TY  - JOUR
A1  - Sharkovska, Yuliya
A1  - Kalk, Philipp
A1  - Lawrenz, Bettina
A1  - Godes, Michael
A1  - Hoffmann, Linda Sarah
A1  - Wellkisch, Kathrin
A1  - Geschka, Sandra
A1  - Relle, Katharina
A1  - Hocher, Berthold
A1  - Stasch, Johannes-Peter
T1  - Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models
N2  - Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Y1  - 2010
UR  - http://journals.lww.com/jhypertension/pages/default.aspx
U6  - https://doi.org/10.1097/Hjh.0b013e32833b558c
SN  - 0263-6352
ER  - 
TY  - JOUR
A1  - Fischer, Stephanie S.
A1  - Kempe, Daniela S.
A1  - Leibrock, Christina B.
A1  - Rexhepaj, Rexhep
A1  - Siraskar, Balasaheb
A1  - Boini, Krishna M.
A1  - Ackermann, Teresa F.
A1  - Foeller, Michael
A1  - Hocher, Berthold
A1  - Rosenblatt, Kevin P.
A1  - Kuro-o, Makoto
A1  - Lang, Florian
T1  - Hyperaldosteronism in Klotho-deficient mice
N2  - Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.
Y1  - 2010
UR  - http://ajprenal.physiology.org/
U6  - https://doi.org/10.1152/ajprenal.00233.2010
SN  - 1931-857X
ER  - 
TY  - JOUR
A1  - Foeller, Michael
A1  - Mahmud, Hasan
A1  - Qadri, Syed M.
A1  - Gu, Shuchen
A1  - Braun, Manuel
A1  - Bobbala, Diwakar
A1  - Hocher, Berthold
A1  - Lang, Florian
T1  - Endothelin B receptor stimulation inhibits suicidal erythrocyte death
N2  - Endothelins (ETs), potent endothelium-derived mediators, stimulate formation of nitric oxide, which, in turn, protects against suicidal erythrocyte death or eryptosis, characterized by phosphatidylserine exposure at the erythrocyte surface and triggered by increase in cytosolic Ca2+ ([Ca2+](i)). The present study explored whether the ET1- receptor ETB influences suicidal erythrocyte death. To this end, [Ca2+](i) (Fluo3-fluorescence) and phosphatidylserine exposure (annexin V-binding) were determined utilizing FACS analysis. Energy depletion increased [Ca2+]i and phosphatidylserine-exposure, effects significantly blunted by ET1 (IC50 approximate to 100 nM) and the ETB receptor- agonist sarafotoxin 6c (IC50 approximate to 10 nM) but not by ET2 and ET3. ET1 and sarafotoxin significantly delayed the kinetics of suicidal erythrocyte death following energy depletion. ETB stimulation did not blunt the effect of Ca2+- ionophore ionomycin (1 mu M) on phosphatidylserine exposure. The in vivo significance was tested using rescued ETB- knockout (etb(-/-)) and wild-type (etb(+/+)) mice. The number of phosphatidylserine-exposing erythrocytes, of reticulocytes and spleen size were significantly larger in etb(-/-) mice than in etb(+/+)-mice. The etb(-/-) erythrocytes were more susceptible to the eryptotic effect of oxidative stress and more rapidly cleared from circulating blood than etb(+/+) erythrocytes. Finally, the spleens from etb(-/-) mice were enlarged and contained markedly more phosphatidylserine- exposing erythrocytes than spleens from etb(+/+) mice. The observations disclose a novel function of ET1, i. e., protection from suicidal erythrocyte death.
Y1  - 2010
UR  - http://www.fasebj.org/
U6  - https://doi.org/10.1096/Fj.10-159483
SN  - 0892-6638
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
T1  - Adenosine A1 receptor antagonists in clinical research and development
N2  - Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists. We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy.
Y1  - 2010
UR  - http://www.nature.com/ki/index.html
U6  - https://doi.org/10.1038/Ki.2010.204
SN  - 0085-2538
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Heiden, S.
