TY  - JOUR
AB  - BACKGROUND: Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms. METHODS: The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in discovery analysis were validated in the KORA-Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP. RESULTS: Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA-Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG. CONCLUSIONS: We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested.
AU  - Lin, J.
AU  - Petrera, A.
AU  - Hauck, S.M.
AU  - Müller, C.L.
AU  - Peters, A.
AU  - Thorand, B.
C1  - 70181
C2  - 55406
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1156-1166
TI  - Associations of proteomics with hypertension and systolic blood pressure: KORA S4/F4/FF4 and KORA-Age1/Age2 Cohort Studies.
JO  - Hypertension
VL  - 81
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - BACKGROUND: Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). We exploited these differences to decipher the roles of transcriptome and metabolome reprogramming in tumor pathogenesis. METHODS: Consecutive adrenal cryosections (7 APAs and 7 paired adjacent adrenal cortex) were analyzed by spatial transcriptomics (10x Genomics platform) and metabolomics (in situ matrix-assisted laser desorption/ionization mass spectrometry imaging) co-integrated with CYP11B2 immunohistochemistry. RESULTS: We identified intratumoral transcriptional heterogeneity that delineated functionally distinct biological pathways. Common transcriptomic signatures were established across all APA specimens which encompassed 2 distinct transcriptional profiles in CYP11B2-immunopositive regions (CYP11B2-type 1 or 2). The CYP11B2-type 1 signature was characterized by zona glomerulosa gene markers and was detected in both APA-KCNJ5MUT and APA-KCNJ5WT. The CYP11B2-type 2 signature displayed markers of the zona fasciculata or reticularis and predominated in APA-KCNJ5MUT. Metabolites that promote oxidative stress and cell death accumulated in APA-KCNJ5WT. In contrast, antioxidant metabolites were abundant in APA-KCNJ5MUT. Finally, APA-like cell subpopulations-negative for CYP11B2 gene expression-were identified in adrenocortical tissue adjacent to APAs suggesting the existence of tumor precursor states. CONCLUSIONS: Our findings provide insight into intra- and intertumoral transcriptional heterogeneity and support a role for prooxidant versus antioxidant systems in APA pathogenesis highlighting genotype-dependent capacities for tumor expansion.
AU  - Gong, S.*
AU  - Sun, N.
AU  - Meyer, L.S.*
AU  - Tetti, M.*
AU  - Koupourtidou, C.*
AU  - Krebs, S.*
AU  - Masserdotti, G.
AU  - Blum, H.*
AU  - Rainey, W.E.*
AU  - Reincke, M.*
AU  - Walch, A.K.
AU  - Williams, T.A.*
C1  - 67782
C2  - 54260
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1555-1567
TI  - Primary aldosteronism: Spatial multi-omics mapping of genotype-dependent heterogeneity and tumor expansion of aldosterone-producing adenomas.
JO  - Hypertension
VL  - 80
IS  - 7
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - BACKGROUND: Inflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit. METHODS: Office blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed. RESULTS: The prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic (GZMB, PRF1, IL2RB) and proinflammatory (FOS, IL1B, hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and IL1B was driven by overweight with IL1B being identified as a mediator between body mass index and elevated systolic blood pressure (adj.β/95% CI, 0.01/0.0002-0.02). The association of GZMB (adjusted odds ratio/95% CI, 1.67/1.26-2.21; P=0.0004) and PRF1 (adjusted odds ratio/95% CI, 1.70/1.26-2.29; P=0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA. CONCLUSIONS: Adolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae.
AU  - Thürmann, L.*
AU  - Bauer, M.*
AU  - Ferland, M.
AU  - Messingschlager, M.*
AU  - Schikowski, T.*
AU  - von Berg, A.*
AU  - Heinrich, J.
AU  - Herberth, G.*
AU  - Lehmann, I.*
AU  - Standl, M.
AU  - Trump, S.*
C1  - 68612
C2  - 54731
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 2425-2436
TI  - Undiagnosed pediatric elevated blood pressure is characterized by induction of pro-inflammatory and cytotoxic mediators.
JO  - Hypertension
VL  - 80
IS  - 11
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - It remains unclear which blood pressure (BP) characteristics best predict cardiovascular risk in different age groups and between sexes. We leveraged data from the MORGAM (MONICA [Monitoring of Trends and Determinants in Cardiovascular Disease], Risk, Genetics, Archiving and Monograph) Project to investigate determinants of BP characteristics and their prognostic importance, in younger and older (P interaction <0.001). Higher systolic BP and mean BP were significantly associated with cardiovascular end point, irrespective of age group (P<0.001), but diastolic BP only demonstrated an independent relationship in the younger group (P<0.001). Brachial pulse pressure was associated with cardiovascular end point in the older age group (P<0.001). In subjects <50 years, diastolic BP significantly improved area under the receiver operating characteristic curve compared with Systematic Coronary Risk Evaluation variables (including systolic BP) alone (0.842 versus 0.840, P=0.03), enhanced continuous net reclassification improvement (0.150 [95% CI, 0.087-0.215]) and improved the prognostic value of the European Society of Cardiology/European Society of Hypertension hypertension definition (categorical net reclassification improvement=0.0255, P=0.005). In conclusion, diastolic BP may provide additional prognostic utility beyond systolic BP, in predicting composite cardiovascular events among younger individuals.
