Hypertension Susceptibility Genes Research Articles

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.

Identifying susceptibility genes for essential hypertension by transcriptome-wide association study

Hypertension is a leading risk factor of cardiovascular disease and mortality in the population worldwide. Recently, hundreds of genomic loci were reported for hypertension by GWAS, however, the most SNPs are located in intergenic regions of genome, where a functional cause is difficult to determine. In the current study, a TWAS of hypertension was conducted using 452,264 individuals including 84,640 patients. KEGG and GO enrichment analyses were performed for the hypertension-related genes identified via TWAS. PPI network analysis based on the STRING database was also performed to detect TWAS-identified genes in hypertension. We have identified 18,420 genes from the GWAS summary data, and of those 1010 non-overlapping genes expression were significantly associated with hypertension after FDR correction (PFDR <0.05) in four tissues (left heart ventricle, aorta, whole blood, and peripheral blood). The KEGG and GO terms were mostly related to autoimmune mechanisms, and the autoimmune-related pathways have also been enriched using GO analysis for PPI genes. We further performed Mendelian randomization analysis, and the results supported a significant association between autoimmunity and hypertension. Moreover, 15 novel hypertension-susceptible genes were identified in all tissues, and five of the genes (RBM6, HLA-DRB5, UHRF1BP1, LYZ, and TMEM116) were associated with autoimmune system, which provide further evidence supporting an autoimmune mechanism in hypertension. In summary, our study supports that an autoimmune mechanism plays an important role in the development of hypertension, and these findings will provide new biological insights that will assist in deciphering the molecular etiology of hypertension.

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.

Single-cell analysis of salt-induced hypertensive mouse aortae reveals cellular heterogeneity and state changes

Elevated blood pressure caused by excessive salt intake is common and associated with cardiovascular diseases in most countries. However, the composition and responses of vascular cells in the progression of hypertension have not been systematically described. We performed single-cell RNA sequencing on the aortic arch from C57BL/6J mice fed a chow/high-salt diet. We identified 19 distinct cell populations representing 12 lineages, including smooth muscle cells (SMCs), fibroblasts, endothelial cells (ECs), B cells, and T cells. During the progression of hypertension, the proportion of three SMC subpopulations, two EC subpopulations, and T cells increased. In two EC clusters, the expression of reactive oxygen species-related enzymes, collagen and contractility genes was upregulated. Gene set enrichment analysis showed that three SMC subsets underwent endothelial-to-mesenchymal transition. We also constructed intercellular networks and found more frequent cell communication among aortic cells in hypertension and that some signaling pathways were activated during hypertension. Finally, joint public genome-wide association study data and our single-cell RNA-sequencing data showed the expression of hypertension susceptibility genes in ECs, SMCs, and fibroblasts and revealed 21 genes involved in the initiation and development of high-salt-induced hypertension. In conclusion, our data illustrate the transcriptional landscape of vascular cells in the aorta associated with hypertension and reveal dramatic changes in cell composition and intercellular communication during the progression of hypertension.

Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang.

Essential hypertension is a common cardiovascular disease with complex etiology, closely related to genetic and environmental factors. The pathogenesis of hypertension involves alteration in vascular resistance caused by sympathetic nervous system (SNS) and renin angiotensin system (RAS). Susceptibility factors of hypertension vary with regions and ethnicities. In this study, we conducted target capture sequencing on 54 genes related to SNS and RAS derived from a collection of Han nationality, consisting of 151 hypertension patients and 65 normal subjects in Xinjiang, China. Six non-synonymous mutations related to hypertension were identified, including GRK4 rs1644731 and RDH8 rs1801058, Mutations are predicted to affect 3D conformation, force field, transmembrane domain and RNA secondary structure of corresponding genes. Based on protein interaction network and pathway enrichment, GRK4 is predicted to participate in hypertension by acting on dopaminergic synapse, together with interacting components. RDH8 is involved in vitamin A (retinol) metabolism and consequent biological processes related to hypertension. Thus, GRK4 and RDH8 may serve as susceptibility genes for hypertension. This finding provides new genetic evidence for elucidating risk factors of hypertension in Han nationality in Xinjiang, which in turn, enriches genetic resource bank of hypertension susceptibility genes.