A1  - von Websky, Karoline
A1  - Rahnenführer, Jörg
A1  - Kalk, Philipp
A1  - Pfab, T.
T1  - Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure
JF  - European journal of medical research : official organ "Deutsche AIDS-Gesellschaft"
N2  - Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might: be able to attenuate acute toxic liver injury.
 Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection.
 Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055).
 In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.
KW  - endothelin
KW  - endothelin-converting enzyme
KW  - neutral endopeptidase
KW  - D-galactosamine
KW  - acute liver failure
Y1  - 2011
SN  - 0949-2321
VL  - 16
IS  - 6
SP  - 275
EP  - 279
PB  - Med. Scientific Publ. Holzapfel
CY  - München
ER  - 
TY  - JOUR
A1  - Geschka, Sandra
A1  - Kretschmer, Axel
A1  - Sharkovska, Yuliya
A1  - Evgenov, Oleg V.
A1  - Lawrenz, Bettina
A1  - Hucke, Andreas
A1  - Hocher, Berthold
A1  - Stasch, Johannes-Peter
T1  - Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats
JF  - PLoS one
N2  - Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.
 Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.
 Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.
Y1  - 2011
U6  - https://doi.org/10.1371/journal.pone.0021853
SN  - 1932-6203
VL  - 6
IS  - 7
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Chaykovska, Lyubov
A1  - von Websky, Karoline
A1  - Rahnenführer, Jan
A1  - Alter, Markus L.
A1  - Heiden, Susi
A1  - Fuchs, Holger
A1  - Runge, Frank
A1  - Klein, Thomas
A1  - Hocher, Berthold
T1  - Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy
JF  - PLoS one
N2  - Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).
 Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-infinity) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-infinity) values; 41% and 28% (p=0.0001 and p=0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mu mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p=0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.
 Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.
Y1  - 2011
U6  - https://doi.org/10.1371/journal.pone.0027861
SN  - 1932-6203
VL  - 6
IS  - 11
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Espe, Katharina M.
A1  - Raila, Jens
A1  - Henze, Andrea
A1  - Krane, Vera
A1  - Schweigert, Florian J.
A1  - Hocher, Berthold
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Impact of vitamin A on clinical outcomes in haemodialysis patients
JF  - Nephrology, dialysis, transplantation
N2  - Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study.
 Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations.
 Results. Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) mu mol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 mu mol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 mu mol/L; HR 1.81, 95% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95% CI 1.41-3.50) and fatal infection (HR 2.19, 95% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 mu mol/L) were more likely to die of any cause (HR 1.43, 95% CI 1.14-1.80), experience SCD (HR 1.97, 95% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95% CI 1.10-1.85).
 Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients.
KW  - haemodialysis
KW  - mortality
KW  - retinol
KW  - retinol-binding protein 4
KW  - sudden death
Y1  - 2011
U6  - https://doi.org/10.1093/ndt/gfr171
SN  - 0931-0509
VL  - 26
IS  - 12
SP  - 4054
EP  - U583
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Kalk, Philipp
A1  - Sharkovska, Yuliya
A1  - Kashina, Elena
A1  - von Websky, Karoline
A1  - Relle, Katharina
A1  - Pfab, Thiemo
A1  - Alter, Markus L.
A1  - Guillaume, Philippe
A1  - Provost, Daniel
A1  - Hoffmann, Katrin
A1  - Fischer, Yvan
A1  - Hocher, Berthold
T1  - Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338
 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent
 Manner
JF  - HYPERTENSION
N2  - Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by <= 46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media: lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-beta 1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-beta 1 expression. (Hypertension. 2011;57:755-763.)
