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3. Mannose-binding lectin genotype and phenotype in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial

Author

Mellbin, L.G., Hamsten, A., Malmberg, K., Steffensen, R., Ryden, L., Ohrvik, J., and Hansen, T.K.

Subjects
Medical research, Medicine, Experimental, Stroke (Disease) -- Genetic aspects -- Care and treatment, Heart attack -- Genetic aspects -- Care and treatment, Cardiac patients -- Care and treatment, Type 2 diabetes -- Genetic aspects -- Care and treatment, Diabetics -- Care and treatment, Lectins, Health
Abstract

OBJECTIVE--The present study characterizes mannose-binding lectin (MBL), an activator of the complement system and thereby important for inflammatory activation, in patients with diabetes and myocardial infarction. RESEARCH DESIGN AND METHODS--Serum [...]

Published
2010
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6. Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart

Author

Bartnik, M., Ryden, L., Malmberg, K., Ohrvik, J., Pyorala, K., Standl, E., Ferrari, R., Simoons, M., and Soler-Soler, J.

Subjects
Cardiovascular diseases -- Risk factors, Cardiovascular diseases -- Research, Cardiovascular diseases -- Diagnosis, Glucose tolerance tests -- Research, Glucose tolerance tests -- Usage, Health
Published
2007

8. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

STRAWBRIDGE RJ, DUPUIS J, PROKOPENKO I, BARKER A, AHLQVIST E, RYBIN D, PETRIE JR, TRAVERS ME, BOUATIA-NAJI N, DIMAS AS, NICA A, WHEELER E, CHEN H, VOIGHT BF, TANEERA J, KANONI S, PEDEN JF, TURRINI F, GUSTAFSSON S, ZABENA C, ALMGREN P, BARKER DJ, BARNES D, DENNISON EM, ERIKSSON JG, ERIKSSON P, EURY E, FOLKERSEN L, FOX CS, FRAYLING TM, GOEL A, GU HF, HORIKOSHI M, ISOMAA B, JACKSON AU, JAMESON KA, KAJANTIE E, KERR-CONTE J, KUULASMAA T, KUUSISTO J, LOOS RJ, LUAN J, MAKRILAKIS K, MANNING AK, MARTÍNEZ-LARRAD MT, NARISU N, NASTASE MANNILA M, OHRVIK J, OSMOND C, PASCOE L, PAYNE F, SAYER AA, SENNBLAD B, SILVEIRA A, STANCÁKOVÁ A, STIRRUPS K, SWIFT AJ, SYVÄNEN AC, TUOMI T, VAN 'T HOOFT FM, WALKER M, WEEDON MN, XIE W, ZETHELIUS B, DIAGRAM CONSORTIUM, GIANT CONSORTIUM, MANUNTA P, MUTHER CONSORTIUM, CARDIOGRAM CONSORTIUM, C4D CONSORTIUM, ONGEN H, MÄLARSTIG A, HOPEWELL JC, SALEHEEN D, CHAMBERS J, PARISH S, DANESH J, KOONER J, OSTENSON CG, LIND L, COOPER CC, SERRANO-RÍOS M, FERRANNINI E, FORSEN TJ, CLARKE R, FRANZOSI MG, SEEDORF U, WATKINS H, FROGUEL P, JOHNSON P, DELOUKAS P, COLLINS FS, LAAKSO M, DERMITZAKIS ET, BOEHNKE M, MCCARTHY MI, WAREHAM NJ, GROOP L, PATTOU F, GLOYN AL, DEDOUSSIS GV, LYSSENKO V, MEIGS JB, BARROSO I, WATANABE RM, INGELSSON E, LANGENBERG C, HAMSTEN A, FLOREZ JC, Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, BOUATIA-NAJI, N, Dimas, A, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, C, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, KERR-CONTE, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, MARTÍNEZ-LARRAD, Mt, Narisu, N, NASTASE MANNILA, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, VAN 'T HOOFT, Fm, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Manunta, P, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, SERRANO-RÍOS, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, F, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, and Florez, Jc

