Hypertension Susceptibility Research Articles

Polymorphism of ADAMTS-13 gene rs28503257 in Iraqipatients with Hypertension

The aim of this study was to investigate the association of polymorphism of ADAMTS-13 gene to the susceptibility of hypertension in patients with hypertension in an Iraqi population. Forty-five hypertensive patients (23 males and 22 females), their age 40-70 years and 35 healthy controls (18 males and 17 females), their age range between 40-70 years. were selected from Wasit Province using a convenient sampling method. Genetic polymorphism of ADAMTS13) rs28503257 A/G was carried out using TaqMan -PCR. In patients and controls, the genotypic and allelic distributions of adisentgrine and metallopeptedase with a thrombospondin type1 motife13(ADAMTS13) rs28503257 A/G of the study populations were consistent with Hardy-Weinberg equilibrium. The genotypes frequecies of ADAMTS-13 rs 28503257 A/G of patients with hypertension manifested non-significant differences when compared with healthy control group AA =40(89%), AG =5(11) in patients vs. 30(86), 5(14) P=0.67 in controls for each genotype respectively. There were no hypertensive patients or controls carrying the genotype GG in the study sample. The A and G allele frequencies in SNP rs28503257 A/G were not significantly different between the two groups (P>0.05). The A allele was the major one in studied groups with a percent of (0.9286) and (0.9444) in control and patients groups respectively. Whereas the A allele was the minor one with a percent of (0.0714) and (0.0556) in these groups respectively. The association analysis revealed that individuals carrying the homozygous AA genotype were assocaited with hypertension OR=1.3333 (CI95% 0.3537 to 5.0259) and P= 0.6709 indicating that a positive association with the disease.However,the individuals with a hetrozygous AG genotype showed negative association with the disease OR= 0.7500 (CI95% 0.1990 to 2.8271) ,P=0.6709. Although no individuals carrying the genotype GG were observed in patients and controls, the odds ratio can be calculated in the presence of other genotypes OR= 0.7802 (CI95% 0.0151 to 40.2986), P= 0. 9019.These results suggest that the A allele may be considered as a risk allele in hypertension whereas the G allele is a protective allele agianst hypertension. The genetic model for ADAMTS-13 in comparison between hypertensive patients and controls .The dominant model indicated that patients of(AG+GG/AA) genotypes decreased the association with hypertension comparing with control with OR=1.333 CI95%0.3537 to 5.025: patients (40/5 and 0.00) in patients vs.(30/5 and 0.00) with OR== 0.7500(CI95%0.1990 to 2.8271) , P =0.6709,P=0.6709.The recessive model revealed that patients carrier the genotype(AA+AG/GG) increased the association with the disease (0.0/40 and 5) in patients compared with controls(0.00/30 and 5) with OR=1.2817(CI95% 0.0248 to 66.199), P=0. 9019.The Over dominant model revealed that patients carrier the genotype (AA+GG/AG) increased the association with the disease (0.040 and 5) in patients compared with controls (0.00/30 and 5) with OR=1.3333(CI95%0.3537 to5.0259),P=0.6709. In coclusion, the polymorphisms ADAMTS-13 rs28503257 variant A/G with are associated with the susceptibility of hypertension.

Renalase rs2296545 variant improve hypertension susceptibility by modifying binding affinity to catecholamines in obstructive sleep apnea

