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1دورية أكاديمية
المؤلفون: Niemantsverdriet, E. (Ellis), Akker, E.B. (Erik) van den, Boeters, D.M. (Debbie M.), Eeden, S.J.F. (Susan) van den, Geluk, A. (Annemieke), Helm-van Mil, A.H.M. (Annette) van der
المصدر: Arthritis Research and Therapy vol. 22 no. 1
الوصف: Following publication of the original article [1], a typesetting error was reported. The equal contribution note for this article was incorrect. The corrected statement is given below. † Ellis Niemantsverdriet and Erik B. van den Akker contributed equally and are joint first authors. † Annemieke Geluk and Annette H. M. van der Helm-van Mil contribu
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/132749Test; urn:hdl:1765/132749
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2دورية أكاديمية
المؤلفون: Arindrarto, W. (Wibowo), Borràs, D.M. (Daniel M.), de Groen, R.A.L. (Ruben A. L.), van den Berg, R.R. (Redmar R.), Locher, I.J. (Irene J.), van Diessen, S.A.M.E. (Saskia A. M. E.), van der Holst, R. (Rosalie), van der Meijden, E.D. (Edith D.), Honders, M.W. (M. Willy), de Leeuw, R.H. (Rick H.), Verlaat, W. (Wina), Jedema, I. (I.), Kroes, W.G.M. (Wilma G. M.), Knijnenburg, J. (Jeroen), Wezel, T. (Tom) van, Vermaat, J.S. (Joost), Valk, P.J.M. (Peter), Janssen, B. (Bart), Knijff, P. (Peter) de, van Bergen, C.A.M. (Cornelis A. M.), Akker, E.B. (Erik) van den, Hoen, P.A.C.T. (Peter A. C. t), Kielbasa, S.M. (Szymon M.), Laros, J.F.J. (Jeroen F.), Griffioen, M., Veelken, H.
المصدر: Leukemia
الوصف: Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/125561Test; urn:hdl:1765/125561
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3دورية أكاديمية
المؤلفون: Knol, M.J. (Maria), Lu, Dongwei, Traylor, M. (Matthew), Adams, H.H.H. (Hieab), Romero, J.R. (Jose Rafael), Smith, A.V. (Davey), Fornage, M. (Myriam), Hofer, E. (Edith), Liu, J. (Juan), Hostettler, Isabel C., Luciano, M. (Michelle), Trompet, S. (Stella), Giese, A.-K. (Anne-Katrin), Hilal, S. (Saima), Akker, E.B. (Erik) van den, Vojinović, D. (Dina), S. Li (Shuo), Sigurdsson, S. (Sigurdur), Lee, S.J. (Sven) van der, Jack Jr., C.R. (Clifford), Wilson, D. (Dana), Yilmaz, P. (Pinar), Satizabal, C.L. (Claudia), Liewald, D.C.M. (David), Grond, J. (Jeroen) van der, Chen, C. (Christopher), Saba, Y. (Yasaman), Lugt, A. (Aad) van der, Bastin, M.E. (Mark), Windham, B.G. (Gwen), Cheng, C-Y. (Ching-Yu), Pirpamer, Lukas, Kantarci, Kejal, Himali, J.J. (Jayandra), Yang, Q. (Qiong), Morris, Zoe, Beiser, A. (Alexa), Tozer, Daniel J., Vernooij, M.W. (Meike), Amin, N. (Najaf), Beekman, M. (Marian), Koh, J.Y. (Jia Yu), Stott, D.J.M. (David), Houlden, H. (Henry), Schmidt, R. (Reinhold), Gottesman, R.F. (Rebecca), MacKinnon, Andrew D., DeCarli, C. (Charles), Guonason, V. (Vilmundur), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Wong, T.Y. (Tien Yin), Rost, N.S. (Natalia), Jukeme, J.W. (J. Wouter), Mosley, T.H. (Thomas), Werring, D.J. (David), Schmidt, H. (Helena), Wardlaw, J.M. (J.), Ikram, M.A. (Arfan), Seshadri, S. (Sudha), Launer, L.J. (Lenore), Markus, H.S. (Hugh S.)