Published
2011

9. Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart

Author

Lenzen M., Ryden L., Ohrvik J., Bartnik M., Malmberg K., Scholte Op Reimer W., Simoons M. L., Andresen D., Camm A. J., Davies W., Capucci A., Levy S., Olsson B., Aliot E., Breithardt G., Cobbe S., Le Heuzey J. -Y., Santini M., Vardas P., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Blanc J. -J., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Graham I., Shelley E., Behar S., Maggioni A., Goncalves L., Grabauskiene V., Asmussen I., Deckers J., Stepinska J., Mareev V., Vasiljevic Z., Riecansky I., Kenda M. F., Alonso A., Lopez-Sendon J. L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Schofield P., Wood D., Battler A., Boersma E., Komajda M., McGregor K., Mulder B., Priori S., Vahanian A., Wijns W., Sanofi-Aventis, Grigoryan S. V., Apetyan I., Aroyan S., Azarapetyan L., Anvari A., Gottsauner-Wolf M., Pfaffenberger S., Aydinkoc K., Kalla K., Penka M., Drexel H., Langer P., Pierard L. A., Legrand V., Blommaert D., Schroeder E., Mancini I., Geelen P., Brugada P., De Zutter M., Vrints C., Vercammen M., Morissens M., Borisov B., Petrov V. A., Marinova M., Assen A., Goudev R., Peychev Y., Stoyanovsky V., Stoynev E., Kranjcevic S., Moutiris J., Ioannides M., Evequoz D., Spacilova J., Novak M., Eisenberger M., Mullerova J., Kautzner J., Riedlbauchova L., Petru` J., Taborsky M., Cappelen H., Sharaf Y. A., Ibrahim B. S. S., Tammam K., Saad A., Elghawaby H., Sherif H. Z., Farouk H., Mielke A., Engelen M., Kirchhof P., Zimmermann P., Aviles F. F., Rubio J., Malpartida F., Corona M., Sanchez L. T., Miguel J., Herrera L., Quesada A., Garcia A. J. M., Gonzalez C. S., Juango M. S. A., Berjon-Reyero J., Alegret J. M., Fernandez J. M. C., Carrascosa C., Romero R. A. F., Lara M. G., Sendon J. L. L., de Diego J. J. G., Martin L. S., Irurita M., Guttierez N. H., Rubio J. R. S., Antorrena I., Paves A. B., Salvador A., Orriach M. D., Garcia A. A., Epelde F., Martinez V. B., Sanchez A. B., Galvez C. P., Rivero R. F., Madrid A. H., Baron-Esquivias G., Peinado R., Guindal J. A. G., Vera T. R., Fernandez E. L., Gayan R., Garcia J., Bodegas A., Lopez J. T., Florez J. M., Cabezas C. L., de Castroviejo E. V. R., Bellido J. M., Ruiz M. E., Savolainen K., Nieminen M., Toivonen L., Syvanne M., Pietila M., Galley D., Beltra C., Gay A., Daubert J. C., Lecocq G., Poulain C., Cleland J. G. F. C., Shelton R., Choudhury A., Abuladze G., Jashi I., Tsiavou A., Giamouzis G., Dagres N., Kostopoulou A., Tsoutsanis D., Stefanadis C., Latsios G., Vogiatzis I., Gotsis A., Bozia P., Karakiriou M., Koulouris S., Parissis J., Kostakis G., Kouris N., Kontogianni D., Athanasios K., Douras A., Tsanakis T., Marketou M., Patsourakos N., Czopf L., Halmosi R., Preda I., Csoti E., Badics A., Strasberg B., Freedberg N. A., Katz A., Zalzstein E., Grosbard A., Goldhammer E., Nahir M., Epstein M., Vider I., Luria D., Mandelzweig L., Aloisi B., Cavallaro A., Antonielli E., Doronzo B., Pancaldo D., Mazzola C., Buontempi L., Calvi V., Giuffrida G., Figlia A., Ippolito F., Gelmini G. -P., Gaibazzi N., Ziacchi V., De Tommasi F., Lombardi F., Fiorentini C., Terranova P., Maiolino P., Albunni M., Pinna-Pintor P., Fumagalli S., Masotti G., Boncinelli L., Rossi D., Santoro G. M., Fioranelli M., Naccarella F., Maranga S. S., Lepera G., Bresciani B., Seragnoli E., Forti M. C., Cortina V., Baciarello G., Cicconetti P., Lax A., Vitali F., Igidbashian D., Scarpino L., Terrazzino S., Tavazzi L., Cantu F., Pentimalli F., Novo S., Coppola G., Zingarini G., Ambrozio G., Moruzzi P., Callegari S., Saccomanno G., Russo P., Carbonieri E., Paino A., Zanetta M., Barducci E., Cemin R., Rauhe W., Pitscheider W., Meloni M., Marchi S. M., Di Gennaro M., Calcagno S., Squaratti P., Quartili F., Bertocchi P., De Martini M., Mantovani G., Komorovsky R., Desideri A., Celegon L., Tarantini L., Catania G., Lucci D., Bianchini F., Puodziukynas A., Kavoliuniene A., Barauskiene V., Aidietis A., Barysiene J., Vysniauskas V., Zukauskiene I., Kazakeviciene N., Georgievska-Ismail L., Poposka L., Vataman E., Grosu A. A., de Swart E., Jansen C., Brons R., Tebbe H., van Hoogenhuyze D. C. A., Veerhoek M. J., Kamps M., Haan D., van Rijn N., Bootsma A., Baur L., van den A., Fransen H., Eurlings L., Meeder J., De Boer M. J., Winter J., Broers H., Werter C., Bijl M., Versluis S., Milkowska M., Wozakowska-Kaplon B., Janion M., Lepska L., Swiatecka G., Kokowicz P., Cybulski J., Gorecki A., Szulc M., Rekosz J., Manczak R., Wnuk-Wojnar A. -M., Trusz-Gluza M., Rybicka-Musialik A., Myszor J., Szpajer M., Cymerman K., Sadowski J., Sniezek-Maciejewska M., Ciesla-Dul M., Gorkiewicz-Kot I., Grodzicki T., Rewiuk K., Kubik L., Lewit J., de Sousa J. M. F. R., Ferreira R., Freitas A., Morais J. C. A., Pires R., Gomes M. J. V., Gago P., Candeias R. A. C., Nunes L., Sa J. V. M., Ventura M., de Oliveira M., Alves L. B., Bostaca I., Olariu C. T., Dan G. A., Dan A., Podoleanu C., Frigy A., Georgescu G. I. M., Arsenescu C., Statescu C., Sascau R., Dimitrascu D. L., Rancea R., Shubik Y. V., Duplyakov D., Shalak M., Danielyan M., Galyavich A., Zakirova V., Hatala R., Kaliska G., Kmec J., Zupan I., Tasie` J., Vokac D., Edvardsson N., Poci D., Gamra H., Denguir H., Sepetoglu A., Arat-Ozkan A., Orynchak M., Paliy E., Vakalyuk I., Malidze D., Prog R., Yabluchansky M. I., Makienko N. V., Potpara T., Knezevic S., Randjelovic M., Lenzen M., Ryden L., Ohrvik J., Bartnik M., Malmberg K., Scholte Op Reimer W., Simoons M.L., Andresen D., Camm A.J., Davies W., Capucci A., Levy S., Olsson B., Aliot E., Breithardt G., Cobbe S., Le Heuzey J.-Y., Santini M., Vardas P., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Blanc J.-J., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Graham I., Shelley E., Behar S., Maggioni A., Goncalves L., Grabauskiene V., Asmussen I., Deckers J., Stepinska J., Mareev V., Vasiljevic Z., Riecansky I., Kenda M.F., Alonso A., Lopez-Sendon J.L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Schofield P., Wood D., Battler A., Boersma E., Komajda M., McGregor K., Mulder B., Priori S., Vahanian A., Wijns W., Sanofi-Aventi, Grigoryan S.V., Apetyan I., Aroyan S., Azarapetyan L., Anvari A., Gottsauner-Wolf M., Pfaffenberger S., Aydinkoc K., Kalla K., Penka M., Drexel H., Langer P., Pierard L.A., Legrand V., Blommaert D., Schroeder E., Mancini I., Geelen P., Brugada P., De Zutter M., Vrints C., Vercammen M., Morissens M., Borisov B., Petrov V.A., Marinova M., Assen A., Goudev R., Peychev Y., Stoyanovsky V., Stoynev E., Kranjcevic S., Moutiris J., Ioannides M., Evequoz D., Spacilova J., Novak M., Eisenberger M., Mullerova J., Kautzner J., Riedlbauchova L., Petru` J., Taborsky M., Cappelen H., Sharaf Y.A., Ibrahim B.S.S., Tammam K., Saad A., Elghawaby H., Sherif H.Z., Farouk H., Mielke A., Engelen M., Kirchhof P., Zimmermann P., Aviles F.F., Rubio J., Malpartida F., Corona M., Sanchez L.T., Miguel J., Herrera L., Quesada A., Garcia A.J.M., Gonzalez C.S., Juango M.S.A., Berjon-Reyero J., Alegret J.M., Fernandez J.M.C., Carrascosa C., Romero R.A.F., Lara M.G., Sendon J.L.L., de Diego J.J.G., Martin L.S., Irurita M., Guttierez N.H., Rubio J.R.S., Antorrena I., Paves A.B., Salvador A., Orriach M.D., Garcia A.A., Epelde F., Martinez V.B., Sanchez A.B., Galvez C.P., Rivero R.F., Madrid A.H., Baron-Esquivias G., Peinado R., Guindal J.A.G., Vera T.R., Fernandez E.L., Gayan R., Garcia J., Bodegas A., Lopez J.T., Florez J.M., Cabezas C.L., de Castroviejo E.V.R., Bellido J.M., Ruiz M.E., Savolainen K., Nieminen M., Toivonen L., Syvanne M., Pietila M., Galley D., Beltra C., Gay A., Daubert J.C., Lecocq G., Poulain C., Cleland J.G.F.C., Shelton R., Choudhury A., Abuladze G., Jashi I., Tsiavou A., Giamouzis G., Dagres N., Kostopoulou A., Tsoutsanis D., Stefanadis C., Latsios G., Vogiatzis I., Gotsis A., Bozia P., Karakiriou M., Koulouris S., Parissis J., Kostakis G., Kouris N., Kontogianni D., Athanasios K., Douras A., Tsanakis T., Marketou M., Patsourakos N., Czopf L., Halmosi R., Preda I., Csoti E., Badics A., Strasberg B., Freedberg N.A., Katz A., Zalzstein E., Grosbard A., Goldhammer E., Nahir M., Epstein M., Vider I., Luria D., Mandelzweig L., Aloisi B., Cavallaro A., Antonielli E., Doronzo B., Pancaldo D., Mazzola C., Buontempi L., Calvi V., Giuffrida G., Figlia A., Ippolito F., Gelmini G.-P., Gaibazzi N., Ziacchi V., De Tommasi F., Lombardi F., Fiorentini C., Terranova P., Maiolino P., Albunni M., Pinna-Pintor P., Fumagalli S., Masotti G., Boncinelli L., Rossi D., Santoro G.M., Fioranelli M., Naccarella F., Maranga S.S., Lepera G., Bresciani B., Seragnoli E., Forti M.C., Cortina V., Baciarello G., Cicconetti P., Lax A., Vitali F., Igidbashian D., Scarpino L., Terrazzino S., Tavazzi L., Cantu F., Pentimalli F., Novo S., Coppola G., Zingarini G., Ambrozio G., Moruzzi P., Callegari S., Saccomanno G., Russo P., Carbonieri E., Paino A., Zanetta M., Barducci E., Cemin R., Rauhe W., Pitscheider W., Meloni M., Marchi S.M., Di Gennaro M., Calcagno S., Squaratti P., Quartili F., Bertocchi P., De Martini M., Mantovani G., Komorovsky R., Desideri A., Celegon L., Tarantini L., Catania G., Lucci D., Bianchini F., Puodziukynas A., Kavoliuniene A., Barauskiene V., Aidietis A., Barysiene J., Vysniauskas V., Zukauskiene I., Kazakeviciene N., Georgievska-Ismail L., Poposka L., Vataman E., Grosu A.A., de Swart E., Jansen C., Brons R., Tebbe H., van Hoogenhuyze D.C.A., Veerhoek M.J., Kamps M., Haan D., van Rijn N., Bootsma A., Baur L., van den A., Fransen H., Eurlings L., Meeder J., De Boer M.J., Winter J., Broers H., Werter C., Bijl M., Versluis S., Milkowska M., Wozakowska-Kaplon B., Janion M., Lepska L., Swiatecka G., Kokowicz P., Cybulski J., Gorecki A., Szulc M., Rekosz J., Manczak R., Wnuk-Wojnar A.-M., Trusz-Gluza M., Rybicka-Musialik A., Myszor J., Szpajer M., Cymerman K., Sadowski J., Sniezek-Maciejewska M., Ciesla-Dul M., Gorkiewicz-Kot I., Grodzicki T., Rewiuk K., Kubik L., Lewit J., de Sousa J.M.F.R., Ferreira R., Freitas A., Morais J.C.A., Pires R., Gomes M.J.V., Gago P., Candeias R.A.C., Nunes L., Sa J.V.M., Ventura M., de Oliveira M., Alves L.B., Bostaca I., Olariu C.T., Dan G.A., Dan A., Podoleanu C., Frigy A., Georgescu G.I.M., Arsenescu C., Statescu C., Sascau R., Dimitrascu D.L., Rancea R., Shubik Y.V., Duplyakov D., Shalak M., Danielyan M., Galyavich A., Zakirova V., Hatala R., Kaliska G., Kmec J., Zupan I., Tasie` J., Vokac D., Edvardsson N., Poci D., Gamra H., Denguir H., Sepetoglu A., Arat-Ozkan A., Orynchak M., Paliy E., Vakalyuk I., Malidze D., Prog R., Yabluchansky M.I., Makienko N.V., Potpara T., Knezevic S., Randjelovic M., and Cardiology