Obstructive sleep apnea (OSA), a condition often linked with hypertension, has an undefined relationship with renalase, a protein known for regulating blood pressure. This study aimed to investigate the relationship between serum renalase levels as well as renalase functional single nucleotide polymorphism (SNP) rs2296545 variant and hypertension in a Han Chinese OSA population. 126 subjects underwent serum renalase detection, with linear regression being performed to evaluate the relationship between serum renalase levels and OSA-related traits. Additional 4275 subjects were obtained rs2296545 genotype information by SNP microarray. And binary logistic regression was used to assess the effect of rs2296545 on hypertension risk. Molecular dynamics simulation and molecular docking were utilized to access the protein structures and the interplay between protein and catecholamines of wild-type and rs2296545 mutant renalase. The results showed that serum renalase levels were significantly higher in the severe OSA group. Further analysis showed renalase levels were positively correlated with blood pressure in the non-OSA group and negatively correlated in the severe OSA group. For rs2296545 polymorphism analysis, the hypertension risk significantly increased for the recessive model CC/GG + CG (OR = 1.211, 95% CI: 1.025–1.431) and the additive model CC/CG (OR = 1.223, 95% CI: 1.025–1.458) in the severe OSA. The rs2296545 polymorphism affected protein structure, and led to increase binding free energy, weakening interactions between renalase and catecholamines. In conclusion, serum renalase levels had independent association with blood pressure. And rs2296545 polymorphism may influence on susceptibility to hypertension by altering protein ability to bind to catecholamines, which might contribute to the intervention of hypertension in the OSA population.

ACE gene polymorphism and susceptibility to hypertension in a Jordanian adult population.

Hypertension is one of the most common and complicated disorders associated with genetic and environmental risk factors. The angiotensin-converting enzyme (ACE) is important in the renin-angiotensin-system pathway. The gene expression of ACE has been investigated as a possible hypertension marker. This study investigates the association between polymorphisms within the ACE1 and ACE2 genes and hypertension susceptibility in a Jordanian population. The study comprised a total of 200 hypertensive patients and 180 healthy controls. A polymerase chain reaction (PCR) was performed to genotype the candidate polymorphism (rs4646994) of the ACE1gene. The Luminex DNA array technique was used for genotyping SNPs (rs4359, rs4344, rs4341, rs4343, and rs2106809) of the ACE1 and ACE2 genes. Our findings suggest no association between SNPs and hypertension regarding allelic and genotypic frequencies. However, rs4359 was significantly associated with diet (pP = 0.049), know HTN (P = 0.042), and number of years DM (P = 0.003). rs4341 was associated with diet (P = 0.032), peripheral vascular disease (P = 0.005), and chronic kidney disease (p = 0.049). While rs4343 was associated with diet (P = 0.031), diabetes mellitus (P = 0.032), and other medication (P = 0.025). Furthermore, the haplotypes of four SNPs of the ACE1 gene showed no significant association with HTN patients and healthy controls. Our findings indicate no association between the polymorphisms in the ACE gene and the risk of hypertension development in the Jordanian adult population.

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-β-PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH. Bioinformatic analyses were used to explore the mechanism by which BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-β signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension. BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9, which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-β signaling by downregulating TGF-β expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin-mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast, Brcc3-/- mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling. These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-β signaling in PASMCs. Such rebalance of BMP/TGF-β pathways is translationally important for PAH alleviation.

Retracted: SOCS3 Gene Polymorphism and Hypertension Susceptibility in Chinese Population: A Two-Center Case-Control Study.

[This retracts the article DOI: 10.1155/2021/8445461.].

Vitamin D deficiency and the vitamin D receptor (VDR) gene polymorphism rs2228570 (FokI) are associated with an increased susceptibility to hypertension among the Bangladeshi population.