المصدر: Neurology vol. 95 no. 24, pp. e3331-e3343
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/133717Test; urn:hdl:1765/133717
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4دورية أكاديمية
المؤلفون: Knol, M.J. (Maria J.), Lu, D. (Dongwei), Traylor, M. (Matthew), Adams, H.H.H. (Hieab), Romero, J.R.J. (José Rafael J), Smith, A.V. (Albert), Fornage, M. (Myriam), Hofer, E. (Edith), Liu, J. (Junfeng), Hostettler, I.C. (Isabel C.), Luciano, M. (Michelle), Trompet, S. (Stella), Giese, A.-K. (Anne-Katrin), Hilal, S. (Saima), Akker, E.B. (Erik) van den, Vojinović, D. (Dina), Li, S. (Shuo), Sigurdsson, S. (Stefan), Lee, S.J. (Sven) van der, Jack Jr., C.R. (Clifford), Wilson, D. (Duncan), Yilmaz, P. (Pinar), Satizabal, C.L. (Claudia), Liewald, D.C.M. (David C M), van der Grond, J. (Jeroen), Chen, C. (Christopher), Saba, Y. (Yasaman), Lugt, A. (Aad) van der, Bastin, M.E. (Mark), Windham, B.G. (Gwen), Cheng, C.Y. (Ching Yu), Pirpamer, L. (Lukas), Kantarci, K. (Kejal), Himali, J.J. (Jayandra), Yang, Q. (Qiong), Morris, Z. (Zoe), Beiser, A. (Alexa), Tozer, D.J. (Daniel J.), Vernooij, M.W. (Meike), Amin, N. (Najaf), Beekman, M. (Marian), Koh, J.Y. (Jia Yu), Stott, D.J. (David. J.), Houlden, H. (Henry), Schmidt, R. (Reinhold), Gottesman, R.F. (Rebecca), MacKinnon, A.D. (Andrew D.), DeCarli, C. (Charles), Gudnason, V. (Vilmundur), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Wong, T.Y. (Tien Yin), Rost, N.S. (Natalia), Jukema, J.W. (Jan Wouter), Mosley, T.H. (Thomas H.), Werring, D.J. (David), Schmidt, H. (Helena), Wardlaw, J.M. (J.), Ikram, M.A. (Arfan), Seshadri, S. (Sudha), Launer, L.J. (Lenore), Markus, H.S. (Hugh)
المصدر: Neurology vol. 95 no. 24, pp. e3331-e3343
الوصف: OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs). METHODS: We performed genom
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/133057Test; urn:hdl:1765/133057
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5دورية أكاديمية
المؤلفون: Niemantsverdriet, E., Akker, E.B. (Erik) van den, Boeters, D.M., Eeden, S.J.F. (Susan) van den, Geluk, A., van der Helm-van Mil, A.H.M.
المصدر: Arthritis Research and Therapy vol. 22 no. 1
مصطلحات موضوعية: Clinically suspect arthralgia, RNA, Gene expression, MLPA, Inflammatory arthritis
الوصف: Background: Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA). Methods: Two hundred thirty-six consecutive patients presenting with arthralgia clinically suspected for progression to RA were followed until IA development or else for median 24 months (IQR 12–26). Baseline whole blood RNA expression was determined for a previously identified set of 133 genes associated with the innate and adaptive immune system by dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used. Results: Twenty percent of CSA patients developed IA. After correction for multiple testing, expression levels of six genes (IFNG, PHEX, IGF-1, IL-7R, CD19, CCR7) at the time of presentation were
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/132372Test; urn:hdl:1765/132372
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6دورية أكاديمية
المؤلفون: Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), Debette, S. (Stéphanie)
المصدر: Nature Communications vol. 11 no. 1
الوصف: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/132445Test; urn:hdl:1765/132445
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7دورية أكاديميةA genome-wide association study identifies genetic loci associated with specific lobar brain volumes
