TY  - JOUR
A1  - Hocher, Berthold
A1  - Armbruster, Franz Paul
A1  - Stöva, Stanka
A1  - Reichetzeder, Christoph
A1  - Groen, Hans Jürgen
A1  - Lieker, Ina
A1  - Khadzhynov, Dmytro
A1  - Slowinski, Torsten
A1  - Roth, Heinz Jürgen
T1  - Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay?
JF  - PLoS one
N2  - Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0040242
SN  - 1932-6203
VL  - 7
IS  - 7
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Oberthür, Dominik
A1  - Slowinski, Torsten
A1  - Querfeld, Uwe
A1  - Schäfer, Franz
A1  - Doyon, Anke
A1  - Tepel, Martin
A1  - Roth, Heinz J.
A1  - Grön, Hans J.
A1  - Reichetzeder, Christoph
A1  - Betzel, Christian
A1  - Armbruster, Franz Paul
T1  - Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients
JF  - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie
N2  - Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
KW  - n-oxPTH
KW  - Chronic Renal Failure
KW  - Kidney Transplantation
KW  - Hemodialysis
KW  - Oxidation
KW  - PTH
KW  - Chronic Renal Failure in Children
Y1  - 2013
U6  - https://doi.org/10.1159/000350149
SN  - 1420-4096
SN  - 1423-0143
VL  - 37
IS  - 4-5
SP  - 240
EP  - 251
PB  - Karger
CY  - Basel
ER  - 
TY  - GEN
A1  - Hocher, Berthold
A1  - Oberthür, Dominik
A1  - Slowinski, Torsten
A1  - Querfeld, Uwe
A1  - Schaefer, Franz
A1  - Doyon, Anke
A1  - Tepel, Martin
A1  - Roth, Heinz J.
A1  - Grön, Hans J.
A1  - Reichetzeder, Christoph
A1  - Betzel, Christian
A1  - Armbruster, Franz Paul
T1  - Modeling of oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) receptor binding and relationship of oxidized to non-oxidized PTH in children with chronic renal failure, adult patients on hemodialysis and kidney transplant recipients
N2  - Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 343 
KW  - n-oxPTH
KW  - chronic renal failure
KW  - kidney transplantation
KW  - hemodialysis
KW  - oxidation
KW  - PTH
KW  - chronic renal failure in children
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-399980
ER  - 
TY  - JOUR
A1  - Horikoshi, Momoko
A1  - Yaghootkar, Hanieh
A1  - Mook-Kanamori, Dennis O.
A1  - Sovio, Ulla
A1  - Taal, H. Rob
A1  - Hennig, Branwen J.
A1  - Bradfield, Jonathan P.
A1  - St Pourcain, Beate
A1  - Evans, David M.
A1  - Charoen, Pimphen
A1  - Kaakinen, Marika
A1  - Cousminer, Diana L.
A1  - Lehtimaki, Terho
A1  - Kreiner-Moller, Eskil
A1  - Warrington, Nicole M.
A1  - Bustamante, Mariona
A1  - Feenstra, Bjarke
A1  - Berry, Diane J.
A1  - Thiering, Elisabeth
A1  - Pfab, Thiemo
A1  - Barton, Sheila J.
A1  - Shields, Beverley M.
A1  - Kerkhof, Marjan
A1  - van Leeuwen, Elisabeth M.
A1  - Fulford, Anthony J.
A1  - Kutalik, Zoltan
A1  - Zhao, Jing Hua
A1  - den Hoed, Marcel
A1  - Mahajan, Anubha
A1  - Lindi, Virpi
A1  - Goh, Liang-Kee
A1  - Hottenga, Jouke-Jan
A1  - Wu, Ying
A1  - Raitakari, Olli T.
A1  - Harder, Marie N.
A1  - Meirhaeghe, Aline
A1  - Ntalla, Ioanna
A1  - Salem, Rany M.
A1  - Jameson, Karen A.
A1  - Zhou, Kaixin
A1  - Monies, Dorota M.
A1  - Lagou, Vasiliki
A1  - Kirin, Mirna
A1  - Heikkinen, Jani
A1  - Adair, Linda S.
A1  - Alkuraya, Fowzan S.