KW  - renovascular hypertension
KW  - cardiac remodeling
KW  - endothelin-converting enzyme
KW  - neutral endopeptidase
KW  - TGF-beta 1
Y1  - 2011
U6  - https://doi.org/10.1161/HYPERTENSIONAHA.110.163972
SN  - 0194-911X
VL  - 57
IS  - 4
SP  - 755
EP  - 763
PB  - LIPPINCOTT WILLIAMS & WILKINS
CY  - PHILADELPHIA
ER  - 
TY  - JOUR
A1  - Vignon-Zellweger, Nicolas
A1  - Relle, Katharina
A1  - Kienlen, Elodie
A1  - Alter, Markus L.
A1  - Seider, Patrick
A1  - Sharkovska, Juliya
A1  - Heiden, Susi
A1  - Kalk, Philipp
A1  - Schwab, Karima
A1  - Albrecht-Kuepper, Barbara
A1  - Theuring, Franz
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice
JF  - Journal of hypertension
N2  - Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice.
 Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation.
 Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.
KW  - cardiovascular diseases
KW  - endothelin
KW  - nitric oxide
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e3283450770
SN  - 0263-6352
SN  - 1473-5598
VL  - 29
IS  - 5
SP  - 961
EP  - 970
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Wang, Zi-Neng
A1  - Schlemm, Ludwig
A1  - Pfab, Thiemo
A1  - Xiao, Xiao-Min
A1  - Chen, You-Peng
A1  - Hocher, Berthold
T1  - Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations
JF  - Journal of hypertension
N2  - Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life.
 Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain.
 Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.
KW  - disproportional intrauterine growth retardation
KW  - insulin resistance
KW  - low birth weight
KW  - ultrasound
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e328349a2e6
SN  - 0263-6352
VL  - 29
IS  - 9
SP  - 1712
EP  - 1718
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Schlemm, Ludwig
A1  - Haumann, Hannah
A1  - Li, Jian
A1  - Rahnenführer, Jan
A1  - Guthmann, Florian
A1  - Bamberg, Christian
A1  - Kalk, Philipp
A1  - Pfab, Thiemo
A1  - Chen, You-Peng
T1  - Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy
JF  - Journal of the renin angiotensin aldosterone system
N2  - Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism.
 Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done.
 Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70% vs. 6.21 +/- 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80%) compared to II mothers delivering boys (6.21 +/- 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension.
 Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.
KW  - ACE I/D polymorphism
KW  - pregnancy
KW  - fetal sex
KW  - pregnancy induced diabetes
KW  - total glycated hemoglobin
KW  - glycemic control during pregnancy
Y1  - 2011
U6  - https://doi.org/10.1177/1470320310387843
SN  - 1470-3203
VL  - 12
IS  - 3
SP  - 254
EP  - 261
PB  - Sage Publ.
CY  - London
ER  - 
TY  - JOUR
A1  - Schildroth, Janice
A1  - Rettig-Zimmermann, Juliane
A1  - Kalk, Philipp
A1  - Steege, Andreas
A1  - Faehling, Michael
A1  - Sendeski, Mauricio
A1  - Paliege, Alexander
A1  - Lai, En Yin
A1  - Bachmann, Sebastian
A1  - Persson, Pontus B.
A1  - Hocher, Berthold
A1  - Patzak, Andreas
T1  - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice
JF  - Nephrology, dialysis, transplantation
N2  - Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established.
 Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused.
 Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA.
 Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.
KW  - endothelin
KW  - ETB receptor-deficient mouse
KW  - glomerular arterioles
KW  - renal haemodynamics
Y1  - 2011
U6  - https://doi.org/10.1093/ndt/gfq534
SN  - 0931-0509
VL  - 26
IS  - 3
SP  - 779
EP  - 789
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Heiden, Susi
A1  - von Websky, Karoline
A1  - Arafat, Ayman M.
A1  - Rahnenführer, Jan
A1  - Alter, Markus L.
A1  - Kalk, Philipp
A1  - Ziegler, Dieter
A1  - Fischer, Yvan
A1  - Pfab, Thiemo
T1  - Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats
JF  - PLoS one
N2  - Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p < 0.05), especially in those receiving furosemide (-41.9%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.