المؤلفون: Lee, S.J. (Sven) van der, Knol, M.J. (Maria J.), Chauhan, G. (Ganesh), Satizabal, C.L. (Claudia), Smith, A.V. (Albert), Hofer, E. (Edith), Bis, J.C. (Joshua), Hibar, D.P. (Derrek P.), Hilal, S. (Saima), Akker, E.B. (Erik) van den, Arfanakis, K. (Konstantinos), Bernard, M. (Manon), Yanek, L.R. (Lisa), Amin, N. (Najaf), Crivello, F. (Fabrice), Cheung, J.W. (Josh W.), Harris, T.B. (Tamara), Saba, Y. (Yasaman), Lopez, O.L. (Oscar), Li, S. (Shuo), van der Grond, J. (Jeroen), Yu, L. (Lei), Paus, T. (Tomas), Roshchupkin, G.V. (Gennady), Amouyel, P. (Philippe), Jahanshad, N. (Neda), Taylor, K.D. (Kent), Yang, Q. (Qiong), Mathias, R.A. (Rasika A.), Boehringer, S. (Stefan), Mazoyer, B. (Bernard), Rice, K. (Ken), Cheng, C.Y. (Ching Yu), Maillard, P. (Pauline), Heemst, D. (Diana) van, Wong, T.Y. (Tien Yin), Niessen, W.J. (Wiro), Beiser, A. (Alexa), Beekman, M. (Marian), Zhao, W. (Wanting), Nyquist, P. (Paul), Chen, C. (Christopher), Launer, L.J. (Lenore), Psaty, B.M. (Bruce M.), Ikram, M.K. (Kamran), Vernooij, M.W. (Meike W.), Schmidt, H. (Helena), Pausova, Z. (Zdenka), Becker, D.M. (Diane), De Jager, P., Thompson, P.M. (Paul), Duijn, C.M. (Cornelia) van, Bennett, D.A. (David), Slagboom, P.E. (Eline), Schmidt, R. (Reinhold), Longstreth Jr, W.T., Ikram, M.A. (Arfan), Seshadri, S. (Sudha), Debette, S. (Stéphanie), Gudnason, V. (Vilmundur), Adams, H.H.H. (Hieab H. H.), DeCarli, C. (Charles)
المصدر: Communications Biology vol. 2 no. 1
الوصف: Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.
وصف الملف: application/pdf
العلاقة: http://repub.eur.nl/pub/119251Test; urn:hdl:1765/119251
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8دورية أكاديمية
المؤلفون: Akker, E.B. (Erik) van den, Pitts, S.J. (Steven J.), Deelen, J. (Joris), Moed, H. (Heleen), Potluri, S. (Shobha), Rooij, J.G.J. (Jeroen) van, Suchiman, H.E.D. (Eka), Lakenberg, N. (Nico), De Dijcker, W.J. (Wesley J.), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Hofman, A. (Albert), De Craen, A.J.M. (Anton J. M.), Houwing-Duistermaat, J.J. (Jeanine), Van Ommen, G.-J.B. (Gert-Jan B.), Cox, D.R. (David), Meurs, J.B.J. (Joyce) van, Beekman, M. (Marian), Reinders, M.J. (Marcel), Slagboom, P.E. (Eline)
المصدر: Blood vol. 127 no. 11, pp. 1512-1515
العلاقة: info:eu-repo/grantAgreement/EC/FP7/259679; http://repub.eur.nl/pub/89332Test; urn:hdl:1765/89332
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9دورية أكاديمية
المؤلفون: Bomer, N. (Nils), Hollander, W. (Wouter) den, Ramos, Y.F.M. (Yolande), Bos, S.D. (Steffan), Breggen, R. (Ruud) van der, Lakenberg, N. (Nico), Pepers, B.A. (Barry), Eeden, A.E. (Annelies) van, Darvishan, A. (Arash), Tobi, E.W. (Elmar), Duijnisveld, B.J. (Bouke), Akker, E.B. (Erik) van den, Heijmans, B.T. (Bastiaan), Roon-Mom, W.M.C. (Willeke) van, Verbeek, F.J. (Fons), Osch, G.J.V.M. (Gerjo) van, Nelissen, R.G.H.H. (Rob), Slagboom, P.E. (Eline), Meulenbelt, I. (Ingrid)
المصدر: Annals of the Rheumatic Diseases: an international peer-reviewed journal for health professionals and researchers in the rheumatic diseases
الوصف: Objectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid). Results: OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (ß=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (ß=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2a/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. Conclusions: Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.