A1  - Al-Odaib, Ali
A1  - Amouyel, Philippe
A1  - Andersson, Ehm Astrid
A1  - Bennett, Amanda J.
A1  - Blakemore, Alexandra I. F.
A1  - Buxton, Jessica L.
A1  - Dallongeville, Jean
A1  - Das, Shikta
A1  - de Geus, Eco J. C.
A1  - Estivill, Xavier
A1  - Flexeder, Claudia
A1  - Froguel, Philippe
A1  - Geller, Frank
A1  - Godfrey, Keith M.
A1  - Gottrand, Frederic
A1  - Groves, Christopher J.
A1  - Hansen, Torben
A1  - Hirschhorn, Joel N.
A1  - Hofman, Albert
A1  - Hollegaard, Mads V.
A1  - Hougaard, David M.
A1  - Hyppoenen, Elina
A1  - Inskip, Hazel M.
A1  - Isaacs, Aaron
A1  - Jorgensen, Torben
A1  - Kanaka-Gantenbein, Christina
A1  - Kemp, John P.
A1  - Kiess, Wieland
A1  - Kilpelainen, Tuomas O.
A1  - Klopp, Norman
A1  - Knight, Bridget A.
A1  - Kuzawa, Christopher W.
A1  - McMahon, George
A1  - Newnham, John P.
A1  - Niinikoski, Harri
A1  - Oostra, Ben A.
A1  - Pedersen, Louise
A1  - Postma, Dirkje S.
A1  - Ring, Susan M.
A1  - Rivadeneira, Fernando
A1  - Robertson, Neil R.
A1  - Sebert, Sylvain
A1  - Simell, Olli
A1  - Slowinski, Torsten
A1  - Tiesler, Carla M. T.
A1  - Toenjes, Anke
A1  - Vaag, Allan
A1  - Viikari, Jorma S.
A1  - Vink, Jacqueline M.
A1  - Vissing, Nadja Hawwa
A1  - Wareham, Nicholas J.
A1  - Willemsen, Gonneke
A1  - Witte, Daniel R.
A1  - Zhang, Haitao
A1  - Zhao, Jianhua
A1  - Wilson, James F.
A1  - Stumvoll, Michael
A1  - Prentice, Andrew M.
A1  - Meyer, Brian F.
A1  - Pearson, Ewan R.
A1  - Boreham, Colin A. G.
A1  - Cooper, Cyrus
A1  - Gillman, Matthew W.
A1  - Dedoussis, George V.
A1  - Moreno, Luis A.
A1  - Pedersen, Oluf
A1  - Saarinen, Maiju
A1  - Mohlke, Karen L.
A1  - Boomsma, Dorret I.
A1  - Saw, Seang-Mei
A1  - Lakka, Timo A.
A1  - Koerner, Antje
A1  - Loos, Ruth J. F.
A1  - Ong, Ken K.
A1  - Vollenweider, Peter
A1  - van Duijn, Cornelia M.
A1  - Koppelman, Gerard H.
A1  - Hattersley, Andrew T.
A1  - Holloway, John W.
A1  - Hocher, Berthold
A1  - Heinrich, Joachim
A1  - Power, Chris
A1  - Melbye, Mads
A1  - Guxens, Monica
A1  - Pennell, Craig E.
A1  - Bonnelykke, Klaus
A1  - Bisgaard, Hans
A1  - Eriksson, Johan G.
A1  - Widen, Elisabeth
A1  - Hakonarson, Hakon
A1  - Uitterlinden, Andre G.
A1  - Pouta, Anneli
A1  - Lawlor, Debbie A.
A1  - Smith, George Davey
A1  - Frayling, Timothy M.
A1  - McCarthy, Mark I.
A1  - Grant, Struan F. A.
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - Timpson, Nicholas J.
A1  - Prokopenko, Inga
A1  - Freathy, Rachel M.
T1  - New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism
JF  - Nature genetics
N2  - Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Y1  - 2013
U6  - https://doi.org/10.1038/ng.2477
SN  - 1061-4036
VL  - 45
IS  - 1
SP  - 76
EP  - U115
PB  - Nature Publ. Group
CY  - New York
ER  -