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Background: The aging of skin is a diversified biological phenomenon, influenced by a combination of genetic and environmental factors. However, the specific mechanism of skin photoaging is not yet completely elucidated. Methods: Gene expression profiles for photoaging patients were obtained from the Gene Expression Omnibus (GEO) collection. We conducted single-cell and intercellular communication investigations to identify potential gene sets. Predictive models were created using LASSO regression. The relationships between genes and immune cells were investigated using single sample gene set enrichment analysis (ssGSEA) and gene set variance analysis (GSVA). The molecular processes of important genes were studied using gene enrichment analysis. A miRNA network was created to look for target miRNAs connected with important genes, and transcriptional regulation analysis was used to identify related transcription factors. Finally, merging gene co-expression networks with drug prediction shows molecular pathways of photoaging and potential treatment targets. Furthermore, we validated the role of key genes, immune cell infiltration, and the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway in photoaging, which were identified through bioinformatics analysis, using in vivo reverse transcription quantitative PCR (RT-qPCR), immunofluorescence labeling, and Western blotting. Results: This study discovered three key genes, including Atp2b1, Plekho2, and Tspan13, which perform crucial functions in the photoaging process. Immune cell infiltration analysis showed increased M1 macrophages and CD4 memory T cells in the photoaging group. Further signaling pathway analysis indicated that these key genes are enriched in multiple immune and metabolic pathways. The significant roles of Atp2b1, Plekho2, Tspan13, M1 macrophages infiltration, CD4 memory T cells infiltration and the AMPK pathway in photoaging was validated in vivo. Conclusion: This research revealed the underlying molecular mechanisms of photoaging, indicating that key genes such as Atp2b1 and Tspan13 play crucial roles in the regulation of immune cell infiltration and metabolic pathways. These findings provide a new theory for the treatment of photoaging and provide prospective targets for the advancement of relevant drugs. [ABSTRACT FROM AUTHOR]

ATP2B1 is a known regulator of calcium (Ca2+) cellular export and homeostasis. Diminished levels of intracellular Ca2+ content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca2+ levels and impairs SARS-CoV-2 infection. Furthermore, a rare homozygous intronic variant of ATP2B1 is shown to be associated with the severity of COVID-19. The mechanism of action during SARS-CoV-2 infection involves the PI3K/Akt signaling pathway activation, inactivation of FOXO3 transcription factor function, and subsequent transcriptional inhibition of the membrane and reticulum Ca2+ pumps ATP2B1 and ATP2A1, respectively. The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 lacks toxicity in vitro, its prophylactic use as a therapeutic agent against COVID-19 is envisioned here. Synopsis: The ATP2B1 and ATP2A1 Ca2+ pumps are deregulated during SARS-CoV-2 infection, due to an impaired PI3K/Akt/FOXO3 pathway, which is antagonised by a small molecule promoting ATP2B1 activity. Moreover, a rare homozygous intronic ATP2B1 variant is associated with COVID19 severity. ATP2B1 (PMCA1) activation protects against SARS-CoV-2 infection. Loss of ATP2B1 increases SARS-CoV-2 viral replication. A nucleotide variant polymorphism (T > C) within the ATP2B1 (PMCA1) locus is associated with severe COVID19. A nontoxic caloxin-derived small molecule (PI-7) has potential for therapeutic applications against SARS‐CoV‐2. The ATP2B1 and ATP2A1 Ca2+ pumps are deregulated during SARS-CoV-2 infection, due to an impaired PI3K/Akt/FOXO3 pathway, which is antagonised by a small molecule promoting ATP2B1 activity. Moreover, a rare homozygous intronic ATP2B1 variant is associated with COVID19 severity. [ABSTRACT FROM AUTHOR]

To evaluate the association between ATP2B1 gene polymorphisms and skeletal fluorosis, a cross-sectional study was conducted. In China, 962 individuals were recruited, including 342 cases of skeletal fluorosis. Four TP2BA1 polymorphisms (rs2070759, rs12817819, rs17249754, and rs7136259) were analysed. The results suggested that rs17249754 and rs7136259 were associated with skeletal fluorosis. After controlling confounders, the protective effect of GG genotype in rs17249754 was apparent in individuals over 45 years old, female, with urine fluoride concentration below 1.6 mg/L, serum calcium above 2.25 mmol/L or serum phosphorus between 1.1 and 1.3. Heterozygote TC in rs7136259 increased the risk of skeletal fluorosis in subjects who are elderly, female, with urinary fluoride more than 1.6 mg/L, serum calcium more than 2.25 mmol/L and blood phosphorus between 1.1 and 1.3 mmol/L. Four loci were found to be tightly related by linkage disequilibrium analysis, and the frequency of distribution of haplotype GCGT was lower in the skeletal fluorosis group. [ABSTRACT FROM AUTHOR]