وصف الملف: application/pdf
العلاقة: info:eu-repo/grantAgreement/EC/FP7/200800; info:eu-repo/grantAgreement/EC/FP7/259679; http://repub.eur.nl/pub/57776Test; urn:hdl:1765/57776
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10دورية أكاديمية
المؤلفون: Deelen, J. (Joris), Beekman, M. (Marian), Uh, H.-W. (Hae-Won), Broer, L. (Linda), Ayers, K.L. (Kristin), Tan, Q. (Qihua), Kamatani, Y. (Yoichiro), Bennet, A.M. (Anna Michaela), Tamm, R. (Riin), Trompet, S. (Stella), Guobjartsson, D.F. (Daníel), Flachsbart, F. (Friederike), Rose, G. (Giuseppina), Viktorin, A. (Alexander), Fischer, K. (Krista), Nygaard, M. (Marianne), Cordell, H.J. (Heather), Crocco, P. (Paolina), Akker, E.B. (Erik) van den, Böhringer, S. (Stefan), Helmer, Q. (Quinta), Nelson, C.P. (Christopher P.), Saunders, G.I. (Gary), Alver, M. (Maris), Andersen-Ranberg, K. (Karen), Breen, G. (Gerome), Breggen, R. (Ruud) van der, Caliebe, A. (Amke), Capri, Y. (Yline), Cevenini, E. (Elisa), Collerton, J.C. (Joanna), Dato, S. (Serena), Davies, K. (Karen), Ford, I. (Ian), Gampe, J. (Jutta), Garagnani, P. (Paolo), Geus, E.J.C. (Eco) de, Harrow, J. (Jennifer), Heemst, D. (Diana) van, Heijmans, B.T. (Bastiaan), Heinsen, F.-A. (Femke-Anouska), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Jeune, B. (Bernard), Jonsson, P.V. (Palmi), Lathrop, M. (Mark), Lechner, D. (Doris), Martin-Ruiz, C. (Carmen), Mcnerlan, S.E. (Susan), Mihailov, E. (Evelin), Montesanto, A. (Alberto), Mooijaart, S.P. (Simon), Murphy, A. (Anne), Nohr, C. (Christian), Paternoster, L. (Lavinia), Postmus, D. (Douwe), Rivadeneira Ramirez, F. (Fernando), Ross, O.A. (Owen), Salvioli, S. (Stefano), Sattar, N. (Naveed), Schreiber, S. (Stefan), Stefansson, H. (Hreinn), Stott, D.J. (David. J.), Tiemeier, H.W. (Henning), Uitterlinden, A.G. (André), Westendorp, R.G.J. (Rudi), Willemsen, G.A.H.M. (Gonneke), Samani, N.J. (Nilesh), Galan, P. (Pilar), Sorensen, H.G., Boomsma, D.I. (Dorret), Jukema, J.W. (Jan Wouter), Rea, D. (Dan), Passarino, G. (Giuseppe), Craen, A.J. (Anton) de, Christensen, K. (Kaare), Nebel, A. (Almut), Zwart, J-A. (John-Anker), Metspalu, A. (Andres), Magnusson, P.K. (Patrik), Blanché, H. (Hélène), Christiansen, L. (Lene), Kirkwood, J.M. (John), Duijn, C.M. (Cornelia) van, Franceschi, C. (Claudio), Houwing-Duistermaat, J.J. (Jeanine), Slagboom, P.E. (Eline)
المصدر: Human Molecular Genetics vol. 23 no. 16, pp. 4420-4432
الوصف: The genetic contribution to the variation in human lifespan is ~25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genomewide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR =1.10, P = 1.74 × 10-8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR =0.72, P = 3.40 × 10-36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decr
العلاقة: info:eu-repo/grantAgreement/EC/FP7/259679; http://repub.eur.nl/pub/54667Test; urn:hdl:1765/54667