Vitamin D receptor (VDR) gene is implicated in hypertension vulnerability due to its role in regulating the renin-angiotensin system (RAS) and blood pressure. In this case-control study, a carefully selected cohort of 111 hypertensive individuals and 100 healthy controls underwent serum analysis using HPLC to measure 25-hydroxy vitamin D levels. Polymorphic variations in the VDR gene were detected and characterized using the PCR-RFLP method. At first, lower 25-hydroxy vitamin D levels were observed in hypertensive individuals compared to controls (p<0.001). The genotype frequency of the VDR gene TaqI showed no significant difference between cases and controls (p>0.05). Similarly, no significant difference was found in the VDR gene BsmI genotype frequency between hypertensive patients and controls (p>0.05). However, a statistically significant distinction was observed in the VDR gene FokI genotype frequency between cases and controls (p<0.01). The odds ratios for FokI genotypes (CC, CT, TT, and CT+TT) were 1.0, 0.590, 1.566, and 0.963, respectively. Furthermore, serum 25-hydroxy vitamin D levels were significantly higher in control subjects compared to hypertensive patients across all genotypes of VDR (p<0.001). Hypertensive patients, excluding those with the FokI VDR gene CC genotype, exhibited significantly higher systolic blood pressure levels compared to the control group (p<0.05). Similarly, hypertensive subjects displayed elevated diastolic blood pressure levels compared to the control group (p<0.001). Overall, the results suggest the presence of a potential inverse correlation between serum 25-hydroxy vitamin D levels and hypertension. The association analysis conducted indicated that there is no significant association between TaqI and bsmI genotypic variants and the risk of developing hypertension. However, it was observed that VDR gene polymorphisms do have a clear association with hypertension susceptibility, as evidenced by the significantly higher occurrence of FokI genotypic variants in hypertensive patients. Our study therefore introduces the possibility of utilizing 25-hydroxy vitamin D deficiency and VDR gene polymorphisms as a biomarker for hypertension.

The bioinformatic analysis of CFTR in essential hypertension

The CFTR gene is associated with cystic fibrosis, a genetic disease primarily affecting the respiratory and digestive systems. Essential hypertension is a common cardiovascular disorder characterized by high blood pressure. In this bioinformatic analysis, various databases and tools were used to investigate the potential mechanisms underlying this association. Gene expression data and epigenetic analyses were used to identify the biological processes between CFTR and hypertension. Additionally, genetic variants within CFTR were analysed for potential effects on hypertension susceptibility. The results of this analysis suggest that CFTR may not play a role in hypertension. Moreover, hypertension has no special epigenetic feather. Further studies are needed to confirm the mechanisms of such a phenomenon.

PTPRD gene variant rs10739150: A potential game-changer in hypertension diagnosis.

High blood pressure, also known as hypertension (HTN), is a complicated disorder that is controlled by a complex network of physiological processes. Untreated hypertension is associated with increased death incidence, rise the need for understanding the genetic basis affecting hypertension susceptibility and development. The current study sought to identify the genetic association between twelve single nucleotide polymorphisms (SNPs) within seven candidate genes (NOS3, NOS1AP, REN, PLA2G4A, TCF7L, ADRB1, and PTPRD). The current study included 200 Jordanian individuals diagnosed with hypertension, compared to 224 healthy controls. Whole blood samples were drawn from each individual for DNA isolation and genotyping. The SNPStats tool was used to assess haplotype, genotype, and allele frequencies by the mean of chi-square (χ2). Except for rs10739150 of PTPRD (P = 0.0003), the genotypic and allelic distribution of the SNP was identical between patients and controls. The prevalence of the G/G genotype in healthy controls (45.5%) was lower than in hypertension patients (64.3%), suggesting that it might be a risk factor for the disease. PTPRD TTC genetic haplotypes were strongly linked with hypertension (P = 0.003, OR = 4.03). This study provides a comprehensive understanding of the involvement of rs10739150 within the PTPRD gene in hypertension. This new knowledge could potentially transform the way we approach hypertension diagnosis, providing an accurate diagnostic tool for classifying individuals who are at a higher risk of developing this condition.

Different sedentary behaviors, genetic susceptibility of hypertension, and new-onset hypertension: Mediating effects of body mass index and grip strength.

