Essential Hypertension Susceptibility Research Articles

Association study of WNK1 genetic variants and essential hypertension risk in the Northern Han Chinese in Beijing.

Background: Essential hypertension (EH) is a complex disorder resulting from interaction of genetic and environmental factors. Lysine deficient protein kinase 1 (WNK1) plays a very important role in maintaining renal potassium, sodium and chlorine ions balance as well as the regulation of blood pressure, so the WNK1 gene is considered a key gene for EH. This study thus sought to evaluate possible genetic associations between the WNK1 genetic variants and EH risk in the Northern Han Chinese population in Beijing. Methods: This study included 476 hypertensive subjects and 491 normotensive subjects. A total of 12 tag SNVs of WNK1 gene were genotyped successfully by TaqMan assay. Comparisons of the genotypic and allelic frequency between cases and controls were made by using the chi-square test. Logistic regression analyses were performed under different genetic models, and haplotype analysis was also conducted. Results: A total of 12 SNVs were identified as the tag SNVs for WNK1 gene. Significant associations were observed between WNK1 gene rs7305099 variant and EH risk, and T allele influenced hypertension risk in a protective manner. After correcting for multiple testing using Bonferroni, the significance remained for the SNV of rs7305099 in three genetic models [allele comparison, p < 0.0002, OR = 0.627, 95%CI (0.491-0.801); homozygote comparison, p < 0.0003, OR = 0.278, 95%CI (0.140-0.552); additive model, p < 0.0003, OR = 0.279, 95%CI (0.140-0.553)]. In the haplotype analyses, we found that the haplotype A-A-A-C-G-G-G was significantly associated with increased risk for EH (p = 0.043, OR = 1.23). Conclusion: Our data suggested that the rs7305099 genetic variant and the haplotype A-A-A-C-G-G-G on WNK1 gene might be associated with the susceptibility of EH in the Northern Han Chinese population. These could provide evidences to the risk assessment, early prevention and individualized therapy of EH to some extent.

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.

Genetic polymorphisms of purinergic P2Y2 receptor were associated with the susceptibility to essential hypertension in Chinese postmenopausal women.

Hypertension has become a prominent public health concern. Essential hypertension (EH) is a polygenic disorder caused by multiple susceptibility genes. It has been previously shown that the purinergic P2Y2 receptor (P2Y2R) regulates blood pressure; however, whether P2Y2R genetic polymorphisms correlate with EH has not been investigated in Chinese. Our study included 500 EH cases and 504 controls who are Chinese postmenopausal women. We used allele-specific polymerase chain reaction (ASPCR) to genotype five single-nucleotide polymorphism (SNPs) in the P2Y2R gene, i.e., rs4944831, rs12366239, rs1783596, rs4382936, and rs10898909. We assessed the association of P2Y2R genetic polymorphisms with EH susceptibility. The results demonstrated that P2Y2R rs4382936A was correlated with a high risk of EH; particularly, the participants with the rs4382936A allele and CA/AA/(CA+AA) genotypes were at higher risks to EH compared to the subjects with the rs4382936C allele and CC genotype. Moreover, haplotype CAG combined by rs1783596-rs4382936-rs10898909 was a susceptible haplotype for EH, whereas haplotype CCG was a protective haplotype for EH. These results may provide new evidence for applying P2Y2R genetic polymorphisms as useful markers in clinic screening or monitoring potential EH cases in a population of Chinese postmenopausal women.

CACNA1C rs1006737 SNP increases the risk of essential hypertension in both Chinese Han and ethnic Russian people of Northeast Asia.