AU  - Vishram-Nielsen, J.K.K.*
AU  - Kristensen, A.M.D.*
AU  - Pareek, M.*
AU  - Laurent, S.*
AU  - Nilsson, P.M.*
AU  - Linneberg, A.*
AU  - Greve, S.V.*
AU  - Palmieri, L.*
AU  - Giampaoli, S.*
AU  - Donfrancesco, C.*
AU  - Kee, F.*
AU  - Mancia, G.*
AU  - Cesana, G.*
AU  - Veronesi, G.*
AU  - Grassi, G.*
AU  - Kuulasmaa, K.*
AU  - Salomaa, V.*
AU  - Palosaari, T.*
AU  - Sans, S.*
AU  - Ferrieres, J.*
AU  - Dallongeville, J.*
AU  - Söderberg, S.*
AU  - Moitry, M.*
AU  - Drygas, W.*
AU  - Tamosiunas, A.*
AU  - Peters, A.
AU  - Brenner, H.*
AU  - Grimsgaard, S.*
AU  - Savallampi, M.*
AU  - Olsen, M.H.*
C1  - 61467
C2  - 50162
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1076-1085
TI  - Predictive importance of blood pressure characteristics with increasing age in healthy men and women: The MORGAM Project.
JO  - Hypertension
VL  - 77
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2021
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Aldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension. Aldosterone-producing cell clusters (APCCs) comprise tight nests of zona glomerulosa cells, strongly positive for CYP11B2 (aldosterone synthase) in immunohistochemistry. APCCs have been suggested as possible precursors of APAs because they frequently carry driver mutations for constitutive aldosterone production, and a few adrenal lesions with histopathologic features of both APCCs and APAs have been identified. Our objective was to investigate the metabolic phenotypes of APCCs (n=27) compared with APAs (n=6) using in situ matrix-assisted laser desorption/ionization mass spectrometry imaging of formalin-fixed paraffin-embedded adrenals from patients with unilateral primary aldosteronism. Specific distribution patterns of metabolites were associated with APCCs and classified 2 separate APCC subgroups (subgroups 1 and 2) indistinguishable by CYP11B2 immunohistochemistry. Metabolic profiles of APCCs in subgroup 1 were tightly clustered and distinct from subgroup 2 and APAs. Multiple APCCs from the same adrenal displayed metabolic profiles of the same subgroup. Metabolites of APCC subgroup 2 were highly similar to the APA group and indicated enhanced metabolic pathways favoring cell proliferation compared with APCC subgroup 1. In conclusion, we demonstrate specific subgroups of APCCs with strikingly divergent distribution patterns of metabolites. One subgroup displays a metabolic phenotype convergent with APAs and may represent the progression of APCCs to APAs.
AU  - Sun, N.
AU  - Meyer, L.S.*
AU  - Feuchtinger, A.
AU  - Kunzke, T.
AU  - Knösel, T.*
AU  - Reincke, M.*
AU  - Walch, A.K.
AU  - Williams, T.A.*
C1  - 58088
C2  - 48340
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 634-644
TI  - Mass spectrometry imaging establishes 2 distinct metabolic phenotypes of aldosterone-producing cell clusters in primary aldosteronism.
JO  - Hypertension
VL  - 75
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - The Reference Values for Arterial Stiffness Collaboration has derived an equation using age and mean blood pressure to estimated pulse wave velocity (ePWV), which predicted cardiovascular events independently of Systematic COoronary Risk Evaluation (SCORE) and Framingham Risk Score. The study aim was to investigate the independent association between ePWV and clinical outcomes in 107 599 apparently healthy subjects (53% men) aged 19 to 97 years from the MORGAM Project who were included between 1982 and 2002 in 38 cohorts from 11 countries. Using multiple Cox-regression analyses, the predictive value of ePWV was calculated adjusting for country of inclusion and either SCORE, Framingham Risk Score, or traditional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, body mass index [BMI], total and high-density lipoprotein cholesterol). Cardiovascular mortality consisted of fatal stroke, fatal myocardial infarction, or coronary death, and the composite cardiovascular end point consisted of stroke, myocardial infarction, or coronary death. Model discrimination was assessed using Harrell's C-statistic. Adjusting for country and logSCORE or Framingham Risk Score, ePWV was associated with all-cause mortality (hazard ratio, 1.23 [95% CI 1.20-1.25] per m/s or 1.32 [1.29-1.34]), cardiovascular mortality (1.26 [1.21-1.32] or 1.35 [1.31-1.40]), and composite cardiovascular end point (1.19 [1.16-1.22] or 1.23 [1.20-1.25]; all P<0.001). However, after adjusting for traditional cardiovascular risk factors, ePWV was only associated with all-cause mortality (1.15 [1.08-1.22], P<0.001) and not with cardiovascular mortality (0.97 [0.91-1.03]) nor composite cardiovascular end point (1.10 [0.97-1.26]). The areas under the last 3 receiver operator characteristic curves remained unchanged when adding ePWV. Elevated ePWV was associated with subsequent mortality and cardiovascular morbidity independently of systematic coronary risk evaluation and Framingham Risk Score but not independently of traditional cardiovascular risk factors.
AU  - Vishram-Nielsen, J.K.K.*
AU  - Laurent, S.*
AU  - Nilsson, P.M.*
AU  - Linneberg, A.*
AU  - Sehested, T.S.G.*
AU  - Greve, S.V.*
AU  - Pareek, M.*
AU  - Palmieri, L.*
AU  - Giampaoli, S.*
AU  - Donfrancesco, C.*
AU  - Kee, F.*
AU  - Mancia, G.*
AU  - Cesana, G.*
AU  - Veronesi, G.*
AU  - Kuulasmaa, K.*
AU  - Salomaa, V.*
AU  - Kontto, J.*
AU  - Palosaari, T.*
AU  - Sans, S.*
AU  - Ferrieres, J.*
AU  - Dallongeville, J.*
AU  - Söderberg, S.*
AU  - Moitry, M.*
AU  - Drygas, W.*
AU  - Tamosiunas, A.*
AU  - Peters, A.