Background: As a complex disease, hypertension (HTN) is influenced by both genetic and environmental factors and their interaction. The calcium signaling pathway is known to be involved in the regulation of blood pressure, and dysfunction in this pathway may contribute to the development of hypertension. Genome-wide association studies (GWAS) have identified several genes in the calcium signaling pathway associated with susceptibility to HTN, including PLCB1, ATP2B1, and ADRB1. The aim of this study was to investigate the possible association between single nucleotide variants (SNVs) in the calcium signaling pathway and HTN., Methods: We genotyped three SNVs: rs1801253 (ADRB1), rs6108168 (PLCB1), and rs17249754 (ATP2B1) in a population of 131 patients with hypertension and 115 healthy controls from Kermanshah province, Iran., Results: Our results showed a strong and significant association between the G allele and the GG and CG genotypes of the rs1801253 variant in the ADRB1 gene and susceptibility to hypertension. However, no significant association was found for the other two SNVs. In addition, the presence of the GCG haplotype (alleles from left to right: rs1801253, rs6108168, and rs17249754) appeared to confer a protective role against HTN., Conclusion: This study has made a significant contribution towards enhancing the comprehension of hypertension development, as well as the early identification of individuals who are at risk., (© 2025 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: The efficacy of current therapeutic schedule is limited owing to fibroprollferative tumor microenvironment (TME) of cholangiocarcinoma, compelling a search for new therapeutic targets. Methods: Gene expression profiles and methylation profiles were obtained from UCSC Xena. Consensus clustering was performed on the transcriptome data of cholangiocarcinoma to determine the different immune subtypes. The differentially expressed genes (DEGs) between hot tumor and cold tumors were identified. ESTIMATE was used to assess immune score, and the cases were separated into relatively superior and inferior immune score groups. Single-sample gene set enrichment analysis was applied to assess 28 immune cells in the cholangiocarcinoma microenvironment. Unsupervised consensus was applied for methylation profiling to distribute the high and low methylation groups. The correlation between DNA methylation and mRNA expression was investigated, and the relationship between the ATP2B1 gene and the immune microenvironment was explored. Finally, 77 cases of intrahepatic cholangiocarcinoma (ICC) were collected for verification. Results: Seven subtypes were related to patient outcomes (P=0.005). The proportions of CD8+ T cells in the "hot" immune type was significantly greater than that in the "cold" immune type (P<0.05). Next, DEGs and DNA methylation-governed genes were intersected, and ATP2B1 was identified as a prognosis factor in ICC (P=0.035). ATP2B1 expression was positively correlated with immune scores (P=0.005, r=0.458), the levels of infiltrating CD8+ T cells (P=0.004, r=0.47), and CD4+ T cells (P=0.027, r=0.37). Immunohistochemistry confirmed that the amounts of CD8+ and CD4+ T cells were significantly higher in ICC tissue samples than in tissues with ATP2B1 overexpression (P<0.05). Conclusions: ATP2B1 overexpression can activate immune signals and prompt cold tumor response. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Hypertension often leads to cardiovascular disease and kidney disease, and hypertention is an important worldwide problem. Body mass index (BMI) has an important role for raising blood pressure. Further, hypertension can be affected by both environmental factors and genetic factors. Many single nucleotide polymorphisms have been associated with hypertension. Genome wide association study (GWAS) is a method of confirming a new locus of increasing the risk of disease, and GWAS has confirmed several single nucleotide polymorphisms (SNPs) that are associated with high blood pressure. This study analyzed the relationship between systolic blood pressure, diastolic blood pressure and SNP of the ATP2B1 gene in 994 Koreans. SNPs that showed the highest statistical significance with systolic and diastolic blood pressures were selected on the multiple linear regression analysis. One-way analysis of variance for systolic and diastolic blood pressures was performed, and multiple logistic regression analysis was performed on the risk of hypertension. The P values were two-tailed, and P＜0.05 was considered significant. Four SNPs were associated with systolic blood pressure and six SNPs were associated with diastolic blood pressure. In addition, a genotype-based analysis showed significant odds ratios for the risk of hypertension in older men (adjusted OR, 5.743; 95% CI, 1.173∼28.121; P=0.031). This study suggests that the ATP2B1 variants affect both the systolic and diastolic blood pressure.

Background: The ATP2B1 gene encodes for a calcium pump, which plays a role in removing Ca2+ from cells and maintaining intracellular Ca2+ homeostasis. Reduction of the intracellular Ca2+ concentration in CD4+ T cells is thought to reduce the severity of colitis, while elevation of Ca2+ in CD4+ T cells induces T cell hyperactivity. Our aim was to clarify the role of ATP2B1 in CD4+ T cells and in inflammatory bowel disease development., Methods: A murine CD4+ T cell-specific knockout (KO) of ATP2B1 was created using a Cre-loxP system. CD4+ T cells were isolated from thymus, spleen, and blood using fluorescence-activated cell sorting. To quantify messenger RNA levels, quantitative real-time polymerase chain reaction was performed., Results: Although the percentages of CD4+ T cells in both KO mouse spleen and blood decreased compared with those of the control samples, both T-bet (a T helper 1 [Th1] activity marker) and GATA3 (a Th2 activity marker) expression levels were further increased in KO mouse blood CD4+ T cells (vs control blood). Diarrhea and colonic wall thickening (with mucosal changes, including crypt distortion) were seen in KO mice but not in control mice. Prior to diarrhea onset, the KO mouse colon length was already noted to be shorter, and the KO mouse stool water and lipid content were higher than that of the control mice. Tumor necrosis factor α and gp91 expressions were increased in KO mouse colon., Conclusions: Lack of ATP2B1 in CD4+ T cells leads to Th1 and Th2 activation, which contributes to colitis via elevation of tumor necrosis factor α and oxidative stress., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