Subjects
Blood Glucose, Male, medicine.medical_specialty, Diabetic Angiopathie, Prognosi, Impaired glucose regulation, Euro Heart Survey, Myocardial Infarction, Coronary Artery Disease, Diabete, Follow-Up Studie, Coronary artery disease, Impaired glucose tolerance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, Humans, Survival analysis, Aged, business.industry, Hazard ratio, Middle Aged, medicine.disease, Impaired fasting glucose, Prognosis, Survival Analysis, Stroke, Endocrinology, Blood sugar regulation, Female, Cardiology and Cardiovascular Medicine, business, Complication, Diabetic Angiopathies, Human, Follow-Up Studies
Abstract

Aims: Although diabetes is known to be a major contributor to cardiovascular diseases, as well as an independent predictor for adverse outcomes in patients with coronary artery disease (CAD), information on the prognosis of patients with CAD and newly diagnosed diabetes or impaired glucose regulation (IGR) is scarce. The objective of this study was to explore 1-year outcome in relation to different glucometabolic states of patients participating in the Euro Heart Survey on diabetes and the heart. Methods and results: In 4676 out of 4961 patients, information on the relation between 1-year outcome and glucometabolic state, which was based on oral glucose tolerance test (OGTT) or fasting glucose plasma, was available. A normal glucose metabolism was identified in 947 patients, IGR (impaired fasting glucose or impaired glucose tolerance) in 1116 patients, and diabetes in 1877 patients of whom 1425 were previously diagnosed and 452 newly diagnosed. In total, 736 patients could not be classified, as no OGTT or fasting plasma glucose was performed. Previously recognized and newly detected diabetes was associated with an increased risk of 1-year mortality when compared with patients with normal glucose regulation [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.5-3.8 and HR 2.0, 95% CI 1.1-3.6, respectively)]. IGR, however, could not be identified as an independent predictor for 1-year mortality (HR 1.1, 95% CI 0.6-1.9). Conclusion: This study confirmed that patients with CAD and known diabetes are at high risk for mortality and cardiovascular events and demonstrated that patients with newly diagnosed diabetes are at intermediate risk for adverse outcomes. IGR, however, could not be identified as an independent predictor for adverse outcomes during the 1-year follow-up period. © The European Society of Cardiology 2006. All rights reserved.