Y1  - 2011
U6  - https://doi.org/10.1371/journal.pone.0017891
SN  - 1932-6203
VL  - 6
IS  - 3
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Sharkovska, Yuliya
A1  - Kalk, Philipp
A1  - von Websky, Karoline
A1  - Relle, Katharina
A1  - Pfab, Thiemo
A1  - Alter, Markus L.
A1  - Fischer, Yvan
A1  - Hocher, Berthold
T1  - Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure.
 Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion.
 Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested.
 Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 % in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 % mortality in vehicle-treated rats, but only 20 % after SLV338 treatment (p = 0.03 compared to sham controls).
 Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case).
 Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
KW  - Renal failure
KW  - endothelin-converting enzyme
KW  - neutral endopeptidase
Y1  - 2011
SN  - 1433-6510
VL  - 57
IS  - 7-8
SP  - 507
EP  - 515
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Heimerl, Dirk
A1  - Slowinski, Torsten
A1  - Godes, Michael
A1  - Halle, Horst
A1  - Priem, Friedrich
A1  - Pfab, Thiemo
T1  - Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth.
 Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy.
 Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin.
 Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.
KW  - GLUT1 XbaI gene polymorphism
KW  - birthweight
KW  - total glycosylated hemoglobin
KW  - insulin resistance
KW  - fetal programming
Y1  - 2011
SN  - 1433-6510
VL  - 57
IS  - 9-10
SP  - 651
EP  - 657
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Zebger-Gong, Hong
A1  - Mueller, Dominik
A1  - Diercke, Michaela
A1  - Haffner, Dieter
A1  - Hocher, Berthold
A1  - Verberckmoes, Steven
A1  - Schmidt, Sven
A1  - D'Haese, Patrick C.
A1  - Querfeld, Uwe
T1  - 1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix
JF  - Journal of hypertension
N2  - Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro.
 Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol.
 Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix.
KW  - calbindin D9k
KW  - calcitriol
KW  - calcium transport
KW  - osteoblast
KW  - osterix
KW  - TRPV5
KW  - TRPV6
KW  - vascular calcification
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e328340aa30
SN  - 0263-6352
VL  - 29
IS  - 2
SP  - 339
EP  - 348
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Wengenmayer, Christina
A1  - Krikov, Maxim
A1  - Mueller, Susanne
A1  - Lucht, Kristin
A1  - Villringer, Arno
A1  - Hocher, Berthold
A1  - Unger, Thomas
A1  - Thoene-Reineke, Christa
T1  - Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival
JF  - Neurological research : a journal of progress in neurosurgery and neurosciences
N2  - Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats.
 Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging.
 Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner.
 Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.
KW  - Endothelin
KW  - Hypertension
KW  - Natriuretic peptides
KW  - Stroke
Y1  - 2011
U6  - https://doi.org/10.1179/016164111X12881719352534
SN  - 0161-6412
VL  - 33
IS  - 2
SP  - 201
EP  - 207
PB  - Routledge, Taylor & Francis Group
CY  - Leeds
ER  - 
TY  - JOUR
A1  - Taal, H. Rob
A1  - St Pourcain, Beate
A1  - Thiering, Elisabeth
A1  - Das, Shikta
A1  - Mook-Kanamori, Dennis O.
A1  - Warrington, Nicole M.
A1  - Kaakinen, Marika
A1  - Kreiner-Moller, Eskil
A1  - Bradfield, Jonathan P.
A1  - Freathy, Rachel M.
A1  - Geller, Frank
A1  - Guxens, Monica
A1  - Cousminer, Diana L.
A1  - Kerkhof, Marjan
A1  - Timpson, Nicholas J.
A1  - Ikram, M. Arfan
A1  - Beilin, Lawrence J.
A1  - Bonnelykke, Klaus
A1  - Buxton, Jessica L.
A1  - Charoen, Pimphen
A1  - Chawes, Bo Lund Krogsgaard
A1  - Eriksson, Johan
A1  - Evans, David M.