OBJECTIVE: We aimed to explore the associations of the ATP2B1 gene polymorphisms with eclampsia. PATIENTS AND METHODS: A total of 150 patients with eclampsia (disease group) and 150 healthy pregnant women (control group) were taken as the subjects of study. The peripheral blood of the two groups of subjects was collected to extract deoxyribonucleic acids (DNAs), and the ATP2B1 gene rs71454161, rs73196661 and rs73196675 polymorphisms were detected by sequencing the Polymerase Chain Reaction (PCR) products, and then, analyzed combined with gene expression determined via Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and clinical indicators, such as 24-h urine protein, platelets, and LDH. RESULTS: A difference was observed in the allele distribution of ATP2B1 gene rs71454161 (p=0.000) and rs73196661 (p=0.011) between the disease group and control group. Disease group exhibited higher frequencies of allele G of rs71454161 and allele T of rs73196661 than control group. Besides, there was a difference in the genotype distribution of ATP2B1 gene rs71454161 (p=0.000), rs73196661 (p=0.000) and rs73196675 (p=0.000) between disease group and control group. Disease group exhibited higher frequencies of genotype GG of rs71454161, genotype TT of rs73196661 and genotype CG of rs73196675 than control group. Moreover, a difference in the distributions of ATP2B1 gene rs71454161 (p=0.000) and rs73196661 (p=0.014) was found between the two groups in the dominant model. Disease group exhibited lower frequencies of AA+AG of rs71454161 and CC+CT of rs73196661 than control group in the dominant model. Differences in the distributions of haplotypes ACC (p=0.000), ATC (p=0.047) and GTC (p=0.000) of ATP2B1 gene rs71454161, rs73196661 and rs73196675 were observed between disease group and control group. Furthermore, a high degree of linkage disequilibrium was detected between rs71454161 and rs73196661 (D'=0.329). The ATP2B1 gene rs73196675 polymorphism was evidently correlated with the gene expression of ATP2B1 (p<0.05), and the patients with genotype GG had a lower expression level of ATP2B1. The ATP2B1 gene rs71454161 was evidently correlated with the 24-h urinary protein in eclampsia patients (p=0.021), and the patients with genotype AG had a higher level of 24-h urinary proteins. The rs73196661 polymorphism was significantly correlated with LDH (p=0.000), and the patients with genotype CC had a higher level of LDH. CONCLUSIONS: The ATP2B1 gene polymorphism was significantly correlated with the occurrence and progression of eclampsia. [ABSTRACT FROM AUTHOR]

Background: The association between the CYP17A1 and ATP2B1 SNPs and essential hypertension (referred to as hypertension) is far from being consistent. In addition to the heterogeneity of hypertension resulting in inconsistent results, gene–gene and gene–environment interactions may play a major role in the pathogenesis of hypertension rather than a single gene or environmental factor.Methods: A case–control study consisting of 1,652 individuals (hypertension, 816; control, 836) was conducted in Maonan ethnic minority of China. Genotyping of the four SNPs was performed by the next-generation sequencing technology.Results: The frequencies of minor alleles and genotypes of four SNPs were different between the two groups (p < 0.001). According to genetic dominance model analysis, three (rs1004467, rs11191548, and rs17249754) SNPs and two haplotypes (CYP17A1 rs1004467G-rs11191548C and ATP2B1 rs1401982G-rs17249754A) were negatively correlated, whereas rs1401982 SNP and the other two haplotypes (CYP17A1 rs1004467A-rs11191548T and ATP2B1 rs1401982A-rs17249754G) were positively associated with hypertension risk (p ≤ 0.002 for all). Two best significant two-locus models were screened out by GMDR software involving SNP–environment (rs11191548 and BMI ≥ 24 kg/m2) and haplotype–environment (CYP17A1 rs1004467G-rs11191548C and BMI ≥ 24 kg/m2) interactions (p ≤ 0.01). The subjects carrying some genotypes increased the hypertension risk.Conclusions: Our outcomes implied that the rs1004467, rs11191548, and rs17249754 SNPs and CYP17A1 rs1004467G-rs11191548C and ATP2B1 rs1401982G-rs17249754A haplotypes have protective effects, whereas the rs1401982 SNP and CYP17A1 rs1004467A-rs11191548T and ATP2B1 rs1401982A-rs17249754G haplotypes showed adverse effect on the prevalence of hypertension. Several SNP–environment interactions were also detected.