The association between different sedentary behaviors and hypertension risk remains unclear. We aimed to explore the relationship between different domains of sedentary behaviors and new-onset hypertension, investigate whether genetic susceptibility to hypertension modifies the relationship, and examine the extent to which the relationship is mediated by body mass index (BMI) and grip strength. 212 714 participants without baseline hypertension in the UK Biobank were enrolled. The three major sedentary behaviors (TV-watching, nonoccupational computer use, and driving) were measured using touch screen questionnaires. The primary outcome was new-onset hypertension. During a median follow-up of 11.9 years, 13 983 participants developed hypertension. There was a linear positive association between TV-watching time and new-onset hypertension (p for nonlinearity =0.868). A J-shaped association was found for nonoccupational computer use time and driving time with new-onset hypertension, with an inflection point of 0.5 h/day for both (both p for nonlinearity <0.001). Polygenetic risk scores for hypertension (based on 118 related single-nucleotide polymorphisms) did not significantly modify these associations (all p-interactions >0.05). Furthermore, the detrimental effects of long-term sedentary behaviors on hypertension were mediated by BMI by 21%-30%, and the beneficial effects of limited sitting time (within 0.5 h/day) for driving and nonoccupational computer use were mediated by grip strength by 6-25%. There was a positive association for hands-independence sedentary behavior (TV-watching), and a J-shaped association for hands-dependence sedentary behaviors (nonoccupational computer use and driving) with new-onset hypertension, regardless of genetic risks of hypertension. These relationships were partly mediated by BMI and grip strength.

Susceptibility to hypertension based on MTHFR rs1801133 single nucleotide polymorphism and MTHFR promoter methylation.

The aetio-pathologenesis of hypertension is multifactorial, encompassing genetic, epigenetic, and environmental factors. The combined effect of genetic and epigenetic changes on hypertension is not known. We evaluated the independent and interactive association of MTHFR rs1801133 single nucleotide polymorphism (SNP) and MTHFR promoter methylation with hypertension among Taiwanese adults. We retrieved data including, MTHFR promoter methylation, MTHFR rs1801133 genotypes (CC, CT, and TT), basic demography, personal lifestyle habits, and disease history of 1,238 individuals from the Taiwan Biobank (TWB). The distributions of hypertension and MTHFR promoter methylation quartiles (β < 0.1338, 0.1338 ≤ β < 0.1385, 0.1385 ≤ β < 0.1423, and β ≥ 0.1423 corresponding to <Q1, Q1-Q2, Q2-Q3, and ≥Q3) among individuals with the rs1801133 genotypes (CC, CT, and TT) were significantly different (P < 0.05). The risk of hypertension was significantly higher among individuals with the TT genotype compared to the reference genotype (CC): odds ratio (OR); 95% confidence interval (CI) = 2.718; 1.503-4.914. The trend of the association of the CT and TT genotypes with hypertension was dose-dependent (P-trend = 0.0041). MTHFR promoter methylation (lower quartiles compared to ≥Q3) was not significantly associated with hypertension. However, its interaction with MTHFR rs1801133 was significant (P = 0.0323). After stratification by rs1801133 genotypes, lower MTHFR promoter methylation quartiles (<Q1, Q1-Q2, Q2-Q3) compared to ≥Q3 were significantly associated with a higher risk of hypertension among individuals carrying the CC genotype: ORs (95% CIs) = 3.225 (1.140-9.124), 4.177 (1.424-12.247), and 8.645 (2.513-29.739) for Q2-Q3, Q1-Q2, and <Q1, respectively. The trend test was significant (P-trend = 0.0009). Independently, rs1801133 TT was associated with a higher risk of hypertension, but methylation was not. Based on genotypes, lower methylation was dose-dependently associated with a higher risk of hypertension in individuals with the CC genotype. Our findings suggest that MTHFR rs1801133 and MTHFR promoter methylation could jointly influence hypertension susceptibility.

Genetic associations between miR‑200bT>C and miR‑495A>C polymorphisms and hypertension susceptibility.