A1  - Hofman, Albert
A1  - Kemp, John P.
A1  - Kim, Cecilia E.
A1  - Klopp, Norman
A1  - Lahti, Jari
A1  - Lye, Stephen J.
A1  - McMahon, George
A1  - Mentch, Frank D.
A1  - Mueller-Nurasyid, Martina
A1  - O'Reilly, Paul F.
A1  - Prokopenko, Inga
A1  - Rivadeneira, Fernando
A1  - Steegers, Eric A. P.
A1  - Sunyer, Jordi
A1  - Tiesler, Carla
A1  - Yaghootkar, Hanieh
A1  - Breteler, Monique M. B.
A1  - Debette, Stephanie
A1  - Fornage, Myriam
A1  - Gudnason, Vilmundur
A1  - Launer, Lenore J.
A1  - van der Lugt, Aad
A1  - Mosley, Thomas H.
A1  - Seshadri, Sudha
A1  - Smith, Albert V.
A1  - Vernooij, Meike W.
A1  - Blakemore, Alexandra I. F.
A1  - Chiavacci, Rosetta M.
A1  - Feenstra, Bjarke
A1  - Fernandez-Banet, Julio
A1  - Grant, Struan F. A.
A1  - Hartikainen, Anna-Liisa
A1  - van der Heijden, Albert J.
A1  - Iniguez, Carmen
A1  - Lathrop, Mark
A1  - McArdle, Wendy L.
A1  - Molgaard, Anne
A1  - Newnham, John P.
A1  - Palmer, Lyle J.
A1  - Palotie, Aarno
A1  - Pouta, Annneli
A1  - Ring, Susan M.
A1  - Sovio, Ulla
A1  - Standl, Marie
A1  - Uitterlinden, Andre G.
A1  - Wichmann, H-Erich
A1  - Vissing, Nadja Hawwa
A1  - DeCarli, Charles
A1  - van Duijn, Cornelia M.
A1  - McCarthy, Mark I.
A1  - Koppelman, Gerard H.
A1  - Estivill, Xavier
A1  - Hattersley, Andrew T.
A1  - Melbye, Mads
A1  - Bisgaard, Hans
A1  - Pennell, Craig E.
A1  - Widen, Elisabeth
A1  - Hakonarson, Hakon
A1  - Smith, George Davey
A1  - Heinrich, Joachim
A1  - Jarvelin, Marjo-Riitta
A1  - Jaddoe, Vincent W. V.
A1  - Adair, Linda S.
A1  - Ang, Wei
A1  - Atalay, Mustafa
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Davis, Oliver S. P.
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Feenstra, Bjarke
A1  - Flexeder, Claudia
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Geller, Frank
A1  - Groen-Blokhuis, Maria
A1  - Goh, Liang-Kee
A1  - Guxens, Monica
A1  - Haworth, Claire M. A.
A1  - Hadley, Dexter
A1  - Hebebrand, Johannes
A1  - Hinney, Anke
A1  - Hirschhorn, Joel N.
A1  - Holloway, John W.
A1  - Holst, Claus
A1  - Hottenga, Jouke Jan
A1  - Horikoshi, Momoko
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Iniguez, Carmen
A1  - Kaakinen, Marika
A1  - Kilpelainen, Tuomas O.
A1  - Kirin, Mirna
A1  - Kowgier, Matthew
A1  - Lakka, Hanna-Maaria
A1  - Lange, Leslie A.
A1  - Lawlor, Debbie A.
A1  - Lehtimaki, Terho
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Lindi, Virpi
A1  - Maggi, Reedik
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Murray, Jeffrey C.
A1  - Nivard, Michel
A1  - Nohr, Ellen Aagaard
A1  - Ntalla, Ioanna
A1  - Oken, Emily
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Panoutsopoulou, Kalliope
A1  - Pararajasingham, Jennifer
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Salem, Rany M.