AU  - Brenner, H.*
AU  - Njolstad, I.*
AU  - Olsen, M.H.*
C1  - 59166
C2  - 48617
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1420-1428
TI  - Does estimated pulse wave velocity add prognostic information? MORGAM prospective cohort project.
JO  - Hypertension
VL  - 75
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase (P=0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG (P<0.001) and an almost 3-fold upregulation of CYP11B (P<0.05) compared with high dietary sodium. Strong immunostaining of the KCNJ5 (G protein-activated inward rectifier potassium channel 4), which is frequently mutated in primary aldosteronism, was demonstrated in the zG. mRNA sequencing transcriptome analysis identified significantly altered expression of genes modulated by the renin-angiotensin-aldosterone system in the zG (n=1172) and zona fasciculata (n=280). These genes included many with a known role in the regulation of aldosterone synthesis and adrenal function. The most highly enriched biological pathways in the zG were related to cholesterol biosynthesis, steroid metabolism, cell cycle, and potassium channels. This study provides mechanistic insights into the physiology and pathophysiology of aldosterone production in a species closely related to humans and shows the suitability of pigs as a translational animal model for human adrenal steroidogenesis.
AU  - Vohra, T.*
AU  - Kemter, E.*
AU  - Sun, N.
AU  - Dobenecker, B.*
AU  - Hinrichs, A.*
AU  - Burrello, J.*
AU  - Gomez-Sanchez, E.P.*
AU  - Gomez-Sanchez, C.E.*
AU  - Wang, J.
AU  - Kinker, I.S.*
AU  - Teupser, D.*
AU  - Fischer, K.*
AU  - Schnieke, A.*
AU  - Peitzsch, M.*
AU  - Eisenhofer, G.*
AU  - Walch, A.K.
AU  - Reincke, M.*
AU  - Wolf, E.*
AU  - Williams, T.A.*
C1  - 60572
C2  - 49416
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1769-1777
TI  - Effect of dietary sodium modulation on pig adrenal steroidogenesis and transcriptome profiles.
JO  - Hypertension
VL  - 76
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
AU  - Wain, L.V.*
AU  - Vaez, A.*
AU  - Jansen, R.*
AU  - Joehanes, R.*
AU  - van der Most, P.J.*
AU  - Erzurumluoglu, A.M.*
AU  - O'Reilly, P.F.*
AU  - Cabrera, C.P.*
AU  - Warren, H.R.*
AU  - Rose, L.M.*
AU  - Verwoert, G.C.*
AU  - Hottenga, J.J.*
AU  - Strawbridge, R.J.*
AU  - Esko, T.*
AU  - Arking, D.E.*
AU  - Hwang, S.J.*
AU  - Guo, X.*
AU  - Kutalik, Z.*
AU  - Trompet, S.*
AU  - Shrine, N.*
AU  - Teumer, A.*
AU  - Ried, J.S.
AU  - Bis, J.C.*
AU  - Smith, A.V.*
AU  - Amin, N.*
AU  - Nolte, I.M.*
AU  - Lyytikäinen, L.-P.*
AU  - Mahajan, A.*
AU  - Wareham, N.J.*
AU  - Hofer, E.*
AU  - Joshi, P.K.*
AU  - Kristiansson, K.*
AU  - Traglia, M.*
AU  - Havulinna, A.S.*
AU  - Goel, A.*
AU  - Nalls, M.A.*
AU  - Sõber, S.*
AU  - Vuckovic, D.*
AU  - Luan, J.*
AU  - Del Greco M, F.*
AU  - Ayers, K.L.*
AU  - Marrugat, J.*
AU  - Ruggiero, D.*
AU  - Lopez, L.M.*
AU  - Niiranen, T.*
AU  - Enroth, S.*
AU  - Jackson, A.U.*
AU  - Nelson, C.P.*
AU  - Huffman, J.E.*
AU  - Zhang, W.*
AU  - Marten, J.*
AU  - Gandin, I.*
AU  - Harris, S.E.*
AU  - Zemunik, T.*
AU  - Lu, Y.*
AU  - Evangelou, E.*
AU  - Shah, N.*
AU  - de Borst, M.H.*
AU  - Mangino, M.*
AU  - Prins, B.P.*
AU  - Campbell, A.*
AU  - Li-Gao, R.*
AU  - Chauhan, G.*
AU  - Oldmeadow, C.*
AU  - Abecasis, G.*
AU  - Abedi, M.*
AU  - Barbieri, C.M.*
AU  - Barnes, M.R.*
AU  - Batini, C.*
AU  - Beilby, J.*
AU  - Blake, T.*
AU  - Boehnke, M.*
AU  - Bottinger, E.P.*
AU  - Braund, P.S.*
AU  - Brown, M.*
AU  - Brumat, M.*
AU  - Campbell, H.*
AU  - Chambers, J.C.*
AU  - Cocca, M.*
AU  - Collins, F.C.*
AU  - Connell, J.*
AU  - Cordell, H.J.*
AU  - Damman, J.J.*
AU  - Davies, G.*
AU  - de Geus, E.J.*
AU  - de Mutsert, R.*
AU  - Deelen, J.*
AU  - Demirkale, Y.*
AU  - Doney, A.S.F.*
AU  - Dörr, M.*
AU  - Farrall, M.*
AU  - Ferreira, T.*
AU  - Frånberg, M.*
AU  - Gao, H.*
AU  - Giedraitis, V.*
AU  - Gieger, C.