This study examined an association of ATP2B1 gene polymorphism and hypertension in the Saudi population. The 246 hypertensive cases and 300 healthy human controls were genotyped. The results showed that genotypes rs.207075 (CA + AA) [p = 0.05; OR: 95% CI, 1.5:(1.0 to 2.4) and p = 0.001, OR: 95% CI, 2.4: (1.5 to 4.0) and rs2681472 (CT + TT) [p = 0.05; OR: 95% CI, 1.5 (1.0 to 2.4) and p = 0.006 OR: 95% CI, 2.0 (1.2 to 3.1) respectively] associated with the risk of hypertension. Cases carrying the recessive models: [(CA + AA)/(CT + TT)] and [(AA)/(TT)] genotypes confer a strong susceptibility risk of hypertension [p = 0.002; OR: (95%CI) 1.8 (1.2 to 2.6) and p = 0.001; OR: (95%CI) 2.6 (1.5 to 4.7) respectively]. However, cases with body-mass-index (BMI)<25, carrying homozygous mutant genotypes [AA, rs2070759, p = 0.007; OR: (95%CI) 2.75(1.37 to 5.5) and (TT, rs2681472, p = 0.05; OR: (95%CI) 1.96 (1.03 to 3.72)] as well as A allele of rs2070759 [p = 0.006; OR: (95%CI) 1.62 (1.16 to 2.25)] and T allele of rs2681472, p = 0.04, 1.43(1.03 to 1.98)] showed a significant association with high risk of hypertension. In short, a significant association between ATP2B1 gene polymorphism and risk of hypertension was noticed. In addition, individuals carrying recessive genotypes have greater risk in developing hypertension than those carrying dominant genotypes. Moreover, cases with high-risk BMI associated with ATP2B1 variants may play a critical role in developing hypertension. Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1973034. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic and environment play a significant role in the etiology of essential hypertension (EH). Recently STK39 rs3754777, ATP2B1 rs2681472 and rs17249754 have been associated with BP variation and hypertension. In this study we aimed to determine firstly whether index variants were associated with the risk of developing EH in Burkina Faso and secondly to characterize cardiovascular risk markers. Methods We conducted a case-control study with 380 participants including 180 case subjects with EH and 200 control subjects with normal BP. We used TaqMan genotyping assays with probes from Applied Biosystems to genotype polymorphisms using the 7500 Real-Time PCR System. Biochemical parameters were measured using chemistry analyzer COBAS C311. Results T-test showed that cardiovascular risk markers such as body mass index, waist circumference, blood sugar, total cholesterol and triglycerides were significantly higher in hypertensive compared to normotensive (all p 3.8; all p 0.05). Conclusion Our results confirmed the significant association of ATP2B1 rs17249754 with the risk of developing EH in Burkinabe and showed an increase of cardiovascular risk markers levels in subjects with EH.

Background and aims: Genetic factors play an important role in the cervico-cerebral large-artery atherosclerotic stenosis (LAS), and ATP2B1 gene has been associated with the process of atherosclerosis disorders, such as coronary artery disease and arterial stiffness. But there is little information about the relationship between ATP2B1 gene and atherosclerosis in the intracranial arteries. We hereby investigated the association of common variants in ATP2B1 gene with LAS in asymptomatic Chinese hypertension patients. Methods: The stenosis of intracranial and extracranial arteries were evaluated in 899 subjects through computerized tomography angiography from the aortic arch to the skull base. A total of 11 ATP2B1 common variants were genotyped. Multivariate logistic regression was carried out in a dominant model with confounding factors adjusted. Results: rs17249754-A (OR = 0.43, p = 0.0002) and rs1401982-G (OR = 0.47, p = 0.0007) were associated with decreased susceptibility of concurrent extra and intracranial stenosis even after Bonferroni correction. These two minor alleles were also significantly associated with less stenotic arteries and moderate-to-severe stenosis. Conclusion: rs17249754 and rs1401982 were associated with asymptomatic LAS in stroke-free Chinese hypertension patients and might benefit early recognition of LAS patients in clinical practice.

Mice lacking hypertension candidate gene ATP2B1 in vascular smooth muscle cells show significant blood pressure elevation. Keywords: essential hypertension; ATP2B1; single nucleotide polymorphism; natural selection; genome-wide association study EN essential hypertension ATP2B1 single nucleotide polymorphism natural selection genome-wide association study N.PAG N.PAG 4 03/16/21 20210311 NES 210311 Introduction The high prevalence of essential hypertension and its uneven distribution across different populations is both a major public health concern and a puzzle in evolutionary biology (Rossier et al., [19]). Essential hypertension, ATP2B1, single nucleotide polymorphism, natural selection, genome-wide association study. [Extracted from the article]

OBJECTIVE: The aim of this study was to analyze the association of ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) gene polymorphism with the incidence of eclampsia, and to investigate the possible underlying mechanism. PATIENTS AND METHODS: ATP2B1 genotype and allele distributions in umbilical venous blood cells were analyzed in 50 control subjects and 117 eclampsia patients via Reverse Transcription- Polymerase Chain Reaction (RT-PCR) and TaqMan genotyping technique. Meanwhile, the differences in the single nucleotide polymorphisms at rs2681472 and rs17249754 in the case group and control group were analyzed using the χ²-test. The risk factors for eclampsia were analyzed via univariate, multivariate, and Logistic regression analyses. Furthermore, the associations of rs2681472 gene polymorphism with risk factors for eclampsia (hypertension and lower extremity edema) were verified via χ²-test. RESULTS: The statistically significant differences were observed in the gestational week, body mass index, blood pressure, and incidence rates of proteinuria and lower extremity edema of pregnant women between the case group and the control group (p<0.05). Meanwhile, the genotype and allele distributions at rs2681472 in the case group were remarkably different from those of the control group (p<0.05). However, no evident differences were observed at rs17249754 between the two groups (p>0.05). According to univariate, multivariate, and logistic regression analyses, hypertension, and lower extremity edema were significantly associated with the incidence of eclampsia (p<0.05). In addition, the gene polymorphism at rs2681472 showed significant differences among subjects with and without hypertension and lower extremity edema (p<0.05). CONCLUSIONS: ATP2B1 gene polymorphism at rs2681472 shows significant differences between eclampsia patients and normal controls. Moreover, its gene polymorphism is closely related to the occurrence of hypertension and lower extremity edema. [ABSTRACT FROM AUTHOR]