Although microRNA (miRNA)-mediated functions and gene expression regulation are involved in the susceptibility to vascular diseases, the potential effect of miRNA polymorphisms on the susceptibility of patients to hypertension (HTN) remains to be sufficiently elucidated. Therefore, the present study aimed to identify the potential association between miRNA (miR)-200bT>C (rs7549819) and miR-495A>C (rs2281611) polymorphisms, which may be implicated in stroke and vascular pathogenesis, and the susceptibility to HTN and relevant risk factors in a Korean cohort recruited from Jeju National University Hospital (Jeju, South Korea). Using an analysis of PCR-restriction fragment length polymorphism, genotype analysis was conducted to assess the frequency of miR-200bT>C and miR-495A>C gene polymorphisms in the HTN group (n=232) and the non-HTN healthy control group (n=247). The results showed significant differences in the genotype distributions of the miR-495A>C polymorphism between the HTN and control groups, specifically with the CC genotype and C allele. However, neither the miR-200bT>C nor the dominant and recessive models were found to be distributed differently between the two groups. Following analysis of the genotype combination of the single nucleotide polymorphisms, the TC/CC and CC/CC combined genotypes of the miR-200bT>C and miR-495A>C polymorphisms were observed to be associated with susceptibility to HTN. The haplotype results demonstrated that the allele combination frequency of haplotype C-A was significantly different between the two groups. The stratified analysis revealed that the miR-200b and miR-495 polymorphisms are associated with the risk of HTN, exhibiting differences in the levels of body-mass index (<28.12 kg/m2), fasting blood glucose (<106.26 mg/dl), high-density lipoprotein cholesterol (<44.29 mg/dl) and systolic blood pressure (≥132.67 mmHg). Data from the present study suggested that the variant of miR-495A>C polymorphism and allelic combinations (haplotype C-A of miR-200bT>C/miR-495A>C) can increase hypertension susceptibility among a Korean population.

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.

In Africa, the burden of hypertension has been rising at an alarming rate for the last two decades and is a major cause for cardiovascular disease (CVD) mortality and morbidity. Hypertension is characterised by elevated blood pressure (BP) ≥ 140/90 mmHg. Current hypertension guidelines recommend the use of antihypertensives belonging to the following classes: calcium channel blockers (CCB), angiotensin converting inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, β-blockers, and mineralocorticoid receptor antagonists (MRAs), to manage hypertension. Still, a considerable number of hypertensives in Africa have their BP uncontrolled due to poor drug response and remain at the risk of CVD events. Genetic factors are a major contributing factor, accounting for 20% to 80% of individual variability in therapy and poor response. Poor response to antihypertensive drug therapy is characterised by elevated BPs and occurrence of adverse drug reactions (ADRs). As a result, there have been numerous studies which have examined the role of genetic variation and its influence on antihypertensive drug response. These studies are predominantly carried out in non-African populations, including Europeans and Asians, with few or no Africans participating. It is important to note that the greatest genetic diversity is observed in African populations as well as the highest prevalence of hypertension. As a result, this warrants a need to focus on how genetic variation affects response to therapeutic interventions used to manage hypertension in African populations. In this paper, we discuss the implications of genetic diversity in CYP11B2, GRK4, NEDD4L, NPPA, SCNN1B, UMOD, CYP411, WNK, CYP3A4/5, ACE, ADBR1/2, GNB3, NOS3, B2, BEST3, SLC25A31, LRRC15 genes, and chromosome 12q loci on hypertension susceptibility and response to antihypertensive therapy. We show that African populations are poorly explored genetically, and for the few characterised genes, they exhibit qualitative and quantitative differences in the profile of pharmacogene variants when compared to other ethnic groups. We conclude by proposing prioritization of pharmacogenetics research in Africa and possible adoption of pharmacogenetic-guided therapies for hypertension in African patients. Finally, we outline the implications, challenges, and opportunities these studies present for populations of non-European descent.