AU  - Giulianini, F.*
AU  - Gow, A.J.*
AU  - Hamsten, A.*
AU  - Harris, T.B.*
AU  - Hofman, A.*
AU  - Holliday, E.G.*
AU  - Hui, J.*
AU  - Jarvelin, M.R.*
AU  - Johansson, Å*
AU  - Johnson, A.D.*
AU  - Jousilahti, P.*
AU  - Jula, A.*
AU  - Kähönen, M.*
AU  - Kathiresan, S.*
AU  - Khaw, K.T.*
AU  - Kolcic, I.*
AU  - Koskinen, S.*
AU  - Langenberg, C.*
AU  - Larson, M.G.*
AU  - Launer, L.J.*
AU  - Lehne, B.*
AU  - Liewald, D.C.M.*
AU  - Lin, L.*
AU  - Lind, L.*
AU  - Mach, F.*
AU  - Mamasoula, C.*
AU  - Menni, C.*
AU  - Mifsud, B.*
AU  - Milaneschi, Y.*
AU  - Morgan, A.*
AU  - Morris, A.D.*
AU  - Morrison, A.C.*
AU  - Munson, P.J.*
AU  - Nandakumar, P.*
AU  - Nguyen, Q.T.*
AU  - Nutile, T.*
AU  - Oldehinkel, A.J.*
AU  - Oostra, B.A.*
AU  - Org, E.*
AU  - Padmanabhan, S.*
AU  - Palotie, A.*
AU  - Paré, G.*
AU  - Pattie, A.*
AU  - Penninx, B.W.J.H.*
AU  - Poulter, N.*
AU  - Pramstaller, P.P.*
AU  - Raitakari, O.T.*
AU  - Ren, M.*
AU  - Rice, K.*
AU  - Ridker, P.M.*
AU  - Riese, H.*
AU  - Ripatti, S.*
AU  - Robino, A.*
AU  - Rotter, J.I.*
AU  - Rudan, I.*
AU  - Saba, Y.*
AU  - Saint Pierre, A.*
AU  - Sala, C.F.*
AU  - Sarin, A.P.*
AU  - Schmidt, R.*
AU  - Scott, R.*
AU  - Seelen, M.A.*
AU  - Shields, D.C.*
AU  - Siscovick, D.*
AU  - Sorice, R.*
AU  - Stanton, A.*
AU  - Stott, D.J.*
AU  - Sundström, J.*
AU  - Swertz, M.A.*
AU  - Taylor, K.D.*
AU  - Thom, S.*
AU  - Tzoulaki, I.*
AU  - Tzourio, C.*
AU  - Uitterlinden, A.G.*
AU  - Völker, U.*
AU  - Vollenweider, P.*
AU  - Wild, S.*
AU  - Willemsen, G.*
AU  - Wright, A.F.*
AU  - Yao, J.*
AU  - Thériault, S.*
AU  - Conen, D.*
AU  - Attia, J.*
AU  - Sever, P.*
AU  - Debette, S.*
AU  - Mook-Kanamori, D.O.*
AU  - Zeggini, E.*
AU  - Spector, T.D.*
AU  - van der Harst, P.*
AU  - Palmer, C.N.A.*
AU  - Vergnaud, A.C.*
AU  - Loos, R.J.F.*
AU  - Polasek, O.*
AU  - Starr, J.M.*
AU  - Girotto, G.*
AU  - Hayward, C.*
AU  - Kooner, J.S.*
AU  - Lindgren, C.M.*
AU  - Vitart, V.*
AU  - Samani, N.J.*
AU  - Tuomilehto, J.*
AU  - Gyllensten, U.*
AU  - Knekt, P.*
AU  - Deary, I.J.*
AU  - Ciullo, M.*
AU  - Elosua, R.*
AU  - Keavney, B.D.*
AU  - Hicks, A.A.*
AU  - Scott, R.A.*
AU  - Gasparini, P.*
AU  - Laan, M.*
AU  - Liu, Y.*
AU  - Watkins, H.*
AU  - Hartman, C.A.*
AU  - Salomaa, V.*
AU  - Toniolo, D.*
AU  - Perola, M.*
AU  - Wilson, J.F.*
AU  - Schmidt, H.*
AU  - Zhao, J.H.*
AU  - Lehtimäki, T.*
AU  - van Duijn, C.M.*
AU  - Gudnason, V.*
AU  - Psaty, B.M.*
AU  - Peters, A.
AU  - Rettig, R.*
AU  - James, A.*
AU  - Jukema, J.W.*
AU  - Strachan, D.P.*
AU  - Palmas, W.*
AU  - Metspalu, A.*
AU  - Ingelsson, E.*
AU  - Boomsma, D.I.*
AU  - Franco, O.H.*
AU  - Bochud, M.*
AU  - Newton-Cheh, C.*
AU  - Munroe, P.B.*
AU  - Elliott, P.*
AU  - Chasman, D.I.*
AU  - Chakravarti, A.*
AU  - Knight, J.*
AU  - Morris, A.P.*
AU  - Levy, D.*
AU  - Tobin, M.D.*
AU  - Snieder, H.*
AU  - Caulfield, M.J.*
AU  - Ehret, G.B.*
C1  - 51582
C2  - 43310
CY  - Philadelphia
SP  - e4-e19
TI  - Novel blood pressure locus and gene discovery using genome-wide association study and expression data sets from blood and the kidney.