Voltage-gated Ca2+ channels play a key role in the regulation of arterial tone and blood pressure. The aim of this study was to determine whether the association of calcium voltage-gated channel subunit alpha1 C (CACNA1C) rs1006737 with essential hypertension (EH) exists in both Chinese Han and ethnic Russian populations of Northeast Asia. We used a case-control study of 2 ethnic groups in the same latitude geographical area to investigate the association between the susceptibility of EH and rs1006737 polymorphism. A total of 1512 EH patients and 1690 controls in Chinese Han people (Heilongjiang Provence, China), 250 EH patients, and 250 controls in ethnic Russian people (Chita, Russia), participated in this study. All participants were genotyped using the TaqMan SNP genotyping assay (Agena Company). Baseline characteristics and the minor allele frequencies of rs1006737 vary substantially among common Chinese Han and ethnic Russian people. Allele A was found to be a risk factor for EH in Chinese Han [(odds ratio) OR 1.705, (confidence interval) 95% CI: 1.332–2.182, P < .001] and ethnic Russian (OR 1.437; 95% CI: 1.110–1.860, P = .006). The GA genotype was significantly associated with an increased risk of hypertension (OR 1.538, 95% CI: 1.188–1.991, P = .001) for Chinese Han people, and the AA genotype (OR 2.412, 95% CI: 1.348–4.318, P = .003) for ethnic Russian people. The results of this study indicate that the A allele of the variant rs1006737 in the CACNA1C gene may be a useful genetic marker for EH risk prediction in Chinese Han and ethnic Russian populations.

Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis.

Background: The current meta-analytic study explored the relation between ACE gene insertion/deletion (I/D), and the risk of EH by reviewing relevant trials so as to determine the association between Angiotensin Converting Enzyme (ACE) gene polymorphism and essential hypertension (EH) susceptibility. Methods: Relevant studies published before May 2019 were collected from the PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP databases. Results: Fifty-seven studies involving a total of 32,862 patients were included. These studies found that ACE gene D allele was associated with higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model, and that Asian population with ACE gene D allele showed a higher EH susceptibility in all these models. Moreover, ACE gene D allele was found closely related to a higher EH susceptibility in the subgroups of HWE, NO HWE, Caucasian population, and Mixed population, with the majority being males in allelic model, homozygote model, and regressive model and the majority being females in allelic model. Conclusion: ACE gene D allele is associated with an overall higher EH susceptibility, which is confirmed in the subgroup analysis of Asian population, HWE, NO HWE, Caucasian population, and Mixed population.

Association between the A46G polymorphism (rs1042713) in the β2-adrenergic receptor gene and essential hypertension susceptibility in the Chinese population: A PRISMA-compliant meta-analysis.

Recently, many studies have been conducted to investigate the relationship between the A46G polymorphism in the β2-adrenergic receptor (ADRB2) gene and essential hypertension risk in the Chinese population. However, the results of previous studies were conflicting. The present study aimed to investigate the association between the ADRB2 A46G polymorphism and the risk of essential hypertension in the Chinese population. We performed a systematic search of possible relevant studies on PubMed, Embase, Ovid, Web of Science, China National Knowledge Infrastructure, Wanfang, and China Biology Medicine disc databases up to January 3, 2020. Two authors independently extracted information from included articles and assessed the quality of each study by the use of the Newcastle-Ottawa Scale. According to the extent of interstudy heterogeneity, either a random-effect model or a fixed-effect model was used to calculate the combined odds ratio (OR) and 95% confidence interval (CI). Finally, 16 studies containing 3390 cases and 2528 controls were included in our meta-analysis. Significant associations were found between the ADRB2 A46G polymorphism and essential hypertension risk in the Chinese population under four genetic models: allele genetic model (OR: 1.14, 95% CI: 1.06-1.23, P = .001, Pheterogeneity = .09), homozygote genetic model (OR: 1.29, 95% CI: 1.11-1.51, P = .001, Pheterogeneity = .25), dominant genetic model (OR: 1.17, 95% CI: 1.05-1.32, P = .005, Pheterogeneity = .04), and recessive genetic model (OR: 1.21, 95% CI: 1.05-1.38, P = .007, Pheterogeneity = .72). The ADRB2 A46G polymorphism may increase the risk of essential hypertension in the Chinese population.

Associations of SUCNR1, GRK4, CAMK1D gene polymorphisms and the susceptibility of type 2 diabetes mellitus and essential hypertension in a northern Chinese Han population.