Association study of hypertension susceptibility genes ITGA9, MOV10, and CACNB2 with preeclampsia in Chinese Han population

Objective Preeclampsia (PE) is a disorder that occurs during the pregnancy and could affect the maternal and perinatal mortality as well as morbidity. The aim of our study is to investigate the associations between the hypertension susceptibility genes ITGA9, MOV10 and CACNB2 with PE in Chinese Han population. Methods A case–control study including 178 PE patients and 202 healthy controls was conducted to assess the associations between three loci (ITGA9 rs155524, MOV10 rs2932538 and CACNB2 rs4373814) and PE. The TaqMan probe assay was applied for genotyping in our study. Quantitative real-time PCR was performed to detect the mRNA expression levels of ITGA9, MOV10 and CACNB2. ELISA was carried out to detect the concentration of serum sFlt-1 or PLGF. Results Our study detected no significant differences in allelic frequencies of three SNPs between PE patients and healthy controls. In the genetic model, the results showed that the patients with ITGA9 rs155524 GA or AA genotypes had a higher risk of PE development compared to those with GG genotype in codominant model. And PE patients had a higher frequency of GA + AA genotypes based on the dominant model. Subgroup analysis showed ITGA9 rs155524 was associated with early-onset PE but not with late-onset PE. No association was observed between MOV10 and CACNB2 with PE in any genetic model and subgroup analysis. Quantitative real-time PCR results showed that ITGA9 mRNA expression level was apparently increased in the placental tissues of PE patients. In addition, ITGA9 expression levels of GA + AA subjects were apparently higher than that in the genotype GG of placental tissues. sFlt-1/PLGF ratio was higher in GA + AA subjects than that in GG subjects. Regression analysis revealed that ratio of sFlt-1/PLGF was positively correlated with ITGA9 mRNA expression level. Conclusion This study has identified ITGA9 is a promising candidate susceptibility gene for early-onset PE. Our findings demonstrated that the high expression of ITGA9 might be associated with an increased risk of PE.

PTGIS is a Novel Susceptibility Gene for Pulmonary Arterial Hypertension

Background: Genetic variants such as inactivating mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene account for approximately 15-20% of the etiology of idiopathic pulmonary arterial hypertension (IPAH). Increasing evidence indicates the existence of other IPAH susceptibility genes. Methods: The whole-genome sequencing was performed in a discovery cohort including 42 IPAH patients who are lacking BMPR2 mutations. Putative IPAH genes were validated in an independent cohort that included 188 IPAH patients and 968 healthy controls. Functional assessments were conducted to analyze the effects of candidate genetic variants on transcript splicing, enzymatic activity and function. Results: An enrichment of rare variants in the gene encoding prostacyclin synthase (PTGIS) was initially identified by the whole-genome sequencing. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In total, fourteen patients (6.1%) were heterozygous for three PTGIS rare variants, including one splice-site variant (c.521 1G>A) and two missense variants (R252Q, A447T). These rare variants conferred a 7.8-fold greater risk of IPAH (95% confidence interval (CI), 3.2 to 18.8; P=5 x 10-6). Inhaled iloprost induced more significantly decrease of pulmonary vascular resistance (P=0.001) and increase of cardiac index (P A variant resulted in aberrant mRNA transcripts. The functional studies showed that the two missense variants caused a decrease in prostacyclin production and increased cell death in pulmonary microvascular endothelial cells. Conclusions: We have identified three loss-of-function rare variants in the PTGIS gene from two independent IPAH cohorts. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation and cause deleterious effects. These results provide a novel finding that PTGIS rare variants are involved in the pathogenesis of IPAH. Funding: The work was supported by the following grants: the Beijing Natural Science Foundation (7181009, 7172180), the National Natural Science Foundation of China (81320108005), the National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), the National Key Research and Development Program of China (2016YFC0901502), Sanming Project of Medicine in Shenzhen-Professor Zhi-Cheng Jing's Group for Precise Medicine Research in Thrombosis and Vascular Disease (SZSM201502001) , and the fund from State Key Laboratory of Cardiovascular Disease (2016-kf04, 2018ZR-02). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study protocol was approved by the ethics committees of Shanghai Pulmonary Hospital and FuWai Hospital. The participants, who were all of Chinese Han ancestry, provided written informed consent.

Hypertension Editors' Picks: Hypertension and Sleep.

Hypertension Editors' Picks: Hypertension and Sleep.

Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension.

Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes (L3MBTL4 rs403814, Pmeta = 6.128 × 10−9; LOC729251, and TCEANC) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that L3MBTL4 is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of L3MBTL4 exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically, L3MBTL4 over-expression could lead to down-regulation of latent transforming growth factor-β binding protein 1 (LTBP1), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention.

A meta-analytical assessment of STK39 three well-defined polymorphisms in susceptibility to hypertension.