Published
2006

10. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart

Author

Bartnik M., Ryden L., Ferrari R., Malmberg K., Pyorala K., Simoons M., Standl E., Soler-Soler J., Ohrvik J., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Shelley E., Behar S., Maggioni A., Grabauskiene V., Deckers J., Asmussen I., Stepinska J., Goncalves L., Mareev V., Riecansky I., Kenda M. F., Lopez-Sendon J. L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Wood D., Alonso A., Boersma E., Crijns H., Gitt A., McGregor K., Mulder B., Nieminen M., Priori S., Tavazzi L., Vahanian A., Vardas P., Wijns W., Aydinkoc K., Spenka M., Wascher T. C., Sourij H., Dusko V., Radivojevic M., Goudev A. R., Tzekova M. L., Simeonov P., Pentchev V., Yotov Y., Torbova S. G., Stoyanovsky V., Stoynev E., Ostrovsky I., Moroz-Vadalazhskaya N., Cocco G., Antoniades L., Kyprianou D., Florian J., Yaghmaee S., Kvasnika J., Krizova A., Rosolova H., Petrlova B., Borivoj S., Poloczek M., Niebauer J., Drechsler K., Sechtem U., Vogelsberg H., Blank E., Breithardt G., Wedekind H., Ksoll B., Laks T., Ambos A., Tupits H., Kalinina L., Anton L., Planken U., Saad A., Andraos A. W., Shafy S. A., Metias B. D., Ibrahim M. A., Tantawi H., Lopez Bescos L., Huelmos A., Fernandez Aviles F., De La Fuente Galan L., Vinuela P. T., Velasco Rami J. A., Soriano F. R., Soledad Alcasena-Juango M., Berjon-Reyero J., Orcajo N. A., Garcia Calabozo R., Masia R., Sala J., Rohlfs I., De Diego J. J. G., Martin L. S., De El Escorial S. L., Latasa M. I., Miranda I. A., Garcia A. A., Andrade M. A., Conde A. C., Ortuno F. M., Climent V., Gonzalo F. E., Martinez V. B., Ortega J. A. R., De Alicante S. J., Galvez C. P., Rivero R. F., Belsue F. V., Rubio J. R. S., Escorihuela A. L., Gonzalez V. B., Iglesias F. C., Minguezy Enriquez De Salamanca I., Rejon F. R., Cobo A. L., Tarin N., Savolainen K., Nieminen M. S., Syvanne M., Pietila M., Mustonen J., Juntunen I., Marco J., Gilliume S., Bassand J. P., Espinosa D. P., Adgey J., Brien A. O., Cleland J. G. F., Reddy D. H., Pathmanathan R. K., Fairbrother K. L., Tabidze G., Tvildiani L., Chumburidze V., Kikalishvili T., Kurashvili R., Khelashvili M., Anifantakis A., Voudris V., Tsiavou N., Toutouzas P. K., Latsios G., Richter D., Karabinos I. K., Giannopoulou G., Gotsis A., Bozia P., Savvopoulou A., Kotsis V., Bozas G., Efstathios M., Koulouris S., Vardas P. E., Marketou M., Papadopoulos G., Patsourakos N., Anastassios L., Keltai M., Ostor E., Borbola J., Liptia C., Lupkovics G., Barnabas N., Matoltsy A., Hontvari L., Sido Z., Szamosi K., Forster T., Nemes A., Szakal I., Topal L., Badics A., Engelthaler G., Nagy A., Di Sciascio G., Cecilia Scimia M., Ambrosio D., Pesola A., Robiglio L., Aloisi B., Cavallaro A., Mazzola C., Ciconte V., Giancotti D., Naccarella F., Maranga S. S., Lepera G., Sergnoli E., Zanetti M., Causarano A., Zoli V., Novo S., Coppola G., Evola G., Tanzi P., Colecchia D., Macali L., Terrana R., Zanetta M., Vegis D., Bernardi D., Tramarin R., Opasich C., Slapikas R., Gustiene O., Petrulioniene Z., Kovaite M., Georgievska-Ismail L., Poposka L., Davceva-Pavlovska J., Peovska I., Bosevski M., Deckers J. W., Jansen C. G., De Boer M. J., Van Rijn N., Brons R., Bootsma A., Van Hoogenhuyze D. C. A., Leenders C. M., Veerhoek M. J., Haan D., Baur L., Van Den Dool A., Fransen H., Nieuwlaat R., Widdershofen J. W. M. G., Broers H., Werter C., Bijl M., Koppelaar C., Ruzyllo W., Przyluski J., Kepka C., Maczynska R., Krzciuk M., Kubicka B., Dluzniewski M., Krzyzak P., Supinski W., Myczka T., Schulowska A., Zinka E., Gsecki M., Budaj A., Kokowicz P., Opolski G., Roik M., Rekosz J., Biegajlo J., Kleinrok A., Czochra W., Rynkiewicz A., Grzybowski A., Bellwon J., De Oliveira E. I., Nobrega J., Ferreira R., Baptista S., Veloso Gomes M. J., Candeias R. A. C., Rufino E., Providencia L. A., Monteiro P., Carrageta M., Bento L., Albert I., Svensson A. M., Petersson A., Torelund G., Patel H., Hage C., Lidin M., Lainscak M., Dernic J., Ambrozic J., Mocnik F. S., Glavnmik A., Fras Z., Latific-Jasnic D., Bunc M., Klemenc M., Lobnik A., Kompara G., Koval O. A., Prog R. V., Tkachenko J., Knyazkova I., Tasic I., Cardiology, Bartnik M., Ryden L., Ferrari R., Malmberg K., Pyorala K., Simoons M., Standl E., Soler-Soler J., Ohrvik J., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Shelley E., Behar S., Maggioni A., Grabauskiene V., Deckers J., Asmussen I., Stepinska J., Goncalves L., Mareev V., Riecansky I., Kenda M.F., Lopez-Sendon J.L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Wood D., Alonso A., Boersma E., Crijns H., Gitt A., McGregor K., Mulder B., Nieminen M., Priori S., Tavazzi L., Vahanian A., Vardas P., Wijns W., Aydinkoc K., Spenka M., Wascher T.C., Sourij H., Dusko V., Radivojevic M., Goudev A.R., Tzekova M.L., Simeonov P., Pentchev V., Yotov Y., Torbova S.G., Stoyanovsky V., Stoynev E., Ostrovsky I., Moroz-Vadalazhskaya N., Cocco G., Antoniades L., Kyprianou D., Florian J., Yaghmaee S., Kvasnika J., Krizova A., Rosolova H., Petrlova B., Borivoj S., Poloczek M., Niebauer J., Drechsler K., Sechtem U., Vogelsberg H., Blank E., Breithardt G., Wedekind H., Ksoll B., Laks T., Ambos A., Tupits H., Kalinina L., Anton L., Planken U., Saad A., Andraos A.W., Shafy S.A., Metias B.D., Ibrahim M.A., Tantawi H., Lopez Bescos L., Huelmos A., Fernandez Aviles F., De La Fuente Galan L., Vinuela P.T., Velasco Rami J.A., Soriano F.R., Soledad Alcasena-Juango M., Berjon-Reyero J., Orcajo N.A., Garcia Calabozo R., Masia R., Sala J., Rohlfs I., De Diego J.J.G., Martin L.S., De El Escorial S.L., Latasa M.I., Miranda I.A., Garcia A.A., Andrade M.A., Conde A.C., Ortuno F.M., Climent V., Gonzalo F.E., Martinez V.B., Ortega J.A.R., De Alicante S.J., Galvez C.P., Rivero R.F., Belsue F.V., Rubio J.R.S., Escorihuela A.L., Gonzalez V.B., Iglesias F.C., Minguezy Enriquez De Salamanca I., Rejon F.R., Cobo A.L., Tarin N., Savolainen K., Nieminen M.S., Syvanne M., Pietila M., Mustonen J., Juntunen I., Marco J., Gilliume S., Bassand J.P., Espinosa D.P., Adgey J., Brien A.O., Cleland J.G.F., Reddy D.H., Pathmanathan R.K., Fairbrother K.L., Tabidze G., Tvildiani L., Chumburidze V., Kikalishvili T., Kurashvili R., Khelashvili M., Anifantakis A., Voudris V., Tsiavou N., Toutouzas P.K., Latsios G., Richter D., Karabinos I.K., Giannopoulou G., Gotsis A., Bozia P., Savvopoulou A., Kotsis V., Bozas G., Efstathios M., Koulouris S., Vardas P.E., Marketou M., Papadopoulos G., Patsourakos N., Anastassios L., Keltai M., Ostor E., Borbola J., Liptia C., Lupkovics G., Barnabas N., Matoltsy A., Hontvari L., Sido Z., Szamosi K., Forster T., Nemes A., Szakal I., Topal L., Badics A., Engelthaler G., Nagy A., Di Sciascio G., Cecilia Scimia M., Ambrosio D., Pesola A., Robiglio L., Aloisi B., Cavallaro A., Mazzola C., Ciconte V., Giancotti D., Naccarella F., Maranga S.S., Lepera G., Sergnoli E., Zanetti M., Causarano A., Zoli V., Novo S., Coppola G., Evola G., Tanzi P., Colecchia D., Macali L., Terrana R., Zanetta M., Vegis D., Bernardi D., Tramarin R., Opasich C., Slapikas R., Gustiene O., Petrulioniene Z., Kovaite M., Georgievska-Ismail L., Poposka L., Davceva-Pavlovska J., Peovska I., Bosevski M., Deckers J.W., Jansen C.G., De Boer M.J., Van Rijn N., Brons R., Bootsma A., Van Hoogenhuyze D.C.A., Leenders C.M., Veerhoek M.J., Haan D., Baur L., Van Den Dool A., Fransen H., Nieuwlaat R., Widdershofen J.W.M.G., Broers H., Werter C., Bijl M., Koppelaar C., Ruzyllo W., Przyluski J., Kepka C., Maczynska R., Krzciuk M., Kubicka B., Dluzniewski M., Krzyzak P., Supinski W., Myczka T., Schulowska A., Zinka E., Gsecki M., Budaj A., Kokowicz P., Opolski G., Roik M., Rekosz J., Biegajlo J., Kleinrok A., Czochra W., Rynkiewicz A., Grzybowski A., Bellwon J., De Oliveira E.I., Nobrega J., Ferreira R., Baptista S., Veloso Gomes M.J., Candeias R.A.C., Rufino E., Providencia L.A., Monteiro P., Carrageta M., Bento L., Albert I., Svensson A.M., Petersson A., Torelund G., Patel H., Hage C., Lidin M., Lainscak M., Dernic J., Ambrozic J., Mocnik F.S., Glavnmik A., Fras Z., Latific-Jasnic D., Bunc M., Klemenc M., Lobnik A., Kompara G., Koval O.A., Prog R.V., Tkachenko J., Knyazkova I., and Tasic I.