Diabetes mellitus and hypertension are both complex diseases that are caused by interactions among multiple genetic and physiological factors. To investigate the association of common single-nucleotide polymorphisms (SNPs) of SUCNR1, GRK4 and CAMK1D genes with the susceptibility of the two diseases in a northern Chinese Han population. 36 SNPs were genotyped in 2304 clinical patients (1152 type 2 diabetes mellitus, 1152 essential hypertension) and 1152 health controls by Sequenom Mass-ARRAY RS1000. In this study, we found that BMI, blood press, pulse pressure, FBG, total cholesterol and triglycerides were associated with an increased risk of type 2 diabetes mellitus (T2DM) and essential hypertension (EH). Three SNPs (SUCNR1: rs73168929; GRK4: rs1557213; CAMK1D: rs17151584) significantly associated with the susceptibility of T2DM and EH at the same time. Also, the susceptibility genotypes of 3 SNPs were significantly correlated with liver and renal function parameters. To the best of our knowledge, the present study is the first to report that three SNPs (SUCNR1: rs73168929; GRK4: rs1557213; CAMK1D: rs17151584) contributed to the risk of T2DM and EH in a northern Chinese Han population. These results provide a favourable evidence for better understand of the underlying common mechanism of these two diseases.

Low serum 25-hydroxyvitamin D levels may increase the detrimental effect of VDR variants on the risk of essential hypertension.

The present cross-sectional study evaluated the association of vitamin D receptor (VDR) variants with serum 25(OH)D3 levels and their interaction on essential hypertension (EH) risk. 1539 patients were eligible in the study population. Two loci in VDR gene (rs2239179, rs2189480) were genotyped by TaqMan probe assays. Logistic regression, Kruskal-Wallis rank test and Chi-square test were used to determine the association among VDR polymorphisms, serum vitamin D metabolites, and the risk of EH. Interaction plots were performed to explain the interaction effects of circulating 25(OH)D3 levels and VDR variants on EH susceptibility. After potential confounding adjustment, we observed that the mutations of VDR (rs2239179/rs2189480) were associated with the increased risk of EH (P < 0.05). Moreover, plasma 25(OH)D3 levels were inversely associated with EH, However, we did not find the association between serum 25(OH)D3 and VDR variants. When comparing with wild-type homozygous and heterozygous genotype carriers with vitamin D sufficiency, hypovitaminosis D and insufficient participants carrying homozygous variant genotype of rs2239179 showed a higher risk of EH, increased by 113% (OR = 2.13, 95% CI: 1.20, 3.80); Notably, the detrimental effect of rs2239179 homozygous variant on EH became stronger in the case of serum 25(OH)D3 <30 ng/ml. However, we did not find the interaction effect between rs2189480 variants and serum 25(OH)D3 levels on the risk of EH. Our results suggested that the mutations of VDR may accelerate the progression of EH etiology, especially when suffering hypovitaminnosis D and insufficiency.

Interaction between mitochondrial NADH dehydrogenase subunit-2 5178 C > A and clinical risk factors on the susceptibility of essential hypertension in Chinese population

BackgroundThe mitochondrial genotype 5178 cytosine/adenine (5178 C > A) within the NADH dehydrogenase subunit-2 gene (ND2) was proved to associate with longevity and predispose resistance to adult-onset diseases. This study aimed to confirm the interactive effects between ND 25178 C > A and clinical risk factors on the susceptibility of essential hypertension in Chinese general population.Materials and MethodsThe relationship between the ND2 5178 C > A variation and the risk of hypertension was investigated in 817 hypertensives and 821 matched normotensives. The interactive effects between ND2 5178 C > A and clinical risk factors were evaluated.ResultsThe ND2 5178 A allele was more frequent in normotensives than in hypertensives (32.64% vs. 24.24%; adjusted OR: 0.62, 95% CI: 0.49–0.79, P = 1.3 × 10− 4). After stratification, the significant association between ND2 5178 C > A and hypertension was found only in current smokers (OR: 0.44, 95% CI: 0.31–0.62), but not in non-current smokers (p < 0.01 for interaction). Smoking status (OR: 1.51, 95% CI: 1.11–2.06) and high triglycerides (OR: 1.57, 95% CI: 1.10–2.24) were found independently associated with hypertension only in carriers of 5178 C allele but not in carriers of 5178 A allele.ConclusionsIn conclusion, ND2 5178 A allele could confer a lower risk for essential hypertension in Chinese by the interaction with smoking status. The higher risk of hypertension imposed by smoking and high TG may be altered by ND2 5178 A allele.