Serine/threonine kinase 39 gene (STK39) is one of the promising hypertension-susceptibility genes identified by a genome-wide association study in 2009, whereas subsequent validation in other ethnic groups is unsatisfactory, with inconsistent and inconclusive findings. We therefore aimed to meta-analytically assess the risk prediction of STK39 three polymorphisms, rs6749447, rs35929607 and rs3754777, for primary hypertension. Literature search and data collection were independently completed by two authors. Nine articles were pooled in this study. Overall analyses failed to see any significant associations of rs6749447, rs35929607 and rs3754777 with hypertension risk (odds ratio: 1.27, 0.95 and 1.21; P = 0.270, 0.507 and 0.153, respectively), and there was evident heterogeneity for three comparisons (I2 > 80%). Meta-regression analyses indicated that smoking was a significant risk factor for the association of rs3754777 with hypertension (P = 0.017). As reflected by the Begg’s and Filled funnel plots, as well as Egger’s tests, there were low probabilities of publication bias. In conclusion, our meta-analytical findings suggest that STK39 might not be a hypertension-susceptibility gene.

STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort.

The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na+/Cl− cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension.Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms—rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)—using the Snapshot method.The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2–15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5–11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02).Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted.

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.

Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System.

Previous genome-wide association studies identified serine threonine kinase 39 (STK39), encoding STE20/SPS1-related proline/alanine-rich kinase, as one of a limited number of hypertension susceptibility genes. A recent meta-analysis confirmed the association of STK39 intronic polymorphism rs3754777 with essential hypertension, among previously reported hypertension-associated STK39 polymorphisms. However, the biochemical function of this polymorphism in the mechanism responsible for hypertension is yet to be clarified. We generated rs3754777G>A knockin human cell lines with clustered regularly interspaced short palindromic repeats-mediated genome engineering. Homozygous (A/A) and heterozygous (G/A) knockin human embryonic kidney cell lines were generated using a double nickase, single-guide RNAs targeting STK39 intron 5 around single-nucleotide polymorphism, and a 100-bp donor single-stranded DNA oligonucleotide. Reverse transcription polymerase chain reaction with sequencing analyses revealed the identical STK39 transcripts among the wild-type and both knockin cell lines. Quantitative reverse transcription polymerase chain reaction showed increased STK39 mRNA expression, and immunoblot analysis revealed increases in total and phosphorylated STE20/SPS1-related proline/alanine-rich kinase with increased phosphorylated Na-K-Cl cotransporter isoform 1 in both knockin cell lines. The largest increases in these molecules were observed in the homozygous cell line. These findings indicated that this intronic polymorphism increases STK39 transcription, leading to activation of the STE20/SPS1-related proline/alanine-rich kinase-solute carrier family 12A signaling cascade. Increased interactions between STE20/SPS1-related proline/alanine-rich kinase and the target cation-chloride cotransporters may be responsible for hypertension susceptibility in individuals with this polymorphism.

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.

Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study.

We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for Japanese patients with myocardial infarction, ischemic stroke, or chronic kidney disease by genome-wide or candidate gene association studies. In the present study, we investigated the possible association of 13 single nucleotide polymorphisms (SNPs) at these 10 loci with the prevalence of hypertension or their association with blood pressure (BP) in community-dwelling individuals in Japan. The study subjects comprised 6,027 individuals (2,250 subjects with essential hypertension, 3,777 controls) who were recruited into the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study on atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center of Inabe General Hospital for an annual health checkup, and they are followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender, body mass index and smoking status revealed that rs2116519 of family with sequence similarity 78, member B (FAM78B; P=0.0266), rs6929846 of butyrophilin, subfamily 2, member A1 (BTN2A1; P= 0.0013), rs146021107 of pancreatic and duodenal homeobox 1 (PDX1; P=0.0031) and rs1671021 of lethal giant larvae homolog 2 (Drosophila) (LLGL2; P=0.0372) were significantly (P<0.05) associated with the prevalence of hypertension. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender, body mass index and smoking status among individuals not taking anti-hypertensive medication revealed that rs6929846 of BTN2A1 was significantly associated with systolic (P=0.0017), diastolic (P=0.0008) and mean (P=0.0005) BP, and that rs2116519 of FAM78B, rs146021107 of PDX1 and rs1671021 of LLGL2 were significantly associated with diastolic (P=0.0495), systolic (P=0.0132), and both diastolic (P=0.0468) and mean (0.0471) BP, respectively. BTN2A1 may thus be a susceptibility gene for hypertension.

A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population.

Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T) insertion(ins)/deletion(del) polymorphism within a poly-T sequence (38T vs 26T) in the ATP1A1 5’-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28–0.93]) accounting for 12.1 mmHg decrease in systolic BP (P = 0.02) and 6.6 mmHg in diastolic BP (P = 0.046). The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/− male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/− mice showed significantly lower blood pressure (P < 0.03) than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na-reabsorption in the kidney thereby decreasing sodium-associated risk for hypertension and sodium-induced endothelial stiffness and dysfunction. Altogether, data support ATP1A1 as a hypertension susceptibility gene in a male Sardinian population, and mandate further investigation of its involvement in hypertension in the general population.