Subjects
Adult, Blood Glucose, Male, Diabetes mellitu, medicine.medical_specialty, Abnormal glucose, Diabetic Angiopathie, Oral glucose tolerance test, Coronary Artery Disease, Impaired glucose tolerance, Coronary artery disease, SDG 3 - Good Health and Well-being, Risk Factors, Diabetes mellitus, Internal medicine, Epidemiology, medicine, Humans, In patient, Aged, Glucose tolerance test, medicine.diagnostic_test, business.industry, Glucose Tolerance Test, Middle Aged, medicine.disease, Surgery, Europe, Diabetes Mellitus, Type 2, Blood sugar regulation, Female, Cardiology and Cardiovascular Medicine, business, Diabetic Angiopathies, Human
Abstract

Aim The objective behind the Euro Heart Survey on diabetes and the heart was to study the prevalence of abnormal glucose regulation in adult patients with coronary artery disease (CAD). Methods and results The survey engaged 110 centres in 25 countries recruiting 4196 patients referred to a cardiologist due to CAD out of whom 2107 were admitted on an acute basis and 2854 had an elective consultation. Patient data were collected via a web-based case record form. An oral glucose tolerance test (OGTT) was used for the characterisation of the glucose metabolism. Thirty-one per cent of the patients had diabetes. An OGTT was performed on the 1920 patients without known diabetes, of whom 923 had acute and 997 had a stable manifestation of CAD, respectively. In patients with acute CAD, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group these proportions were 37% and 14%. Conclusion This survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be a routine procedure. The knowledge of glucometabolic state among these patients should influence their future management because it has great potential to improve the outcome.

Published
2004

11. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, Nica A, Wheeler E, Chen H, Voight BF, Taneera J, Kanoni S, Peden JF, Turrini F, Gustafsson S, Zabena C, Almgren P, Barker DJ, Barnes D, Dennison EM, Eriksson JG, Eriksson P, Eury E, Folkersen L, Fox CS, Frayling TM, Goel A, Gu HF, Horikoshi M, Isomaa B, Jackson AU, Jameson KA, Kajantie E, Kerr-Conte J, Kuulasmaa T, Kuusisto J, Loos RJ, Luan J, Makrilakis K, Manning AK, Martínez-Larrad MT, Narisu N, Nastase Mannila M, Ohrvik J, Osmond C, Pascoe L, Payne F, Sayer AA, Sennblad B, Silveira A, Stancáková A, Stirrups K, Swift AJ, Syvänen AC, Tuomi T, van 't Hooft FM, Walker M, Weedon MN, Xie W, Zethelius B, DIAGRAM Consortium, GIANT Consortium, Mulić, Rosanda, MuTHER Consortium, CARDIoGRAM Consortium, and C4D Consortium, Ongen H, Mälarstig A, Hopewell JC, Saleheen D, Chambers J, Parish S, Danesh J, Kooner J, Ostenson CG, Lind L, Cooper CC, Serrano-Ríos M, Ferrannini E, Forsen TJ, Clarke R, Franzosi MG, Seedorf U, Watkins H, Froguel P, Johnson P, Deloukas P, Collins FS, Laakso M, Dermitzakis ET, Boehnke M, McCarthy MI, Wareham NJ, Groop L, Pattou F, Gloyn AL, Dedoussis GV, Lyssenko V, Meigs JB, Barroso I, Watanabe RM, Ingelsson E, Langenberg C, Hamsten A, Florez JC.