JO  - Hypertension
VL  - 70
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2017
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10(-5)). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.
AU  - Zeller, T.*
AU  - Schurmann, C.*
AU  - Schramm, K.
AU  - Müller, C.*
AU  - Kwon, S.Y.*
AU  - Wild, P.S.*
AU  - Teumer, A.*
AU  - Herrington, D.*
AU  - Schillert, A.*
AU  - Iacoviello, L.*
AU  - Kratzer, A.*
AU  - Jagodzinski, A.*
AU  - Karakas, M.*
AU  - Ding, J.*
AU  - Neumann, J.T.*
AU  - Kuulasmaa, K.*
AU  - Gieger, C.
AU  - Kacprowski, T.*
AU  - Schnabel, R.B.*
AU  - Roden, M.*
AU  - Wahl, S.
AU  - Rotter, J.I.*
AU  - Ojeda, F.*
AU  - Carstensen-Kirberg, M.*
AU  - Tregouet, D.A.*
AU  - Dörr, M.*
AU  - Meitinger, T.
AU  - Lackner, K.J.*
AU  - Wolf, P.A.*
AU  - Felix, S.B.*
AU  - Landmesser, U.*
AU  - Costanzo, S.*
AU  - Ziegler, A.*
AU  - Liu, Y.*
AU  - Völker, U.*
AU  - Palmas, W.*
AU  - Prokisch, H.
AU  - Guo, X.*
AU  - Herder, C.*
AU  - Blankenberg, S.*
AU  - Homuth, G.*
C1  - 51695
C2  - 43415
CY  - Philadelphia
SP  - 713-750
TI  - Transcriptome-wide analysis identifies novel associations with blood pressure.
JO  - Hypertension
VL  - 70
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2017
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9 10(-5)). Replication was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar-Kyoto rats; (2) circulating metabolite change after salt-induced blood pressure elevation in spontaneously hypertensive stroke-prone rats; and (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarboxylic acid, showed concordant association with blood pressure (systolic BP [SBP]: β [95% confidence interval], 1.31 [0.83-1.78], P=6.81×10(-8); diastolic BP [DBP]: 0.81 [0.5-1.11], P=2.96×10(-7)) and mortality (hazard ratio [95% confidence interval], 1.49 [1.08-2.05]; P=0.02) in TwinsUK. The blood pressure association was replicated in KORA and Hertfordshire. In the animal experiments, we showed that oral hexadecanedioate increased both circulating hexadecanedioate and blood pressure in Wistar-Kyoto rats, whereas blood pressure elevation with oral sodium chloride in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity to noradrenaline was significantly increased in mesenteric resistance arteries from hexadecanedioate-treated rats compared with controls, indicated by the shift to the left of the concentration-response curve (P=0.013). Relaxation to carbachol did not show any difference. Our findings indicate that hexadecanedioate is causally associated with blood pressure regulation through a novel pathway that merits further investigation.
AU  - Menni, C.*
AU  - Graham, D.*
AU  - Kastenmüller, G.
AU  - Alharbi, N.H.*
AU  - Alsanos, S.M.*
AU  - McBride, M.*
AU  - Mangino, M.*
AU  - Titcombe, P.*
AU  - Shin, S.Y.*
AU  - Psatha, M.*
AU  - Geisendorfer, T.*
AU  - Huber, A.*
AU  - Peters, A.
AU  - Wang-Sattler, R.
AU  - Xu, T.
AU  - Brosnan, M.J.*
AU  - Trimmer, J.*
AU  - Reichel, C.*
AU  - Mohney, R.P.*
AU  - Soranzo, N.*
AU  - Edwards, M.H.*
AU  - Cooper, C.*
AU  - Church, A.C.*
AU  - Suhre, K.
AU  - Gieger, C.
AU  - Dominiczak, A.F.*
AU  - Spector, T.D.*
AU  - Padmanabhan, S.*
AU  - Valdes, A.M.*
C1  - 45098
C2  - 37238
CY  - Philadelphia
SP  - 422-429
TI  - Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate.
JO  - Hypertension
VL  - 66
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2015
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options.
AU  - Fernandes-Rosa, F.L.*
AU  - Williams, T.A.*
AU  - Riester, A.*
AU  - Steichen, O.*
AU  - Beuschlein, F.*
AU  - Boulkroun, S.*
AU  - Strom, T.M.
