rs4844880, and rs3753519 was conducted in obese youth and compared with 568 lean blood donors. Results. Mean relative body mass index in obese cohort was 164.7 ± 27.1%. Hypertension was detected in 12.4%, impaired fasting glucose in 8.9%, impaired glucose tolerance in 10.8%, diabetes in 2.7%, and dyslipidemia in 31.4% children and adolescents. None of the studied HSD11B1 polymorphisms displayed significant difference in frequency between obese and lean individuals. MetS was diagnosed in 27.6% of 203 patients with obesity aged 10–18 years. Further genotype-stratified analyses of relationship between HSD11B1 variants and particular features of MetS did not confirm increased susceptibility to develop early-onset hyperglycaemia, dyslipidaemia and hypertension in carriers of specific genotypes at rs4844880, rs846910, rs3753519, and rs12086634 (p ≥ 0.05 in all tests). Conclusion. Our study does not support the implication of the HSD11B1 polymorphisms in early-onset obesity and other features of MetS.

Risk of arterial hypertension development due to T393C gene polymorphism of α-subunit of G-protein

According to foreign researchers, T393С gene polymorphism of α-subunit of the G-protein (rs7121) affects the sympathetic-adrenal system and the risk of hypertension. There are also data on the dependence of the manifestations of this polymorphism on the associated risk factors. However, these data are contradictory, which may be explained by ethnic differences in patients. In Ukraine there were no studies on this issue. We have studied 166 hypertensive patients and 90 healthy individuals. Determination of the polymorphism was performed by polymerase chain reaction with subsequent analysis of restriction fragments. The study found no statistically significant difference in the distribution of genotypes T393T, T393С, С393С in patients with hypertension and healthy subjects (p&gt;0,05). The risk for hypertension in carriers of genotypes T393T + T393С relatively to С393С genotype was not significantly different (OR=1,44, 95% CI 0,74-2,80; p=0,283). During the analysis of the effect of smoking on the manifestations of T393С gene polymorphism α-subunit of the G-protein, no statistically significant difference were found (p&gt;0,05). T393C gene polymorphism of α-subunit of G-protein did not affect the risk of hypertension.

Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation

Germline mutations in the gene encoding for bone morphogenetic protein receptor 2 (BMPR2) are a cause of pulmonary arterial hypertension (PAH). We conducted a study to determine the influence, if any, of a BMPR2 mutation on clinical outcome. The French Network of Pulmonary Hypertension obtained data for 223 consecutive patients displaying idiopathic or familial PAH in whom point mutation and large size rearrangements of BMPR2 were screened for. Clinical, functional, and hemodynamic characteristics, as well as outcomes, were compared in BMPR2 mutation carriers and noncarriers. Sixty-eight BMPR2 mutation carriers (28 familial and 40 idiopathic PAH) were compared with 155 noncarriers (all displaying idiopathic PAH). As compared with noncarriers, BMPR2 mutation carriers were younger at diagnosis of PAH (36.5 +/- 14.5 vs. 46.0 +/- 16.1 yr, P < 0.0001), had higher mean pulmonary artery pressure (64 +/- 13 vs. 56 +/- 13 mm Hg, P < 0.0001), lower cardiac index (2.13 +/- 0.68 vs. 2.50 +/- 0.73 L/min/m(2), P = 0.0005), higher pulmonary vascular resistance (17.4 +/- 6.1 vs. 12.7 +/- 6.6 mm Hg/L/min/m(2), P < 0.0001), lower mixed venous oxygen saturation (59 +/- 9% vs. 63 +/- 9%, P = 0.02), shorter time to death or lung transplantation (P = 0.044), and younger age at death (P = 0.002), but similar overall survival (P = 0.51). BMPR2 mutation carriers with PAH present approximately 10 years earlier than noncarriers, with a more severe hemodynamic compromise at diagnosis.