Subjects
obesity, genetic variants, proinsulin, endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE:Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10, 701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16, 378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88 ; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

12. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. 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B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

15. Mannose-binding lectin geno- and phenotype in patients with type 2 diabetes and myocardial infarction -a report from the DIGAMI 2 trial

Author

Mellbin, L G, Hamsten, A, Malmberg, K, Steffensen, Rudi Nora, Rydén, L, Ohrvik, J, and Hansen, Troels Krarup

Subjects
chemical and pharmacologic phenomena, bacterial infections and mycoses
Abstract

Udgivelsesdato: 2010-Aug-6 AbstractObjective: The present study characterizes mannose-binding lectin (MBL), an activator of the complement system and thereby important for inflammatory activation, in patients with diabetes and myocardial infarction. Research Design and Methods: Serum (S)-MBL was determined at hospital admission in 387 patients with type 2 diabetes (median age 70 years; males 68%) with myocardial infarction, while genotyping was performed in 287 patients. Cardiovascular events (cardiovascular mortality and non-fatal MI or stroke) were recorded during 2.5 years. Results: Median S-MBL was 1212 mug/l (IQR 346-2681 mug/l). Fifty-four percent in the geno/phenotype subgroup had a high-coding (median S-MBL=2658 mug/l; IQR 1715-3829) and 46% a low-coding MBL genotype (median S-MBL=373mug/l; IQR 100-765). S-MBL did not correlate with age, BMI, creatinine clearance, glucose or HbA1c. Cardiovascular events occurred in 136 (35%) patients. S-MBL did not predict events in univariable analyses (HR 0.93; CI 95% 0.85-1.01;p=0.09). In unadjusted analyses, the risk of events was lower in patients with a high genotype and S-MBL above the median for their genotype (HR 0.49; 95% CI 0.26-0.92; p= 0.026) than for patients with a low genotype and S-MBL below the median for their genotype. The prediction capacity of the geno- and phenotype model was of borderline significance in adjusted Cox regression. Conclusions: Patients with type 2 diabetes and myocardial infarction have MBL genotypes that are similar to those known in the general population. The combination of a low-coding MBL genotype with a low S-MBL appears to be prognostically unfavorable, but the association is blunted by traditional risk markers.

Published
2010

24. Plasma CD93 concentration is a potential novel biomarker for coronary artery disease

Author

Malarstig, A., Silveira, A., Wagsater, D., Ohrvik, J., Backlund, A., Samnegård, Ann, Khademi, M., Hellenius, M. -L, Leander, K., Olsson, T., Uhlén, Mathias, de Faire, U., Eriksson, P., Hamsten, A., Malarstig, A., Silveira, A., Wagsater, D., Ohrvik, J., Backlund, A., Samnegård, Ann, Khademi, M., Hellenius, M. -L, Leander, K., Olsson, T., Uhlén, Mathias, de Faire, U., Eriksson, P., and Hamsten, A.

Abstract

Objectives. A common nonsynonymous single nucleotide polymorphism (SNP) in the CD93 gene (rs3746731, Pro541Ser) has been associated with risk of coronary artery disease (CAD). CD93 is a transmembrane glycoprotein, which is detectable in soluble form in human plasma. We investigated whether the concentration of soluble CD93 in plasma is related to risk of myocardial infarction (MI) and CAD, using a case-control study of premature MI (n = 764) and a nested case-control analysis of a longitudinal cohort study of 60-year-old subjects (analysis comprising 844 of 4232 subjects enrolled at baseline). In addition, SNPs in the CD93 gene were studied in relation to plasma CD93 concentration and CD93 mRNA expression. Methods and Results. A sensitive and specific enzyme-linked immunosorbent assay was established for determination of the plasma CD93 concentration. Subjects were divided into three groups according to tertiles of the distribution of CD93 concentration. Lower odds ratios for risk of MI and incidence of CAD were observed in the middle CD93 tertile (142-173 mu g L(-1)): odds ratio (95% confidence interval), 0.69 (0.49-0.97) and 0.61 (0.40-0.94), respectively. These associations were independent of traditional CAD risk factors. The minor allele of a SNP in the 3' untranslated region of CD93(rs2749812) was associated with increased plasma CD93 concentrations (P = 0.03) and increased CD93 mRNA expression levels (P = 0.02). Conclusion. The results of the present study suggest that the concentration of soluble CD93 in plasma is a potential novel biomarker for CAD, including MI.

Published
2011
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25. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., Wallace, C., Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., and Wallace, C.

Abstract

Contains fulltext : 98050.pdf (publisher's version ) (Open Access), Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular f

Published
2011

26. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J.R., Travers, M.E., Bouatia-Naji, N., Dimas, A.S., Nica, A., Wheeler, E., Chen, H., Voight, B.F., Taneera, J., Kanoni, S., Peden, J.F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D.J., Barnes, D., Dennison, E.M., Eriksson, J.G., Eriksson, P., Eury, E., Folkersen, L., Fox, C.S., Frayling, T.M., Goel, A., Gu, H.F., Horikoshi, M., Isomaa, B., Jackson, A.U., Jameson, K.A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R.J., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., et al., Strawbridge, R.J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J.R., Travers, M.E., Bouatia-Naji, N., Dimas, A.S., Nica, A., Wheeler, E., Chen, H., Voight, B.F., Taneera, J., Kanoni, S., Peden, J.F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D.J., Barnes, D., Dennison, E.M., Eriksson, J.G., Eriksson, P., Eury, E., Folkersen, L., Fox, C.S., Frayling, T.M., Goel, A., Gu, H.F., Horikoshi, M., Isomaa, B., Jackson, A.U., Jameson, K.A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R.J., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., and et al.