AU  - Monticone, S.*
AU  - Amar, L.*
AU  - Meatchi, T.*
AU  - Mantero, F.*
AU  - Cicala, M.V.*
AU  - Quinkler, M.*
AU  - Fallo, F.*
AU  - Allolio, B.*
AU  - Bernini, G.*
AU  - Maccario, M.*
AU  - Giacchetti, G.*
AU  - Jeunemaitre, X.*
AU  - Mulatero, P.*
AU  - Reincke, M.*
AU  - Zennaro, M.C.*
C1  - 31502
C2  - 34543
CY  - Philadelphia
SP  - 354-361
TI  - Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
JO  - Hypertension
VL  - 64
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Elucidation of the molecular mechanisms leading to autonomous aldosterone secretion is a prerequisite to define potential targets and biomarkers in the context of primary aldosteronism. After a genome-wide association study with subjects from the population-based Cooperative Health Research in the Region of Augsburg F4 survey, we observed a highly significant association (P=6.78×10(-11)) between the aldosterone to renin ratio and a locus at 5q32. Hypothesizing that this locus may contain genes of relevance for the pathogenesis of primary aldosteronism, we investigated solute carrier family 26 member 2 (SLC26A2), a protein with known transport activity for sulfate and other cations. Within murine tissues, adrenal glands showed the highest expression levels for SLC26A2, which was significantly downregulated on in vivo stimulation with angiotensin II and potassium. SLC26A2 expression was found to be significantly lower in aldosterone-producing adenomas in comparison with normal adrenal glands. In adrenocortical NCI-H295R cells, specific knockdown of SLC26A2 resulted in a highly significant increase in aldosterone secretion. Concomitantly, expression of steroidogenic enzymes, as well as upstream effectors including transcription factors such as NR4A1, CAMK1, and intracellular Ca(2+) content, was upregulated in knockdown cells. To substantiate further these findings in an SLC26A2 mutant mouse model, aldosterone output proved to be increased in a sex-specific manner. In summary, these findings point toward a possible effect of SLC26A2 in the regulation of aldosterone secretion potentially involved in the pathogenesis of primary aldosteronism.
AU  - Spyroglou, A.*
AU  - Bozoglu, T.*
AU  - Rawal, R.
AU  - de Leonardis, F.*
AU  - Sterner, C.*
AU  - Boulkroun, S.*
AU  - Benecke, A.G.*
AU  - Monti, L.*
AU  - Zennaro, M.C.*
AU  - Petersen, A.-K.
AU  - Döring, A.
AU  - Rossi, A.*
AU  - Bidlingmaier, M.*
AU  - Warth, R.*
AU  - Gieger, C.
AU  - Reincke, M.*
AU  - Beuschlein, F.*
C1  - 30768
C2  - 33846
CY  - Philadelphia
SP  - 1102-1109
TI  - Diastrophic dysplasia sulfate transporter (SLC26A2) is expressed in the adrenal cortex and regulates aldosterone secretion.
JO  - Hypertension
VL  - 63
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5x10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4x10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure-and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
AU  - Lieb, W.*
AU  - Jansen, H.*
AU  - Loley, C.*
AU  - Pencina, M.J.*
AU  - Nelson, C.P.*
AU  - Newton-Cheh, C.*
AU  - Kathiresan, S.*
AU  - Reilly, M.P.*
AU  - Assimes, T.L.*
AU  - Boerwinkle, E.*
AU  - Hall, A.S.*
AU  - Hengstenberg, C.*
AU  - Laaksonen, R.*
AU  - McPherson, R.*
AU  - Thorsteinsdottir, U.*
AU  - Ziegler, A.*
AU  - Peters, A.
AU  - Thompson, J.R.*
AU  - König, I.R.*
AU  - Erdmann, J.*
AU  - Samani, N.J.*
AU  - Vasan, R.S.*
AU  - Schunkert, H.*
C1  - 24678
C2  - 31645
SP  - 995-1001
TI  - Genetic predisposition to higher blood pressure increases coronary artery disease risk.
JO  - Hypertension
VL  - 61
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2013
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - The histone methyltransferase enhancer of zeste homolog 2 (Ezh2) mediates trimethylation of lysine 27 in histone 3, which acts as a repressive epigenetic mark. Ezh2 is essential for maintaining pluripotency of stem cells, but information on its role in differentiated cells is sparse. Whole-genome mRNA expression arrays identified 964 genes that were regulated by >2-fold 72 hours after small interfering RNA-mediated silencing of Ezh2 in human umbilical vein endothelial cells. Among them, genes associated with the gene ontology terms cell communication and cell adhesion were significantly overrepresented, suggesting a functional role for Ezh2 in the regulation of angiogenesis. Indeed, adhesion, migration, and tube formation assays revealed significantly altered angiogenic properties of human umbilical vein endothelial cells after silencing of Ezh2. To identify direct target genes of Ezh2, we performed chromatin immunoprecipitation experiments followed by whole-genome promoter arrays (chromatin immunoprecipitation-on-chip) and identified 5585 genes associated with trimethylation of lysine 27 in histone 3. Comparative analysis with our mRNA expression data identified 276 genes that met our criteria for putative Ezh2 target genes, upregulation by >2-fold after Ezh2 silencing and association with trimethylation of lysine 27 in histone 3. Notably, we observed a striking overrepresentation of genes involved in wingless-type mouse mammary tumor virus integration site (WNT) signaling pathways. Epigenetic regulation of several of these genes by Ezh2 was specifically confirmed by polymerase chain reaction analysis of DNA enrichment after chromatin immunoprecipitation using an antibody specific for trimethylation of lysine 27 in histone 3. Combining mRNA expression arrays and chromatin immunoprecipitation-on-chip analysis, we identified 276 Ezh2 target genes in endothelial cells. Ezh2-dependent repression of genes involved in cell adhesion and communication contributes to the regulation of angiogenesis.
AU  - Dreger, H.*
AU  - Ludwig, A.*
AU  - Weller, A.*
AU  - Stangl, V.*
AU  - Baumann, G.*
AU  - Meiners, S.
AU  - Stangl, K.*
C1  - 11152
C2  - 30523
SP  - 1176-1183
TI  - Epigenetic regulation of cell adhesion and communication by enhancer of zeste homolog 2 in human endothelial cells.
JO  - Hypertension
VL  - 60
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K(+) selectivity, Na(+) influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca(2+) channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.