Association of variants in renal salt reabsorption-related gene SLC12A3 with essential hypertension in a Mongolian population.

Mounting evidence has implicated the SLC12A3 gene in essential hypertension. Here, we examined the potential associations of common variants of the SLC12A3 gene with blood pressure traits in Mongolians in China. Genomic DNA was extracted from 508 unrelated Mongolian patients with essential hypertension and 246 normotensive Mongolian subjects for genotyping. The genotype distributions of all selected polymorphisms were consistent with Hardy-Weinberg equilibrium. The presence of the G allele in the rs7187932 polymorphism was found to be associated with an increased risk of hypertension (OR: 1.30; 95%CI = 1.00-1.38; P = 0.048), whereas the rs2399594 G allele was associated with a reduced risk for hypertension (OR: 0.76; 95%CI = 0.60-0.97; P = 0.030). No significant difference was observed for other alleles. Haplotype analysis revealed an association of the rs2399594 and rs711746 GG haplotype with a reduced risk for hypertension (OR: 0.76; 95%CI = 0.60-0.97; P = 0.029). No significant association was observed between other haplotypes and hypertension. These results suggest that the SLC12A3 gene is a susceptibility gene for hypertension in the Mongolian population.

Association of NPRA and NPRC gene variants and hypertension in Mongolian population.

NPRA and NPRC are candidate susceptibility genes for essential hypertension (EH) and play a key role in the regulation of plasma levels and biological effects of natriuretic peptides. The aims of the present study were to find new genetic markers in the NPRA and NPRC genes and to assess relationships between variants and EH. A total of 797 unrelated Mongolian herdsmen were enrolled, including 389 EH patients and 408 normotensive controls. Genotyping was performed using the polymerase chain reaction/ligase detection reaction assay. The distribution of the T-allele frequency of rs1847018 in NPRC differed significantly between hypertensive subjects and controls. There was an association between rs1847018 and EH in the additive model in NPRC (P < 0.05). There were no significant differences in the genotype and allele frequency distributions for any of the 3 single nucleotide polymorphisms in NPRA between EH and normotensive individuals. In NPRA, the frequency of haplotype TCA in the EH group was significantly lower than in controls, while the frequency of haplotype TCG was significantly higher in the EH group than in controls; Individuals who possessed the TCA haplotype had a significantly lower risk of EH, whereas the presence of haplotype TCG was significantly associated with a higher risk of EH. However, there was no significant difference between the EH group and controls in any of the 8 haplotypes in NPRC. Rs1847018 is a genetic marker of EH in NPRC, and the frequency of haplotype TCA and TCG in NPRA is associated with EH in the Mongolian population.

PEAR1 is not a human hypertension-susceptibility gene

Objective: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. Aim: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. Methods: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. Results: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant (p ≥ 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios ≤ 1.09; p ≥ 0.09). Conclusion: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans.

Association of Two Well-defined Polymorphisms in Leptin and Leptin Receptor Genes with Hypertension and Circulating Leptin: A Meta-analysis

The genes encoding adipose-derived hormone leptin and its receptor (LEPR) are increasingly deemed as hypertension-susceptibility genes. In this meta-analysis, we summarized the association of the II/I polymorphism in leptin gene and Gln223Arg polymorphism in LEPR gene with hypertension and circulating leptin. PubMed and Embase were systematically searched. Data extraction and study quality were assessed in duplicate. Statistical analyses were carried out with the STATA software (v. 11.2). A total of 11 articles written in English were eligible. Overall analysis identified a significant association between II/I polymorphism I allele and increased risk of hypertension under allelic (odds ratio; 95% confidence interval; P: 1.48; 1.06-2.08; 0.022) and homozygous genotypic (2.27; 1.20-4.29; 0.012) models. The magnitude of the association for II/I polymorphism I allele with hypertension was substantiated in Asians and for essential hypertension under both genetic models. Overall and subgroup analyses failed to reveal any significance for the association between the Gln223Arg polymorphism and hypertension risk. Carriers of Gln223Arg polymorphism Gln/Gln genotype had significantly higher circulating leptin than the Arg/Arg genotype carriers (weighted mean difference; 95% confidence interval; P: 1.61 ng/mL; 0.02-3.20; 0.047), and this significance persisted in essential hypertension subgroup (1.69 ng/mL; 0.02-3.35; 0.047). There were low probabilities of publication bias for the above comparisons. Our findings support the contributory role of the II/I polymorphism in leptin gene in the pathogenesis of hypertension, and this role was more evident in Asians and for essential hypertension.