Objective: The pathogenesis for hypertension is complicated. Except environmental factors, genetic variations are a large part of reasons account for hypertension. With the rapid development of sequencing techniques, genome wide association study (GWAS) provide an effective method for understanding the complicated genetic backgroundof multifactorial diseases. More than 150 genes associated with essential hypertension were knew today, of which, ATP2B1 is most prominent. Whether in Europe or in East Asia, the association between essential hypertension and ATP2B1 is statistically significant in different people with different genetic background. Here we reviewed the relationship between genetic polymorphisms of ATP2B1 and essential hypertension. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease (CVD) is the primary cause of morbidity and premature mortality in chronic kidney disease (CKD). The transcription factor 7-like 2 (TCF7L2) gene product TCF4 is a transcription factor that acts as a downstream effector in the canonical Wnt signaling pathway and may be important in the development of both type 2 diabetes and renal development and disease. It is, therefore, plausible that mutations in this gene could manifest themselves in reduced kidney function or kidney disease through their effects on hyperglycemia as well as independent of this mechanism. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which removes bivalent calcium ions from eukaryotic cells against very large concentration gradients and is responsible for controlling the contraction and dilation of vascular smooth muscles. Aim and Objectives: The aims of this study are (1) to evaluate single-nucleotide polymorphisms (SNPs) of TCF7L2 gene as cardiovascular risk predictors in CKD and (2) to evaluate SNPs of ATP2B1 gene as cardiovascular risk predictors in CKD. Subjects and Methods: Fifty clinically diagnosed CKD patients in the age group between 20 and 60 years of both genders were selected as cases and fifty healthy participants from the master health checkup department were selected as controls. Genomic DNA was extracted based on the spin column kit method. The DNA samples were stored at −20°C until analysis. Genotyping for TCF7L2 gene rs7903146 (C/T) and ATP2B1 gene rs11105354 (A/G) was carried out through polymerase chain reaction. Results: T allele frequency was observed in 12 controls and 23 cases (odds ratio [OR] = 2.2, 95% confidence interval [CI]: 1.0–4.7). CC genotype was observed in 38 controls and 27 cases and CT genotype in 22 cases and 12 controls. A allele was found in 38 cases and 23 controls (OR = 2, 95% CI: 1.1–3.8). The mean values of cholesterol, low-density lipoprotein, triglycerides, glucose, insulin, urea, and creatinine were high in cases when compared to controls. Conclusion: T allele of TCF7L2 gene rs7903146 (C/T) and A allele of ATP2B1 (A/G) gene rs11105354 (A/G) are associated with CVD in CKD patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate the correlation between adenosine triphosphate (ATP) 2B1 gene polymorphism in cerebral infarction (CI) patients and the onset of CI. PATIENTS AND METHODS: A total of 100 CI patients (CI group) and 88 healthy people who received physical examination (Control group) were enrolled as study subjects. Meanwhile, 4 mL of venous blood was extracted from each subject. The single nucleotide polymorphisms of rs19203, rs13412 and rs28313 in the promoter region of adenosine triphosphate (ATP) 2B1 gene were classified via conformation-difference gel electrophoresis. Chi-square was adopted to test whether the frequency of ATP2B1 genotype distribution conformed to genetic equilibrium law. Meanwhile, the correlations between ATP2B1 alleles and gene polymorphism sites and the onset of CI were analyzed. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the level of vascular endothelial growth factor (VEGF) in the serum of CI patients. Furthermore, the correlation of ATP2B1 gene polymorphism with the expression level of VEGF was analyzed. RESULTS: Hardy-Weinberg equilibrium analysis revealed that the polymorphisms of three ATP2B1 gene loci were in accordance with genetic equilibrium distribution (p>0.05). According to the results of genetic correlation analysis, the polymorphisms and alleles of ATP2B1 rs19203 and rs13412 were statistically correlated with the onset of CI (p<0.05). However, the rs28313 polymorphism and alleles were not correlated with the onset of CI (p>0.05). In addition, a statistically significant correlation between the polymorphisms of rs19203 and rs13412 and the expression level of VEGF was found in CI patients (p<0.05). CONCLUSIONS: Rs19203 and rs13412 in the promoter region of the ATP2B1 gene are correlated with the onset of CI. However, rs28313 bears no relationship with CI. [ABSTRACT FROM AUTHOR]

Background and aims: Genetic factors play an important role in the cervico-cerebral large-artery atherosclerotic stenosis (LAS), and ATP2B1 gene has been associated with the process of atherosclerosis disorders, such as coronary artery disease and arterial stiffness. But there is little information about the relationship between ATP2B1 gene and atherosclerosis in the intracranial arteries. We hereby investigated the association of common variants in ATP2B1 gene with LAS in asymptomatic Chinese hypertension patients. Methods: The stenosis of intracranial and extracranial arteries were evaluated in 899 subjects through computerized tomography angiography from the aortic arch to the skull base. A total of 11 ATP2B1 common variants were genotyped. Multivariate logistic regression was carried out in a dominant model with confounding factors adjusted. Results: rs17249754-A (OR = 0.43, p = 0.0002) and rs1401982-G (OR = 0.47, p = 0.0007) were associated with decreased susceptibility of concurrent extra and intracranial stenosis even after Bonferroni correction. These two minor alleles were also significantly associated with less stenotic arteries and moderate-to-severe stenosis. Conclusion: rs17249754 and rs1401982 were associated with asymptomatic LAS in stroke-free Chinese hypertension patients and might benefit early recognition of LAS patients in clinical practice. [ABSTRACT FROM AUTHOR]