Abstract

Contains fulltext : 95931.pdf (publisher's version ) (Closed access), OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of approximately 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

27. Genetic variants of TNFSF4 and risk for carotid artery disease and stroke

Author

Olofsson, P, Söderström, L, Jern, C, Sirsjö, A, Ria, M, Sundler, E, de Faire, U, Wiklund, Per-Gunnar, Ohrvik, J, Hedin, U, Paulsson-Berne, G, Hamsten, A, Eriksson, P, Hansson, G, Olofsson, P, Söderström, L, Jern, C, Sirsjö, A, Ria, M, Sundler, E, de Faire, U, Wiklund, Per-Gunnar, Ohrvik, J, Hedin, U, Paulsson-Berne, G, Hamsten, A, Eriksson, P, and Hansson, G

Abstract

In two independent human cohorts, the minor allele of SNP rs3850641 in TNFSF4 was significantly more frequent in individuals with myocardial infarction than in controls. In mice, Tnfsf4 expression is associated with increased atherosclerosis. The expression of TNFSF4 in human atherosclerosis and the association between genotype and cerebrovascular disease have not yet been investigated. TNFSF4 messenger RNA (mRNA) levels were significantly higher in human atherosclerotic lesions compared with controls (730 +/- 30 vs 330 +/- 65 arbitrary units, p < 0.01). TNFSF4 was mainly expressed by macrophages in atherosclerotic lesions. In cell culture, endothelial cells upregulated TNFSF4 in response to tumor necrosis factor alpha (TNF-alpha; 460 +/- 110 vs 133 +/- 8 arbitrary units, p < 0.001 after 6 h of stimulation). We analyzed the TNFSF4 gene in 239 patients who had undergone carotid endarterectomy and 138 matching controls from The Biobank of Karolinska Carotid Endarterectomies and Stockholm Heart Epidemiology Program cohorts and 929 patients and 1,382 matching controls from the Sahlgrenska Academy Study on Ischemic Stroke and Case Control Study of Stroke cohorts, limiting inclusion to patients with ischemic stroke. Participants were genotyped for the rs3850641 SNP in TNFSF4. Genotype associations were neither found with TNFSF4 mRNA levels nor with atherosclerosis associated systemic factors or risk for stroke. This study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke.

Published
2008
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28. Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity

Author

Nilsson, Kent W., Sjoberg, R L, Damberg, M, Leppert, J, Ohrvik, J, Alm, P O, Lindstrom, L, Oreland, L, Nilsson, Kent W., Sjoberg, R L, Damberg, M, Leppert, J, Ohrvik, J, Alm, P O, Lindstrom, L, and Oreland, L

Abstract

Background: A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity. Methods: A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of Vastmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior. Results: The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A- gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%. Conclusions. The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.

Published
2006
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36. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population

Author

Sierra-Johnson, J., primary, Fisher, R. M., additional, Romero-Corral, A., additional, Somers, V. K., additional, Lopez-Jimenez, F., additional, Ohrvik, J., additional, Walldius, G., additional, Hellenius, M.-L., additional, and Hamsten, A., additional

Published
2008
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45. Do psychosocial factors predict disability and health at a 3-year follow-up for patients with non-acute musculoskeletal pain? A validation of the Orebro Musculoskeletal Pain Screening Questionnaire.

Author

Westman A, Linton SJ, Ohrvik J, Wahlén P, and Leppert J

Abstract

PURPOSE: Early identification and intervention with those that run the risk of developing long-term disability would offer a great opportunity for reducing costs and personal suffering associated with long-term work absenteeism. The Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) has been used and validated in several studies for participants with mainly acute pain problems. The aim of this study was to validate the OMPSQ for patients with non-acute pain problems (e.g. 1-6 months sick leave) and compare to other relevant questionnaires. METHOD: One hundred and fifty-eight patients with musculoskeletal pain and disability recruited to a multidisciplinary rehabilitation project completed a battery of questionnaires at baseline and at 3-year follow-up visits. The main analysis involved the relationship between risk levels in the questionnaire and sick leave and perceived health after 3 years. RESULTS: The OMSPQ predicted future sick leave and health and was found to have six factors. The function and pain factors were the best predictors of sick leave after 3 years, while the distress factor was the best predictor of perceived mental health and return to work-expectancy was borderline significant. Perceived physical health at 3 years was best predicted by the function and pain factors with the fear-avoidance factor being marginally significant. CONCLUSION: The results demonstrate that psychosocial factors as measured by OMPSQ are related to work disability and perceived health even 3 years after treatment for patients with non-acute pain problems. The OMSPQ was a good predictor of outcome. [ABSTRACT FROM AUTHOR]

Published
2008
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47. Basal glucometabolic status has an impact on long-term prognosis following an acute myocardial infarction in non-diabetic patients.

Author

Tennerz Å, Nilsson G, Forberg R, Ögrvik J, Malmberg K, Berne C, Leppert J, Tenerz, A, Nilsson, G, Forberg, R, Ohrvik, J, Malmberg, K, Berne, C, and Leppert, J

Abstract

Objectives: Patients with diabetes are known to have a worse prognosis after an acute myocardial infarction (AMI) compared with non-diabetic patients. The primary aim of this study was to investigate the effect of glucometabolic status on long-term prognosis in non-diabetic patients with an AMI. The second aim was to evaluate the extent to which blood glucose levels at admission depended on acute stress, assessed as serum cortisol, previous glucometabolic status, measured as haemoglobin A1c (HbA1c), or both.Design: In a prospective study of patients with an AMI, blood glucose, HbA1c and cortisol were measured at admission. Fasting blood glucose was determined before discharge and also afterwards, if necessary, for classification. Patients were followed-up for 5.5 years.Subjects: Of the 305 consecutive patients 24% were diagnosed as diabetic and 76% as non-diabetic.Main Outcome Measures: Death or non-fatal myocardial re-infarction.Results: In non-diabetic patients, a Cox regression model was used. With death or re-infarction as endpoint, the following prognostic factors had an impact on event-free survival: age (P<0.001), HbA1c (P=0.002), cortisol (P<0.001) and thrombolytic treatment (P=0.001). There was a correlation between cortisol and blood glucose at admission (r=0.44, P<0.001). Fasting blood glucose day 5 showed no association with event-free survival.Conclusions: In non-diabetic patients with AMI, admission HbA1c and cortisol were predictors for 5.5-year survival without recurrent non-fatal myocardial infarction. The glucometabolic status of importance for prognosis was detected by HbA1c but not by fasting blood glucose or admission blood glucose, of which the latter was influenced by cortisol. [ABSTRACT FROM AUTHOR]

Published
2003

48. Double blind comparative study of remoxipride and haloperidol in acute schizophrenic patients.

Author

Boer, J., Ravelli, D., Huisman, J., Ohrvik, J., Verhoeven, W., and Westenberg, H.