Association analysis of MTHFR (rs1801133 and rs1801131) and MTRR (rs1801394) gene polymorphisms towards the development of hypertension in the Bai population from Yunnan, China

ABSTRACT Objective Hypertension is one of the leading causes of human death and disability. MTHFR and MTRR regulate folate metabolism and are closely linked to hypertension, although the relationship is inconsistent among different ethnic groups. The present study aims to investigate the effects of MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), and MTRR A66G (rs1801394) polymorphisms on hypertension susceptibility in the Bai nationality of the Yunnan Province, China. Methods This case–control study included 373 hypertensive patients and 240 healthy controls from the Chinese Bai population. The genotyping of MTHFR and MTRR gene polymorphisms was carried out by using the KASP method. The effects of genetic variations of MTHFR and MTRR genes on hypertension risk were evaluated with odds ratios (OR) and 95% confidence intervals (95% CI). Results The present study revealed that the CT and TT genotypes and T allele of MTHFR C677T locus were considerably associated with an increased risk of hypertension. In addition, MTHFR A1298C locus CC genotype could significantly increase the hypertension risk. The T-A and C–C haplotypes of MTHFR C677T and MTHFR A1298C could increase the risk of hypertension. Further stratified analysis by risk rank of folate metabolism indicated that people with poor utilization of folic acid were more prone to develop hypertension. In the hypertension group, the MTHFR C677T polymorphism was significantly associated with fasting blood glucose, fructosamine, apolipoprotein A1, homocysteine, superoxide dismutase, and malondialdehyde levels. Conclusion Our study suggested that genetic variations of MTHFR C677T and MTHFR A1298C were significantly associated with susceptibility to hypertension in the Bai population from Yunnan, China.

INSR and ISR‑1 gene polymorphisms and the susceptibility of essential hypertension: A meta‑analysis.

INSR and ISR-1 may be candidate genes for essential hypertension (EH). However, the genetic association between the INSR and ISR-1 gene polymorphisms and EH risk remains contradictory. To determine a more precise association of the INSR and ISR-1 gene polymorphisms and EH, the present study performed a meta-analysis. Eligible studies up to Jan 2021 were retrieved from multiple databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the genetic associations between the allele, dominant and recessive models of INSR Nsil, RsaI and ISR-1 G972R polymorphisms and EH susceptibility. A total of 10 case-control studies encompassing 2,782 subjects including 1,289 cases and 1,493 controls were evaluated for the present meta-analysis. Neither of the allele, dominant and recessive models of INSR Nsil and ISR-1 G972R polymorphisms was associated with EH risk (P>0.05). While the allele [P=0.0008, OR=0.58, (95% CI)=(0.42, 0.80)], dominant [P=0.02, OR=0.59, (95% CI)=(0.38, 0.92)] and recessive models [P=0.003, OR=0.38, (95% CI)=(0.20, 0.72)] of INSR Rsal polymorphism were associated with decreased risk of EH. Subgroup analysis according to ethnicity showed that the significant associations between the allele, dominant and recessive models of INSR Rsal polymorphism and EH risk were observed in Caucasian populations, but not in Asian populations (P>0.05). In conclusion, the INSR Rsal polymorphism is probably a protective factor for EH. To identify the result, additional case-control designed research with larger numbers of subjects are required.

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study

BackgroundGenetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population.MethodsThe study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed.ResultsThe genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291–1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.882, P < 0.001) may increase risk of hypertension.ConclusionsCYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

Association of Different Combinations of ALDH2 rs671, APOE rs429358, rs7412 Polymorphisms with Hypertension in Middle-Aged and Elderly People: A Case-Control Study.