A1  - Sebert, Sylvain
A1  - Siitonen, Niina
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Teo, Yik-Ying
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Zeggini, Eleftheria
A1  - Boomsma, Dorret I.
A1  - Cooper, Cyrus
A1  - Estivill, Xavier
A1  - Gillman, Matthew
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Hocher, Berthold
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - Lakka, Timo A.
A1  - McCarthy, Mark I.
A1  - Melbye, Mads
A1  - Mohlke, Karen L.
A1  - Dedoussis, George V.
A1  - Ong, Ken K.
A1  - Pearson, Ewan R.
A1  - Pennell, Craig E.
A1  - Price, Thomas S.
A1  - Power, Chris
A1  - Raitakari, Olli T.
A1  - Saw, Seang-Mei
A1  - Scherag, Andre
A1  - Simell, Olli
A1  - Sorensen, Thorkild I. A.
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Wilson, James F.
A1  - Ang, Wei
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Groen-Blokhuis, Maria
A1  - Guxens, Monica
A1  - Hadley, Dexter
A1  - Hottenga, Jouke Jan
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Kaakinen, Marika
A1  - Kowgier, Matthew
A1  - Lawlor, Debbie A.
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Nivard, Michel
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Sebert, Sylvain
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Standl, Marie
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Boomsma, Dorret I.
A1  - Estivill, Xavier
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - McCarthy, Mark I.
A1  - Pennell, Craig E.
A1  - Power, Chris
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Ikram, M. Arfan
A1  - Fornage, Myriam
A1  - Smith, Albert V.
A1  - Seshadri, Sudha
A1  - Schmidt, Reinhold
A1  - Debette, Stephanie
A1  - Vrooman, Henri A.
A1  - Sigurdsson, Sigurdur
A1  - Ropele, Stefan
A1  - Coker, Laura H.
A1  - Longstreth, W. T.
A1  - Niessen, Wiro J.
A1  - DeStefano, Anita L.
A1  - Beiser, Alexa
A1  - Zijdenbos, Alex P.
A1  - Struchalin, Maksim
A1  - Jack, Clifford R.
A1  - Nalls, Mike A.
A1  - Au, Rhoda
A1  - Hofman, Albert
A1  - Gudnason, Haukur
A1  - van der Lugt, Aad
A1  - Harris, Tamara B.
A1  - Meeks, William M.
A1  - Vernooij, Meike W.
A1  - van Buchem, Mark A.
A1  - Catellier, Diane
A1  - Gudnason, Vilmundur
A1  - Windham, B. Gwen
A1  - Wolf, Philip A.
A1  - van Duijn, Cornelia M.
A1  - Mosley, Thomas H.
A1  - Schmidt, Helena
A1  - Launer, Lenore J.
A1  - Breteler, Monique M. B.
A1  - DeCarli, Charles
T1  - Common variants at 12q15 and 12q24 are associated with infant head circumference
JF  - Nature genetics
N2  - To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Y1  - 2012
U6  - https://doi.org/10.1038/ng.2238
SN  - 1061-4036
VL  - 44
IS  - 5
SP  - 532
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Ikram, M. Arfan
A1  - Fornage, Myriam
A1  - Smith, Albert V.
A1  - Seshadri, Sudha
A1  - Schmidt, Reinhold
A1  - Debette, Stephanie
A1  - Vrooman, Henri A.
A1  - Sigurdsson, Sigurdur
A1  - Ropele, Stefan
A1  - Taal, H. Rob
A1  - Mook-Kanamori, Dennis O.
A1  - Coker, Laura H.
A1  - Longstreth, W. T.
A1  - Niessen, Wiro J.
A1  - DeStefano, Anita L.
A1  - Beiser, Alexa
A1  - Zijdenbos, Alex P.
A1  - Struchalin, Maksim
A1  - Jack, Clifford R.
A1  - Rivadeneira, Fernando
A1  - Uitterlinden, Andre G.
A1  - Knopman, David S.