The dominant models of KCNJ11 E23K and KCNMB1 E65K are associated with essential hypertension (EH) in Asian: Evidence from a meta-analysis.

The K channel, subfamily J, member-11 (KCNJ11) E23K and β1 subunit of large-conductance Ca-activated K channel (KCNMB1) E65K polymorphisms were shown to be associated with the risk of essential hypertension (EH). However, the results were inconclusive with relatively small sample size. Thus, we carried out a meta-analysis to investigate the genetic association between KCNJ11 E23K and KCNMB1 E65K polymorphisms and essential hypertension risk. Relative studies were collected using PubMed, Web of Science, the Cochrane Library databases, Chinese National Knowledge Infrastructure and Embase databases. Pooled odds ratios with 95% confidence intervals were used to assess the strength of associations. The dominant models of KCNJ11 E23K (P = .006, OR [95%CI] = 0.45 [0.25, 0.79]) and KCNMB1 E65K (P = .04, OR [95%CI] = 0.91 [0.83, 1.00]) were significantly associated with essential hypertension risk. No significant association was detected between the allelic and recessive models of KCNJ11 E23K and KCNMB1 E65K and the susceptibility of EH. Subgroup analysis stratified by ethnicity showed that the dominant model of KCNMB1 E65K was associated with EH risk in Asian population (P = .003, OR [95%CI] = 0.83 [0.74, 0.94]), but not in Caucasian (P = .74, OR [95%CI] = 1.02 [0.89, 1.18]). The dominant model of KCNJ11 E23K and KCNMB1 E65K might be susceptible factors for essential hypertension. To confirm this result, large-scale case-control studies with more subjects are necessary.

ADRB3 Gene Trp64Arg Polymorphism and Essential Hypertension: A Meta-Analysis Including 9,555 Subjects.

Background: Presence of the β3-Adrenergic receptor (ADRB3) gene Trp64Arg (T64A) polymorphism may be associated with an increased susceptibility for essential hypertension (EH). A clear consensus, however, has yet to be reached.Objective and methods: To further elucidate the relationship between the ADRB3 gene Trp64Arg polymorphism and EH, a meta-analysis of 9,555 subjects aggregated from 16 individual studies was performed. The combined odds ratios (ORs) and their corresponding 95% confidence intervals (CI) were evaluated using either a random or fixed effect model.Results: We found a marginally significant association between ADRB3 gene Trp64Arg polymorphism and EH in the whole population under the additive genetic model (OR: 1.200, 95% CI: 1.00–1.43, P = 0.049). Association within the Chinese subgroup, however, was significant under allelic (OR: 1.150, 95% CI: 1.002–1.320, P = 0.046), dominant (OR: 1.213, 95% CI: 1.005–1.464, P = 0.044), heterozygous (OR: 1.430, 95% CI:1.040–1.970, P = 0.03), and additive genetic models (OR: 1.280, 95% CI: 1.030–1.580, P = 0.02). A significant association was also found in the Caucasian subgroup under allelic (OR: 1.850, 95% CI: 1. 260–2.720, P = 0.002), dominant (OR: 2.004, 95% CI: 1.316–3.052, P = 0.001), heterozygous (OR: 2.220, 95% CI: 1.450–3.400, P = 0.0002), and additive genetic models (OR: 2.000, 95% CI: 1. 330–3.010, P = 0.0009).Conclusions: The presence of the ADRB3 gene Trp64Arg polymorphism is positively associated with EH, especially in the Chinese and Caucasian population. The Arg allele carriers of ADRB3 gene Trp64Arg polymorphism may be at an increased risk for developing EH.