Hypertensive patients have a younger trend, and studies on the role of genetic factors in hypertension susceptibility have been inconsistent. Aldehyde dehydrogenases 2 (ALDH2) and apolipoprotein E (APOE) are involved in the pathophysiological processes of hypertension. To investigate the relationship of ALDH2 and APOE polymorphisms with hypertension in middle-aged (30-59 years old) and elderly (≥60 years old) persons. Two thousand six hundred and ten hypertensive patients and 1921 controls were included (between 30 and 100 years old). The genotypes of common polymorphisms in APOE and ALDH2 genes (APOE rs429358, rs7412, and ALDH2 rs671) of the subjects were analyzed by polymerase-chain reaction (PCR)-microarray. Statistical analyses (Student's t-test, Mann-Whitney U-test, χ 2 test, and logistic regression analysis) were performed with SPSS v21.0. There were 4531 participants (66.60 ± 12.10 years old) in this study, including 3057 (67.5%) males and 1474 (32.5%) females. There were no significant differences in distributions of ALDH2 rs671, APOE rs429358/rs7412 genotypes and alleles between hypertensive patients and controls. Persons with ALDH2 rs671 G/A or A/A genotype were less likely to have hypertension (G/A+A/A vs G/G: gender-, age-, smoking-, and drinking-adjusted OR 0.885, 95% CI 0.785-0.997, P=0.045), while ALDH2 rs671 A/A+APOE rs429358 or rs7412 wild-type genotype may decrease the risk of hypertension. In middle-aged group, ALDH2 rs671 G/A+APOE rs429358 T/C carriers (adjusted OR 0.547, 95% CI 0.350-0.856, P=0.008), and ALDH2 rs671 A/A+APOE rs7412 C/C genotypes (adjusted OR 0.567, 95% CI 0.361-0.891, P=0.014) were less likely to have hypertension. In elderly group, APOE rs7412 T/T carriers were more likely to have hypertension (rs671 T/T vs C/C: adjusted OR 4.755, 95% CI 1.075-21.027, P=0.040; rs671 T/T vs C/C or C/T: adjusted OR 4.734, 95% CI 1.071-20.928, P=0.040). Polymorphism-polymorphism interactions of ALDH2 rs671 and APOE rs429358/rs7412 may effect on hypertension susceptibility. Different genotypes comparison shows different roles in middle-aged and elderly people, respectively.

S-22-7: GENOMIC ANALYSES OF HYPERTENSION-ASSOCIATED DISEASES ACROSS ETHNIC GROUPS AND SPECIES

To explore genetic architecture of hypertension and end-organ damages, we performed integrative genomic analyses in both humans and inbred hypertensive rat strains. In humans, noting that hypertension is more prevalent and contributes to the increased risk of stroke in people of East Asian ancestry, we performed a multi-stage GWAS for blood pressure (BP) principally in East Asians and meta-analysis in East Asians and Europeans. We reported 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. Some of the ancestry-specific association signals are influenced by a selective sweep. These data provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP. In rats, we also performed genomic analyses of BP and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP). By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n = 1415) and fine congenic mapping (maximum n = 8704) plus comparative analysis with human, transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY). We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this analysis, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein-kinin/renin-angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. Furthermore, to unravel the mechanisms underlying antihypertensive drug-induced amelioration of end-organ damages, we performed transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred rat strains (SHRSP and WKY). Noticeable changes of mRNA expression were induced particularly by RAS blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the KKS/RAS (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. Taken together, we provide genetic epidemiological evidence for ethnic differences in hypertension susceptibility and also in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, likely across species.

The combined effects of GSTM1/GSTT1 and MTHFR C677T polymorphisms on the systemic arterial hypertension susceptibility: A genetic association study in Brazilian diabetic patients

This genetic association study included 150 hypertensive diabetic patients and 150 normotensives non-diabetic subjects. Glutathione S-transferases M1 and T1 (GSTM1/GSTT1) deletion polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T SNP (rs1801133) genotyping were performed by SYBR Green multiplex real-time and RFLP-PCR, respectively. Both GSTM1 and GSTT1 null (OR = 4.52, p = 0.04, and OR = 4.27, p = 0.01) and mutant (677TT) genotypes (OR = 2.95, p = 0.02) conferred risk to hypertension susceptibility. The combined genotypes (MTHFR:GSTT1:GSTM1) revealed a significant association: W/−/+, W/+/−, H/−/−, H/−/+, M/+/−, and M/+/+. These findings suggesting a probable oxidative hypothesis for hypertensive diabetic patients from the interaction of the detoxification mechanism and the homocysteine metabolism. The imbalance in antioxidant enzymes contributes to the establishment of oxidative stress in conjunction with hyperhomocysteinemia and reactive oxygen species production. We concluded that these findings suggest that both polymorphisms may contribute to hypertension susceptibility in diabetic patients.