Experiments were performed in 110 ISA Brown egg production hens (Gallus gallus), kept from 15 to 26 weeks of age in enriched (furnished) housing technology. The present objective was to investigate the presence of single nucleotide polymorphisms (SNPs) of the ATP2B1 gene and their effects on calcium homeostasis in laying hens. The plasma membrane calcium-transporting ATPase 1 gene (ATP2B1) in hens is located on chromosome 1, region 43 273 706 - 43 305 815 bp. The ATP2B1 gene has 21 exons, and in this study three were genotyped. In each experimental group of animals, only alleles without deletions in exon 10 and only allele A in exon 12 were found. In exon 8, only genotypes CC/CC, TT/CC and TT/TT were found. These genotypes are associated with femur breaking strength, bone diameter, bone marrow diameter and compact bone thickness. No significant effects of SNPs in exon 8 on bone characteristics were found. [ABSTRACT FROM AUTHOR]

Hypertension is a well-established risk factor for adverse cardiovascular events, and older age is a risk factor for the development of hypertension. Genomewide association studies have linked ATP2B1, the gene for the plasma membrane calcium ATPase 1 ( PMCA1), to blood pressure ( BP) and hypertension. Here, we present the effects of reduction in the expression of PMCA1 on BP and small artery structure and function when combined with advancing age. Heterozygous PMCA1 null mice ( PMCA1Ht) were generated and conscious BP was measured at 6 to 18 months of age. Passive and active properties of isolated small mesenteric arteries were examined by pressure myography. PMCA1Ht mice exhibited normal BP at 6 and 9 months of age but developed significantly elevated BP when compared to age-matched wild-type controls at ≥12 months of age. Decreased lumen diameter, increased wall thickness and increased wall:lumen ratio were observed in small mesenteric arteries from animals 9 months of age and older, indicative of eutrophic remodelling. Increases in mesenteric artery intrinsic tone and global intracellular calcium were evident in animals at both 6 and 18 months of age. Thus, decreased expression of PMCA1 is associated with increased BP when combined with advancing age. Changes in arterial structure precede the elevation of BP. Pathways involving PMCA1 may be a novel target for BP regulation in the elderly. [ABSTRACT FROM AUTHOR]

Objective: We examined an interaction according to the estimated 24-h urinary sodium excretion on the association betweenATP2B1rs17249754 and incident hypertension.Methods: We assessed the incidence of hypertension in 1780 participants aged 45 to 75 years without cardiovascular diseases. DNA genotyping was performed using the Affymetrix Single Nucleotide Polymorphism (SNP) array 5.0. Because of previously reported associations with hypertension in various populations including Koreans,ATP2B1rs17249754 was determined. Sodium intake was assessed by estimating the 24-h urinary sodium excretion with a Kawasaki formula from a spot urine sample. We utilized Cox proportional hazard models to test an interaction according to urinary sodium excretion on the association betweenATP2B1rs17249754 and incident hypertension.Results: The incident hypertension was increased as sodium excretion level was increased. We confirmed that theATP2B1rs17249754 polymorphism had significant association with hypertension. We found that the association was modified by urinary sodium excretion level (p-value = 0.006); the mutant type (AA allele, previously recognized as a protective allele) with <4 g/day urinary sodium excretion had an inverse association on hypertension compared with the wild types (GG+GA) (HR = 0.39, 95% confidence interval (CI) 0.17–0.90), whereas the mutant type with ≥6 g/day urinary sodium demonstrated a significantly increased risk of hypertension (HR = 1.89, 95% CI 1.05–3.43).Conclusions: In this 6-year longitudinal study, our findings suggest that excessive sodium intake estimated from urinary sodium excretion significantly modified the risk of developing hypertension associated withATP2B1rs17249754 genetic trait. That is, carriers withATP2B1rs17249754 homozygote mutant allele may be at higher risk of hypertension, when they consume excessive sodium intake. [ABSTRACT FROM PUBLISHER]

The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1 , encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP. [ABSTRACT FROM AUTHOR]

The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, ( Pmca1, Atp2b1 ), in calcium absorption and homeostasis has not been previously demonstrated in vivo . Since global germ-line deletion of the Pmca1 in mice is associated with embryonic lethality, we selectively deleted the Pmca1 in intestinal absorptive cells. Mice with loxP sites flanking exon 2 of the Pmca1 gene ( Pmca1 fl/fl ) were crossed with mice expressing Cre recombinase in the intestine under control of the villin promoter to give mice in which the Pmca1 had been deleted in the intestine ( Pmca1 EKO mice). Pmca1 EKO mice were born at a reduced frequency and were small at the time of birth when compared to wild-type ( Wt ) littermates. At two months of age, Pmca1 EKO mice fed a 0.81% calcium, 0.34% phosphorus, normal vitamin D diet had reduced whole body bone mineral density (P < 0.037), and reduced femoral bone mineral density (P < 0.015). There was a trend towards lower serum calcium and higher serum parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) concentrations in Pmca1 EKO mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1 EKO mice (P < 0.004). Following the administration of 200 ng of 1α,25(OH) 2 D 3 intraperitoneally to Wt mice, active intestinal calcium transport increased ∼2-fold, whereas Pmca1 EKO mice administered an equal amount of 1α,25(OH) 2 D 3 failed to show an increase in active calcium transport. Deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization, and a failure to up-regulate calcium absorption in response to 1α,25(OH) 2 D 3 . [ABSTRACT FROM AUTHOR]