Association of sodium ion transporter gene polymorphisms with essential hypertension among ethnic Koreans from Mudanjiang

OBJECTIVE To assess the association of SLC12A3 and SCNN1B gene polymorphisms (rs11643718 and rs12447134) with essential hypertension among ethnic Koreans from Mudanjiang, China. METHODS For 204 patients with essential hypertension and 186 healthy controls, the genotypes of rs11643718 and rs12447134 loci were determined with an improved multiplex ligase detection reaction (iMLDR) method. RESULTS Allelic and genotypic frequencies of rs11643718 of SLC12A3 gene are associated with the onset of disease hypertension (P <0.05) as well as systolic blood pressure (P < 0.01, under a recessive model). No association was found between rs12447134 of SCNN1B gene with the onset of disease (P > 0.05) but diastolic blood pressure (P < 0.05, under a recessive model). CONCLUSION The polymorphisms of rs11643718 locus is associated with the susceptibility for essential hypertension among ethnic Koreans from Mudanjiang area and can be used as a predictor for the disease.

Positive association between ALDH2 rs671 polymorphism and essential hypertension: A case-control study and meta-analysis.

Background and objectiveSeveral studies have been conducted to examine the association between aldehyde dehydrogenase 2 family (ALDH2) rs671 polymorphism and essential hypertension (EH). However, the results remain inconsistent. This study aimed to clarify the association between ALDH2 rs671 polymorphism and EH susceptibility.MethodsOne thousand and ninety-four cases and 1236 controls who were ethnic Han Chinese were collected for this population-based case-control study. A meta-analysis was performed to calculate the pooled odds ratio and 95% confidence interval, using allele contrast, dominant, recessive, and co-dominant models using fixed or random-effect models.ResultsSignificant differences were observed between EH cases and controls at the level of both genotype (χ2 = 6.656, P<0.05) and alleles (χ2 = 6.314, P<0.05). An additional meta-analysis using 4204 cases and 5435 controls established that rs671 was significantly associated with EH (P<0.00001).ConclusionThe results of our case-control study and meta-analysis showed that there is a significant association between ALDH2 rs671 polymorphism and EH susceptibility. In addition, the results of the breakdown analysis by gender suggest a male-specific association between the ALDH2 rs671 polymorphism and EH.

A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility.

The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH). A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays. We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01-1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52-0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility. Our pilot study was the first to show that gene-gene and gene-environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future.

A genome-wide association study of essential hypertension in an Australian population using a DNA pooling approach.

Despite the success of genome-wide association studies (GWAS) in detecting genetic loci involved in complex traits, few susceptibility genes have been detected for essential hypertension (EH). We aimed to use pooled DNA GWAS approach to identify and validate novel genomic loci underlying EH susceptibility in an Australian case-control population. Blood samples and questionnaires detailing medical history, blood pressure, and prescribed medications were collected for 409 hypertensives and 409 age-, sex- and ethnicity-matched normotensive controls. Case and control DNA were pooled in quadruplicate and hybridized to Illumina 1M-Duo arrays. Allele frequencies agreed with those reported in reference data and known EH association signals were represented in the top-ranked SNPs more frequently than expected by chance. Validation showed that pooled DNA GWAS gave reliable estimates of case and control allele frequencies. Although no markers reached Bonferroni-corrected genome-wide significance levels (5.0×10-8), the top marker rs34870220 near ASGR1 approached significance (p=4.32×10-7), as did several candidate loci (p<1×10-6) on chromosomes 2, 4, 6, 9, 12, and 17. Four markers (located in or near genes NHSL1, NKFB1, GLI2, and LRRC10) from the top ten ranked SNPs were individually genotyped in pool samples and were tested for association between cases and controls using the χ 2 test. Of these, rs1599961 (NFKB1) and rs12711538 (GLI2) showed significant difference between cases and controls (p<0.01). Additionally, four top-ranking markers within NFKB1 were found to be in LD, suggesting a single strong association signal for this gene.

The Association of Mitofusion-2 Gene Polymorphisms with Susceptibility of Essential Hypertension in Northern Han Chinese Population.