Effects of Pre-Pregnancy Overweight/Obesity on the Pattern of Association of Hypertension Susceptibility Genes with Preeclampsia.

The aim of this study was to explore the effects of pre-pregnancy overweight/obesity on the pattern of association of hypertension susceptibility genes with preeclampsia (PE). Ten single-nucleotide polymorphisms (SNPs) of the 10 genome-wide association studies (GWAS)-significant hypertension/blood pressure (BP) candidate genes were genotyped in 950 pregnant women divided into two cohorts according to their pre-pregnancy body mass index (preBMI): preBMI ≥ 25 (162 with PE and 159 control) and preBMI < 25 (290 with PE and 339 control). The PLINK software package was utilized to study the association (analyzed four genetic models using logistic regression). The functionality of PE-correlated loci was analyzed by performing an in silico database analysis. Two SNP hypertension/BP genes, rs805303 BAG6 (OR: 0.36−0.66) and rs167479 RGL3 (OR: 1.86), in subjects with preBMI ≥ 25 were associated with PE. No association between the studied SNPs and PE in the preBMI < 25 group was determined. Further analysis showed that two PE-associated SNPs are functional (have weighty eQTL, sQTL, regulatory, and missense values) and could be potentially implicated in PE development. In conclusion, this study was the first to discover the modifying influence of overweight/obesity on the pattern of association of GWAS-significant hypertension/BP susceptibility genes with PE: these genes are linked with PE in preBMI ≥ 25 pregnant women and are not PE-involved in the preBMI < 25 group.

Polymorphisms of hypertension susceptibility genes as a risk factors of preeclampsia in the Caucasian population of central Russia

IntroductionThe study was designed to assess the effects of hypertension (HT) susceptibility genes polymorphisms in the development of preeclampsia (PE) in Caucasians from Central Russia. MethodsPE patients (n = 452) and women control group (n = 498) were genotyped for 10 polymorphisms of HT/blood pressure (BP) susceptibility genes (according to the previously published GWAS in Caucasian populations) including AC026703.1 (rs1173771), HFE (rs1799945), BAG6 (rs805303), PLCE1 (rs932764), OBFC1 (rs4387287), ARHGAP42 (rs633185), CERS5 (rs7302981), ATP2B1 (rs2681472), TBX2 (rs8068318) and RGL3 (rs167479). A logistic regression method was applied to search for associations between SNPs and PE. The relationship between SNP-SNP interactions and PE risk was analyzed by performing MB-MDR. ResultsThe rs1799945 gene in HFE significantly independently increased the risk of developing PE (OR = 2.24) and rs805303 in BAG6 was associated with a reduced risk in the occurrence of PE (OR = 0.55–0.78). Among the 10 SNPs examined, nine SNPs were associated with PEs within the 10 most significant SNP-SNP interaction models. Loci rs7302981 CERS5, rs805303 BAG6 and rs932764 PLCE1 contributed to the largest number of epistatic models (50% or more). DiscussionThe present study is the first to report an association between polymorphisms of HT/BP susceptibility genes important for GWAS and the risk of PE in Caucasians from Central Russia. Our pathway-based functional annotation of the PE risk variants highlights the potential regulatory function (epigenetic/eQTL/sQTL/non-synonymous) that nine genetic risk markers and their 115 highly correlated variants exert on 155 genes. The study shows that these genes may function cooperatively in key signaling pathways in PE biology.