Preeclampsia, characterized by hypertension and proteinuria, remains a leading cause of maternal morbidity and mortality. Recently, a genome-wide association study (GWAS) identified the single-nucleotide polymorphism, rs2681472, as a new hypertension susceptibility genetic variant. The purpose of this study was to evaluate the association between preeclampsia and rs268172 in a Northern Han Chinese population. We genotyped 1218 unrelated Northern Han Chinese women, including 515 patients with preeclampsia and 703 healthy controls. No significant differences were detected in the allele frequencies between patients and controls (P = .23). When patients were divided into early-onset and late-onset preeclampsia according to gestational age of disease onset, the allele frequencies significantly differed between controls and patients with early-onset preeclampsia (P = .02). Genotype frequencies also were significantly different between controls and patients early-onset preeclampsia when data were analyzed under additive (P = .03) and dominant (P = .009) models. We replicated this association in an independent Northern Han Chinese population and observed a significant difference in the allele frequencies between patients with early-onset preeclampsia and controls (P = .011). We report that rs2681472 is associated with early-onset preeclampsia in Northern Han Chinese women. [ABSTRACT FROM PUBLISHER]

Genome-wide association studies have identified the ATP2B1 gene associated with blood pressure (BP), the evidence from large scale Chinese population was still rare. We performed the current replication study to test the association of the ATP2B1 gene and hypertension and BP in two unrelated Chinese cohorts including 2,831 unrelated individuals with hypertension and 1,987 controls in total. We also examined the influences of the ATP2B1 gene on the arterial stiffness through evaluation of carotid-femoral pulse wave velocities (cf-PWV) in 164 untreated hypertensives. The major findings of this study were that four loci--rs10858911, rs2681472, rs17249754 and rs1401982--associated with any or all of four traits: hypertension ( P = 0.001-4.6E-05; odds ratio, 0.83-0.87), systolic BP ( P = 0.003-0.004), diastolic BP ( P = 0.002-0.003) and cf-PWV ( P = 0.002-0.004). All the comparisons were adjusted for sex, age, age and body mass index. We validated the association of the ATP2B1 gene and susceptibility to hypertension, BP traits and cf-PWV in Chinese population. In addition, further genetic and functional research was warranted to elucidate the concrete locus in the ATP2B1 gene that influenced the manifestation of BP and vascular function. [ABSTRACT FROM AUTHOR]

The 12q21 locus, which lies near the plasma membrane calcium-transporting ATPase 1 gene ( ATP2B1), has one of the strongest associations with blood pressure and hypertension in Europeans and Asians. We performed an association analysis of the ATP2B isomers ATP2B2, ATP2B3, and ATP2B4 with blood pressure and hypertension in 7,551 Korean individuals and observed a link with ATP2B2 and ATP2B4. To examine the regulation of blood pressure by ATP2B, ATP2B1 and ATP2B4 mRNA was reduced in vascular smooth muscle cells by siRNA. The expression pattern of 23 ATP2B-related genes was analyzed by quantitative real-time PCR, which differed between treatment with ATP2B1 and ATP2B4 siRNA. The reduction in ATP2B1 mRNA induced a significant change in mRNA levels in the calcium pump RYR1 and the ATP2B-binding protein HOMER1. Conversely, the decrease in ATP2B4 mRNA significantly altered mRNA expression of the calcium pump SLC8A1 and the ATP2B-binding proteins CASK and DLG4. These results suggest that blood pressure is differentially regulated through calcium signaling between ATP2B1 and ATP2B4. [ABSTRACT FROM AUTHOR]

Objective. Recent genome-wide association studies showed that the rs2681472 polymorphism near the ATP2B1 gene was associated with hypertension susceptibility in Europeans. Subsequently, several studies have investigated the association among East Asian populations. However, the results have been inconsistent. In this study, a meta-analysis was performed to assess the association of the ATP2B1 rs2681472 polymorphism with hypertension risk in East Asians. Methods. Published literature from PubMed, ISI Web of Science and Embase databases were retrieved. All studies evaluating the association between rs2681472 (rs17249754 or rs11105378) and hypertension risk in East Asians were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Results. Seven studies (15 909 cases/18 529 controls) were identified. The results suggested that rs2681472 was significantly associated with hypertension risk in East Asians (OR = 1.18, 95% CI 1.10-1.27, p = 0.000). Sensitivity analysis confirmed the positive association. No publication bias was detected (Begg's test, p = 0.368; Egger's test, p = 0.346). Conclusions. The present meta-analysis confirmed the significant association of the ATP2B1 gene polymorphism with hypertension susceptibility in East Asians. Further studies that include gene-gene and gene-environment interactions should be considered to investigate the identified associations in the future. [ABSTRACT FROM AUTHOR]

The article discusses a study that suggests that hypertension receptivity gene ATP2B1 plays an important roles in the regulation of blood pressure (BP) through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells. It informs that ATP2Bi has been studied as one of the genes for hypertension receptivity in separate studies of Japanese, Korean and European populations. The article also mentions that the study showed the value of the systemic candidate gene approach.