Background: Mitofusion-2 (Mfn2) played an important role in regulating vascular smooth muscle cells proliferation, insulin resistance and endoplasmic reticulum stress, which were found to be involved in the development of hypertension. So we inferred that the Mfn2 gene may participate in the pathogenesis of hypertension. The aim of this study was to determine whether common single nucleotide polymorphisms (SNPs) in Mfn2 gene were associated with essential hypertension (EH) in northern Han Chinese.Methods: We genotyped 6 tagging SNPs of Mfn2 gene (rs2336384, rs2295281, rs17037564, rs2236057, rs2236058 and rs3766741) with the TaqMan assay in 626 hypertensive patients and 618 controls.Results: Logistic regression analysis indicated that CC+CA genotype of rs2336384 and AA+AG genotype of rs2236057 were significantly associated with increased risk of EH (OR=1.617, P=0.005; OR=1.418, P=0.031, respectively). GG genotype of rs2236058 and GG+CG genotype of rs3766741 were found to be significantly associated with decreased risk of EH (OR=0.662, P=0.023; OR=0.639, P=0.024).When stratified by gender, for rs2336384, rs2236057 and rs2236058, significant association was observed in males, but not in females. Haplotype analysis indicated that the CCAACC haplotype was positively correlated with EH and there was a negative correlation between ACAGGG haplotype and EH.Conclusions: This study demonstrated that Mfn2 gene polymorphisms were associated with essential hypertension in northern Han Chinese population, especially in male subjects.

Altered erythrocyte membrane protein composition mirrors pleiotropic effects of hypertension susceptibility genes and disease pathogenesis.

The study was designed to assess the effects of polymorphisms in genes associated with essential hypertension on the variation of erythrocyte membrane proteins (EMPs) in hypertensive patients. Major EMPs content was analyzed in blood from 1162 unrelated Russians (235 hypertensive patients, 176 healthy controls, and 751 random individuals from the Central Russia population). Essential hypertension patients were genotyped for 11 polymorphisms of essential hypertension susceptibility genes including ADD1 (rs4961), GNB3 (rs5443, rs16932941), NOS3 (rs1799983, rs2070744), ACE (rs5186), AGTR1 (rs5186), AGT (rs699, rs4762), MR (rs5534), and TGFB1 (rs1800471). EMP contents and their relationship with the genetic loci were analyzed using various statistical tests. Sex-specific differences in EMP contents between the cases and controls were observed. Regardless of sex, hypertensives exhibited mainly decreased levels of alpha (SPTA1) and beta-spectrin (SPTB) and increased levels of glucose transporter (GLUT1) as compared with healthy subjects (P ≤ 0.001). EMP correlated differently in essential hypertension patients and controls. Almost 70% of the joint variation in the EMP levels is explained by five gender-specific principal components. The essential hypertension susceptibility genes showed considerable effects on the levels of spectrins and glucose transporter. A joint variation of the genes explained about half the total polygenic variance in the GLUT1, SPTA1, and SPTB levels in hypertensives. The study showed that essential hypertension susceptibility genes are the important factors of the inherited EMP variation, and their pleitropic effects may be mirrored in the altered expression of genes encoding cytoskeletal proteins and those related to intracellular glucose metabolism.

The human ATF1 rs11169571 polymorphism increases essential hypertension risk through modifying miRNA binding

Activating transcription factor 1 (ATF1) may be involved in essential hypertension (EH) by induction of NADPH oxidase 1 (NOX1) and radical oxygen species (ROSs) production. Abnormal expression of ATF1 was found in EH in previous microarray analysis. Here we tested whether a single nucleotide polymorphism (SNP) located in the 3′-untranslated region (3′UTR) of ATF1 was associated with EH susceptibility by affecting microRNA (miRNA) binding. In silico analysis indicated that rs11169571 (T>C) was a candidate SNP to modulate miRNA: ATF1 mRNA complex, with the greatest changed energy for hsa-miR-1283, and the luciferase reporter analysis showed that miR-1283 inhibited the activity of the reporter vector carrying –T allele, but not the –C allele. In addition, inhibition of miR-1283 in HA-VSMCs enhanced the expression of ATF1 mRNA as well as the ROS levels. Further case-control study showed that rs11169571 was significantly associated with increased risk of EH. Finally, we observed an increased ATF1 protein level in peripheral blood of EH patients with CC carriers compared to TT carriers of rs11169571, with an intermediate ATF1 level in TC carriers. These results suggested that rs11169571 of ATF1 gene may be associated with EH, and the SNP-modified posttranscriptional gene regulation by miRNAs could be a potentially pathogenetic mechanism of EH.