AU  - Mulatero, P.*
AU  - Tauber, P.*
AU  - Zennaro, M.C.*
AU  - Monticone, S.*
AU  - Lang, K.*
AU  - Beuschlein, F.*
AU  - Fischer, E.*
AU  - Tizzani, D.*
AU  - Pallauf, A.*
AU  - Viola, A.*
AU  - Amar, L.*
AU  - Williams, T.A.*
AU  - Strom, T.M.
AU  - Graf, E.
AU  - Bandulik, S.*
AU  - Penton, D.*
AU  - Plouin, P.F.*
AU  - Warth, R.*
AU  - Allolio, B.*
AU  - Jeunemaitre, X.*
AU  - Veglio, F.*
AU  - Reincke, M.*
C1  - 7283
C2  - 29643
SP  - 235-240
TI  - KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism.
JO  - Hypertension
VL  - 59
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04 -12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/ L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P < 0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls. (Hypertension. 2012; 60: 618-624.). Online Data Supplement
AU  - Reincke, M.*
AU  - Fischer, E.*
AU  - Gerum, S.*
AU  - Merkle, K.*
AU  - Schulz, S.*
AU  - Pallauf, A.*
AU  - Quinkler, M.*
AU  - Hanslik, G.*
AU  - Lang, K.*
AU  - Hahner, S.*
AU  - Allolio, B.*
AU  - Meisinger, C.
AU  - Holle, R.
AU  - Beuschlein, F.*
AU  - Bidlingmaier, M.*
AU  - Endres, S.*
C1  - 8554
C2  - 30280
SP  - 618-624
TI  - Observational study mortality in treated primary aldosteronism: The German Conn's registry.
JO  - Hypertension
VL  - 60
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - The present study aimed to explore the anti-inflammatory effects and peroxisome proliferator-activated receptor-γ (PPARγ)-activating properties of the angiotensin type 1 receptor blocker telmisartan by analysis of serum interleukin 6 levels and monocytic PPARγ target gene expression in drug-naïve patients with the metabolic syndrome. This was a 14-week, randomized, double-blind, placebo-controlled 2-center study with telmisartan 80 mg/d and telmisartan 160 mg/d in 54 patients with the metabolic syndrome. In addition to clinical laboratory measurements, peripheral monocytes were extracted by negative isolation using a Dynal Monocyte kit to evaluate ligand-activated PPARγ target gene expression (CD36 and CD163) at baseline and study end using quantitative real-time RT-PCR. In this low-risk patient population, telmisartan (80 and 160 mg) treatment did not significantly affect serum interleukin 6 levels. Expression of the PPARγ target gene CD36 in monocytes was markedly induced by telmisartan from baseline to study end (telmisartan 80 mg: 2.3±1.5-fold change versus placebo [P value not significant]; telmisartan 160 mg: 3.5±0.9-fold change versus placebo [P<0.05]). The recently reported PPARγ target gene CD163 was slightly induced by telmisartan (telmisartan 80 mg: 1.1±0.3-fold change versus placebo [P value not significant]; telmisartan 160 mg: 1.4±0.4-fold change versus placebo [P value not significant]), which did not reach statistical significance. This is the first clinical description of monocytic PPARγ target gene regulation with high-dose telmisartan treatment. These data implicate that the angiotensin type 1 receptor blocker telmisartan activates PPARγ in circulating monocytes of patients with the metabolic syndrome.
AU  - Bähr, I.N.*
AU  - Tretter, P.*
AU  - Krüger, J.*
AU  - Stark, R.G.
AU  - Schimkus, J.*
AU  - Unger, T.*
AU  - Kappert, K.*
AU  - Scholze, J.*
AU  - Parhofer, K.G.*
AU  - Kintscher, U.*
C1  - 6869
C2  - 29372
SP  - 725-732
TI  - High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-γ target genes in patients with the metabolic syndrome.
JO  - Hypertension
VL  - 58
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2011
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - 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.
AU  - Tabara, Y.*
AU  - Kohara, K.*
AU  - Kita, Y.*
AU  - Hirawa, N.*
AU  - Katsuya, T.*
AU  - Ohkubo, T.*
AU  - Hiura, Y.*
AU  - Tajima, A.*
AU  - Morisaki, T.*
AU  - Miyata, T.*
AU  - Nakayama, T.*
AU  - Takashima, N.*
AU  - Nakura, J.*
AU  - Kawamoto, R.*
AU  - Takahashi, N.*
AU  - Hata, A.*
AU  - Soma, M.*
AU  - Imai, Y.*
AU  - Kokubo, Y.*
AU  - Okamura, T.*
AU  - Tomoike, H.*
AU  - Iwai, N.*
AU  - Ogihara, T.*
AU  - Inoue, I.*
AU  - Tokunaga, K.*
AU  - Johnson, T.*
AU  - Caulfield, M.*
AU  - Munroe, P.*
AU  - Global Blood Pressure Genetics
AU  - Umemura, S.*
AU  - Miki, T.*
C1  - 6081
C2  - 27990
SP  - 973-980
TI  - Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: The Japanese millennium genome project.
JO  - Hypertension
VL  - 56
IS  - 5
PB  - American Heart Assoc.