Plasma membrane calcium-transporting ATPase 1 ( ATP2B1) is associated significantly with blood pressure in Caucasians and Asians. ATP2B1 regulates calcium homeostasis and belongs to the P-type calcium pump family; several studies have identified diverse proteins that bind to ATP2B1. We hypothesized that ATP2B1 regulates blood pressure through ATP2B1-interacting genes. To this end, 20 potential ATP2B1-interacting genes were selected, 197 SNPs of which were analyzed for their association of systolic and diastolic blood pressure. These 20 genes were categorized into 2 groups: ATP2B1-binding genes and ATP2B1-cleaving calpain family members. Three ATP2B1-binding genes (CALM1, NOS1, and PDLIM1) were associated with blood pressure, and a SNP in CALM1 (rs2401887) generated the strongest association signal (beta=−3.60 ±0.92, p=8.9×10 for systolic blood pressure and beta=−1.40 ±0.62, p=0.02 for diastolic blood pressure). Of the calpain family members, 3 genes (CAPN6, CAPN9, and CAPN10) were associated with blood pressure, and the CAPN10 SNP rs4676348 yielded the strongest association signal (beta=−0.88 ±0.27, p=0.001 for systolic blood pressure and beta=−0.58 ±0.18, p=0.015 for diastolic blood pressure). Further, the interaction of CALM1 to ATP2B1 was examined using the blood pressure of individuals who carried both variants of CALM1 and ATP2B1 genes. Similarly the interaction of CAPN10 to ATP2B1 was also examined. The CALM1 variant (rs2401887) and CAPN10 variants (rs4676348) appear to decrease blood pressure further in addition to the decrease by the variant (rs17249754) of ATP2B1, which suggests that ATP2B1 might regulate blood pressure through the ATP2B1-interacting genes CALM1 and CAPN10. [ABSTRACT FROM AUTHOR]

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. [ABSTRACT FROM AUTHOR]

Blood pressure, one of the important vital signs, is affected by multiple genetic and environmental factors. Recently, several genome-wide association (GWA) studies have successfully identified genetic factors that influence blood pressure and hypertension risk. In this study, we report results of the Korean Association REsource (KARE, 8842 subjects) GWA study on blood pressure and hypertension risk. In all, 10 single-nucleotide polymorphisms (SNPs) that showed significant association with hypertension were further analysed for replication associations in the Health2 project (7861 subjects). Among these 10 SNPs, 3 were replicated in the Health2 cohort for an association with systolic or diastolic blood pressure. The most significant SNP (rs17249754 located in ATPase, Ca++ transporting, plasma membrane 1 (ATP2B1)) has been previously reported, and the other two SNPs are rs1378942 in the c-src tyrosine kinase (CSK) gene and rs12945290 in the arylsulphatase G (ARSG) gene. An additional hypertension case–control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 × 10−9) cohorts. One more SNP, rs995322, located in the CUB and Sushi multiple domains 1 (CSMD1), is also associated with increased risk of hypertension (meta-analysis, P-value=1.00 × 10−4). Despite the difficulty of obtaining replication results for a complex trait genetic association between blood pressure and hypertension, we were able to identify consistent genetic factors in both the Korean cohorts in ATP2B1, CSK, ARSG and CSMD1 genes. [ABSTRACT FROM AUTHOR]

Ca2+ gradients across the plasma membrane, required for Ca2+ homeostasis and signaling, are maintained in part by plasma membrane Ca2+-ATPase (PMCA) isoforms 1–4. Gene targeting has been used to analyze the functions of PMCA1, PMCA2, and PMCA4 in mice. PMCA1 null mutant embryos die during the preimplantation stage, and loss of a single copy of the PMCA1 gene contributes to apoptosis in vascular smooth muscle. PMCA2 deficiency in sensory hair cells of the inner ear causes deafness and balance defects, most likely by affecting both intracellular Ca2+ and extracellular Ca2+ in the endolymph. PMCA2 is required for viability of certain neurons, consistent with a major role in maintenance of intracellular Ca2+. Surprisingly, loss of PMCA2 in lactating mammary glands causes a sharp reduction in milk Ca2+, consistent with a macrocalcium secretory function. Although PMCA4 is widely expressed and is the most abundant isoform in some tissues, null mutants appear healthy. However, male PMCA4 null mutants are infertile due to a failure of hyperactivated sperm motility resulting from the absence of PMCA4 in the sperm tail, and Ca2+ signaling in B lymphocytes, involving interactions between PMCA4, CD22, and the tyrosine phosphatase SHP-1, is defective. Studies of bladder smooth muscle from PMCA4 null mutants and PMCA1 heterozygous mice suggest that PMCA1 and PMCA4 play different roles in smooth muscle contractility, with PMCA1 contributing to overall Ca2+ clearance and PMCA4 being required for carbachol-stimulated contraction. These phenotypes indicate that PMCA1 serves essential housekeeping functions, whereas PMCA4 and particularly PMCA2 serve more specialized physiological functions. [ABSTRACT FROM AUTHOR]