A1  - Hartikainen, Anna-Liisa
A1  - Pennell, Craig E.
A1  - Thiering, Elisabeth
A1  - Steegers, Eric A. P.
A1  - Hakonarson, Hakon
A1  - Heinrich, Joachim
A1  - Palmer, Lyle J.
A1  - Jarvelin, Marjo-Riitta
A1  - McCarthy, Mark I.
A1  - Grant, Struan F. A.
A1  - St Pourcain, Beate
A1  - Timpson, Nicholas J.
A1  - Smith, George Davey
A1  - Sovio, Ulla
A1  - Nalls, Mike A.
A1  - Au, Rhoda
A1  - Hofman, Albert
A1  - Gudnason, Haukur
A1  - van der Lugt, Aad
A1  - Harris, Tamara B.
A1  - Meeks, William M.
A1  - Vernooij, Meike W.
A1  - van Buchem, Mark A.
A1  - Catellier, Diane
A1  - Jaddoe, Vincent W. V.
A1  - Gudnason, Vilmundur
A1  - Windham, B. Gwen
A1  - Wolf, Philip A.
A1  - van Duijn, Cornelia M.
A1  - Mosley, Thomas H.
A1  - Schmidt, Helena
A1  - Launer, Lenore J.
A1  - Breteler, Monique M. B.
A1  - DeCarli, Charles
A1  - Adair, Linda S.
A1  - Ang, Wei
A1  - Atalay, Mustafa
A1  - vanBeijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Coin, Lachlan
A1  - Davis, Oliver S. P.
A1  - Elliott, Paul
A1  - Flexeder, Claudia
A1  - Frayling, Tim
A1  - Gaillard, Romy
A1  - Groen-Blokhuis, Maria
A1  - Goh, Liang-Kee
A1  - Haworth, Claire M. A.
A1  - Hadley, Dexter
A1  - Hebebrand, Johannes
A1  - Hinney, Anke
A1  - Hirschhorn, Joel N.
A1  - Holloway, John W.
A1  - Holst, Claus
A1  - Hottenga, Jouke Jan
A1  - Horikoshi, Momoko
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Kilpelainen, Tuomas O.
A1  - Kirin, Mirna
A1  - Kowgier, Matthew
A1  - Lakka, Hanna-Maaria
A1  - Lange, Leslie A.
A1  - Lawlor, Debbie A.
A1  - Lehtimaki, Terho
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Lindi, Virpi
A1  - Maggi, Reedik
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Murray, Jeffrey C.
A1  - Nivard, Michel
A1  - Nohr, Ellen Aagaard
A1  - Ntalla, Ioanna
A1  - Oken, Emily
A1  - Panoutsopoulou, Kalliope
A1  - Pararajasingham, Jennifer
A1  - Rodriguez, Alina
A1  - Salem, Rany M.
A1  - Sebert, Sylvain
A1  - Siitonen, Niina
A1  - Strachan, David P.
A1  - Teo, Yik-Ying
A1  - Valcarcel, Beatriz
A1  - Willemsen, Gonneke
A1  - Zeggini, Eleftheria
A1  - Boomsma, Dorret I.
A1  - Cooper, Cyrus
A1  - Gillman, Matthew
A1  - Hocher, Berthold
A1  - Lakka, Timo A.
A1  - Mohlke, Karen L.
A1  - Dedoussis, George V.
A1  - Ong, Ken K.
A1  - Pearson, Ewan R.
A1  - Price, Thomas S.
A1  - Power, Chris
A1  - Raitakari, Olli T.
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A1  - Scherag, Andre
A1  - Simell, Olli
A1  - Sorensen, Thorkild I. A.
A1  - Wilson, James F.
T1  - Common variants at 6q22 and 17q21 are associated with intracranial volume
JF  - Nature genetics
N2  - During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Y1  - 2012
U6  - https://doi.org/10.1038/ng.2245
SN  - 1061-4036
VL  - 44
IS  - 5
SP  - 539
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  -