Associations between CLCNKA_B tag SNPs with essential hypertension and interactions between genetic and environmental factors in an island population in China

Objective: Essential hypertension (EH) is known as the result from the interaction of environmental and genetic factors. We selected tag SNPs of CLCNKA_B genes as gene markers, to elucidate the relationship between CLCNKA_B and EH, and to determine the possible interaction among tag SNPs and dietary factors in island of China. Methods: A case-control study was conducted in Changshan islands of China, blood samples of 806 participants were genotyped, and the general characteristics and dietary habits of them were collected. Unconditional logistic regression (ULR) was used to assess the effects of CLCNKA_B tag SNPs and dietary factors on EH. Generalized multifactor dimensionality reduction (GMDR) was used to test gene–environment interaction for EH risk. Results: Four SNPs were identified as the tag SNPs of CLCNKA_B. Recessive model for rs5253 and rs2275166 were marginal associated with the decrease risk of EH (OR = 0.36, 95% CI = 0.12–1.07 for rs5253; OR = 0.40, 95% CI = 0.16–1.05 for rs2275166). In GMDR, the five-factor interaction model of rs1010069, salt, marine products, meat and edible oil consumption was the best model, with a maximum CVC of 10/10 and a TBA of 0.638 (p = 0.001). In ULR, compared with subjects carried wild genotypes and null dietary risk factor, those with three or more dietary risk factors and mutation genotypes had 5.90-fold EH risk (95% CI:2.24–15.53). Conclusion: Though the single loci of tag SNPs of CLCNKA_B are not enough to significantly increase the EH susceptibility, the combination of CLCNKA tag SNP, salt, marine products, meat and edible oil consumption is associated with elevated risk.

The interactions between alcohol consumption and DNA methylation of the ADD1 gene promoter modulate essential hypertension susceptibility in a population-based, case-control study.

The potential effects of the interactions between DNA methylation (CpG1 and CpG2-5 methylation levels) of the α-adducin (ADD1) gene promoter and ADD1 tagSNPs (tag single-nucleotide polymorphisms) or the environmental factors on essential hypertension (EH) risk have not been clarified. Thus, we performed an age- and gender-matched case-control study to investigate the association between ADD1 tagSNPs and EH. A total of 1020 subjects with EH and 1020 normotensive subjects were genotyped by melting temperature shift technology. Logistic regression was used to assess the associations of ADD1 tagSNPs, environmental factors and EH. The generalized multifactor dimensionality reduction (GMDR) method was applied to explore the potential interactions. Under additive, dominant and recessive models, no significant associations were evidenced between EH and rs3755885, rs2071694, rs4963 or rs3775067 with the complete data set or the gender-stratified analysis after adjusting for triglycerides, body mass index and alcohol consumption. However, we observed a significant association between rs4961 and EH under the dominant model after Bonferroni correction when adjusting for confounding factors in the entire sample (odds ratio (OR)=0.64, 95% confidence interval (CI)=0.50-0.83, P=0.001). In GMDR, the two-factor interaction model of alcohol consumption and DNA methylation (CpG1 methylation) was the best model, with a maximum cross-validation consistency of 9/10 and testing balance accuracy of 0.63 (P=0.01). Our results indicate that the SNP rs4961 has a protective role in the development of EH. In conclusion, the interactions between alcohol consumption and DNA methylation (CpG1 methylation) of the ADD1 gene promoter have a significant role in modifying EH susceptibility.