PY  - 2010
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Growth hormone (GH) can influence left ventricular myocardial growth, structure, and function. The GH secretagogue receptor (GHSR, ghrelin receptor) is known to be involved in GH release and is expressed in the myocardium. We hypothesized that genetic variants within the GHSR are associated with parameters of left ventricular mass (LVM) and geometry. Ten single-nucleotide polymorphisms (SNPs) covering the gene region were genotyped in 1230 members of the general population ( Monitoring Trends and Determinants on Cardiovascular Diseases Augsburg Echocardiographic Substudy). Linkage disequilibrium analysis revealed a linkage disequilibrium block consisting of 5 SNPs forming 2 common haplotypes. One haplotype was found significantly more often in subjects without left ventricular hypertrophy ([LVH] 69% versus 59%; permutated P = 0.0015), whereas the second haplotype was significantly more frequent in individuals with LVH (32% versus 26%; P = 0.019). Homozygous subjects presented with an increase of risk with respect to all heart size parameters. A significantly increasing frequency of the risk haplotype could be observed from the lowest (20.9%) to the highest quintile (31.0%) of gender-specific LVM distributions (P = 0.0096). We found association of the minor alleles of individual single nucleotide polymorphisms contributing to the haplotypes with higher LVM indices, septal wall thickness, and different LVH criteria consistent in men and women in matched cases and controls ( LVM, women: 144.8 +/- 30.9 [noncarrier] versus 171.3 +/- 36.0 [homozygous], P = 0.001; men: 186.7 +/- 42.4 versus 236.3 +/- 64.5, P = 0.002). These data suggest that common variants in the GHSR region are associated with parameters of LVM and geometry independent of blood pressure and body mass in the general population and, thus, may be involved in the pathogenesis of LVH.
AU  - Baessler, S.*
AU  - Kwitek, A.E.*
AU  - Fischer, M.*
AU  - Köhler, M.*
AU  - Reinhard, W.*
AU  - Erdmann, J.*
AU  - Riegger, G.*
AU  - Döring, A.
AU  - Schunkert, H.*
AU  - Hengstenberg, C.*
C1  - 4825
C2  - 23843
SP  - 920-927
TI  - Association of the Ghrelin receptor gene region with left ventricular hypertrophy in the general population: Results of the MONICA/KORA Augsburg echocardiographic substudy.
JO  - Hypertension
VL  - 47
PY  - 2006
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4 +/- 3.17 mmHg versus CT 134.2 +/- 0.97 min Hg and TT 134.3 +/- 0.53 mm Hg; P=0.03) and diastolic blood pressure levels (CC 85.4 +/- 2.06 mm Hg versus CT 80.3 +/- 0.63 mm Hg and TT 80.7 +/- 0.34 mm Hg; P=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96; P=0.016) in the entire study population, with similar trends in men (4.30 [95% Cl, 1.08 to 17.15]) and women (2.93 [95% Cl, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function.
AU  - Mayer, B.*
AU  - Döring, A.
AU  - Löwel, H.
C1  - 5220
C2  - 23360
SP  - 766-771
TI  - Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy.
JO  - Hypertension
VL  - 46
IS  - 4 
PY  - 2005
SN  - 0194-911x
ER  - 

TY  - JOUR
AU  - Luchner, A.*
AU  - Hengstenberg, C.*
AU  - Löwel, H.
AU  - Trawinski, J.*
AU  - Baumann, M.*
AU  - Riegger, G.A.*
AU  - Schunkert, H.*
AU  - Holmer, S.*
C1  - 22080
C2  - 20727
SP  - 99-104
TI  - N-Terminal Pro-Brain Natriuretic Peptide after Myocardial Infarction : A Marker of Cardio-Renal Function.
JO  - Hypertension
VL  - 39
PY  - 2002
SN  - 0194-911x
ER  - 

TY  - JOUR
AU  - Hengstenberg, C.*
AU  - Holmer, S.R.*
AU  - Mayer, B.*
AU  - Löwel, H.
AU  - Engel, S.
AU  - Hense, H.-W.*
AU  - Riegger, G.A.J.*
AU  - Schunkert, H.*
C1  - 21372
C2  - 19488
SP  - 704-709
TI  - Evaluation of the Aldosterone Synthase (CYP11B2) Gene Polymorphism in Patients with Myocardial Infarction.
JO  - Hypertension
VL  - 35
PY  - 2000
SN  - 0194-911x
ER  - 

TY  - JOUR
AB  - The Munich Blood Pressure Study (MBS), a 1980-81 cross-sectional study (with follow-up) of a random sample of 3198 Munich citizens aged 30-69 years (response rate 69%), revealed hypertensive blood pressure (BP) values in 17.7% of men and 10.7% of women (WHO criteria). One of the main goals of the MBS was to search for social, behavioral, and environmental risk factors for hypertension. The relationship between BP and five possible risk factors - alcohol consumption (g/day), cigarette smoking, oral contraceptive use, years of education, obesity (BMI) - has been examined. The major emphasis of this report is the relationship of alcohol consumption to BP. Multiple linear and logistic regression analyses were run controlling for both age and sex. All second- and third-order interactions between the independent variables were tested during a backward stepping procedure. Alcohol consumption appeared as a significant main effect in many of the analyses. The coefficient of the alcohol variable ranged from 0.02 to 0.06 for men and women in the separate linear regression analyses for systolic and diastolic BP. Thus, for example, according to the model, the daily consumption of 1 liter of beer (40 g alcohol) may cause an increase in diastolic BP in women of 2.4 mm Hg.
AU  - Cairns, V.
AU  - Keil, U.
AU  - Kleinbaum, D.G.
AU  - Doering, A.*
AU  - Stieber, J.*
C1  - 41275
C2  - 38654
SP  - 124-131
TI  - Alcohol consumption as a risk factor for high blood pressure. Munich blood pressure study.
JO  - Hypertension
VL  - 6
IS  - 1
PY  - 1984
SN  - 0194-911x
ER  -