Abstract

In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III). Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were ten early withdrawals, four in the remoxipride group and six patients in the haloperidol group. The Present State Examination (PSE) profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven per cent of the patients in the remoxipride group and 34% of the patients in the haloperidol group showed clinically relevant improvement (reduction of BPRS total score ≥ 50%). All extrapyramidal symptoms except 'glabella tap' occurred significantly less frequently in the remoxipride group as compared to the haloperidol group. Substantially lower incidences of EPS were found by active questioning in the remoxipride group compared to the haloperidol group. In addition, considerably lower incidences were observed in the remoxipride group with respect to drowsiness/somnolence, tiredness/fatigue and concentrating difficulty. At the end of treatment 66% of the patients in the haloperidol group and 22% in the remoxipride group were using anticholinergics. No consistent changes were found in the mean plasma HVA level in either treatment group. In responders (reduction of BPRS total score ≥ 50%) lower baseline HVA levels were observed in both treatment groups. This study indicates that the newly developed neuroleptic remoxipride is an effective antipsychotic compound, which is clinically safe and well tolerated. In particular, few EPS were induced by remoxipride, as compared to haloperidol. [ABSTRACT FROM AUTHOR]

Published
1990
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49. Copeptin, IGFBP-1, and cardiovascular prognosis in patients with type 2 diabetes and acute myocardial infarction: a report from the DIGAMI 2 trial.

Author

Mellbin LG, Rydén L, Brismar K, Morgenthaler NG, Ohrvik J, Catrina SB, Mellbin, Linda G, Rydén, Lars, Brismar, Kerstin, Morgenthaler, Nils G, Ohrvik, John, and Catrina, Sergiu B

Abstract

Objective: To determine whether C-terminal provasopressin (copeptin) explains the prognostic importance of insulin growth factor binding protein-1 (IGFBP-1) in patients with myocardial infarction and type 2 diabetes.Research Design and Methods: Copeptin and IGFBP-1 were analyzed in 393 patients participating in the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial.Results: Copeptin was associated with IGFBP-1 (Spearman rank correlation test, r = 0.53; P < 0.001). During follow-up there were 138 cardiovascular events (cardiovascular death, myocardial infarction, and stroke). In univariate Cox proportional hazard regression analyses both biomarkers were predictors of events: the hazard ratio for log copeptin was 1.59 (95% CI 1.41-1.81; P < 0.001) and for log IGFBP-1 was 1.49 (1.26-1.77; P < 0.001). In the final model, adjusting for age and renal function, copeptin was the only independent predictor (1.35 [1.16-1.57]; P < 0.001).Conclusions: Copeptin is an independent predictor of cardiovascular events and appears to at least partly explain the prognostic impact of IGFBP-1 in patients with type 2 diabetes and myocardial infarction. Copeptin may be a pathogenic factor to address to improve outcome in these patients. [ABSTRACT FROM AUTHOR]

Published
2010
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50. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

Author

van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, Mckeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia H T, Luk, Andrea O Y, Lee, Heung Man, Lim, Cadmon K P, Szeto, Cheuk Chun, Wing Yee, So, Chan, Juliana C N, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, Mcknight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, Ac, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kr, Riihelä, M, Ryysy, L, Laukkanen, Kh, Nyländen, P, Sademies, A, Anderson, S, Asplund, B, Byskata, U, Liedes, P, Kuusela, M, Virkkala, T, Nikkola, A, Ritola, E, Niska, Tm, Saarinen, H, Oukko-Ruponen, Se, Virtanen, T, Lyytinen, Va, Kari, Ph, Simonen, T, Kaprio, Sa, Kärkkäinen, J, Rantaeskola, B, Kääriäinen, Tp, Haaga, J, Pietiläinen, Al, Klemetti, S, Nyandoto, T, Rontu, E, Satuli-Autere, S, Toivonen, Kr, Lansimaki, Hv, Ahonen, R, Ivaska-Suomela, M, Jauhiainen, A, Laine, Mm, Pellonpää, T, Puranen, R, Airas, Ma, Laakso, J, Rautavaara, K, Erola, Rm, Jatkola, E, Lönnblad, Tr, Malm, A, Mäkelä, J, Rautamo, E, Hentunen, P, Lagerstam, J, Feodoroff, M, Gordin, D, Heikkilä, O, Hietala, K, Fagerudd, J, Korolainen, M, Kyllönen, L, Kytö, J, Lindh, S, Pettersson-Fernholm, K, Rosengård-Bärlund, M, Sandelin, A, Thorn, L, Tuomikangas, J, Vesisenaho, T, Wadén, J, Sipilä, V, Kalliomäki, Ft, Koskelainen, J, Nikkanen, R, Savolainen, N, Sulonen, H, Valtonen, E, Norvio, L, Hämäläinen, A, Toivanen, E, Parta, Ja, Pirttiniemi, I, Aranko, S, Ervasti, S, Kauppinen-Mäkelin, R, Kuusisto, A, Leppälä, T, Nikkilä, K, Pekkonen, L, Jokelainen, Ks, Kananen, K, Karjalainen, M, Kemppainen, P, Mankinen, Am, Reponen, A, Sankari, M, Suominen, P, Lappalainen, A, Liimatainen, M, Santaholma, J, Aimolahti, A, Huovinen, E, Ilkka, V, Lehtimäki, M, Pälikkö-Kontinen, E, Vanhanen, A, Koskinen, E, Siitonen, T, Huttunen, E, Ikäheimo, R, Karhapää, P, Kekäläinen, P, Laakso, M, Lakka, T, Lampainen, E, Moilanen, L, Tanskanen, S, Niskanen, L, Tuovinen, U, Vauhkonen, I, Voutilainen, E, Rcw, Ma, Chan, Jcn, Huang, Y, Lan, Hy, Lok, S, Tomlinson, B, Tsui, Skw, Yu, W, Yip, Kyl, Chan, Tf, Fan, X, So, Wy, Szeto, Cc, Tang, N, Luk, Ao, Tian, X, Jiang, G, Tam, Cht, Lee, Hm, Lim, Ckp, Chan, Kkh, Xie, F, Acw, Ng, Cheung, Gpy, Yeung, Mw, Mai, S, Zhang, S, Yu, P, Weng, M, Maxwell, Ap, Mcknight, Aj, Savage, Da, Walker, J, Thomas, S, Viberti, Gc, Boulton, Ajm, Marshall, S, Demaine, Ag, Millward, Ba, Bain, Sc, Sandholm, N, Forsblom, C, Harjutsalo, V, Mäkinen, Vp, Ahola, Aj, Dahlström, E, Lehto, M, Lithovius, R, Panduru, Nm, Parkkonen, M, Saraheimo, M, Söderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, Lm, Tolonen, N, Groop, Ph, Mckay, Gj, Salem, Rm, Isakova, T, Palmer, C, Guiducci, C, Taylor, A, Mirel, Db, Williams, Ww, Hirschhorn, Jn, Florez, Jc, Brennan, Ep, Sadlier, Dm, Martin, F, Godson, C, Mayer, L, Gubitosi-Klug, R, Bourne, P, Schutta, M, Lackaye, Me, Gregory, Ns, Kruger, D, Jones, Jk, Bhan, A, Golden, E, Aiello, L, Larkin, M, Nathan, D, Ziegler, G, Caulder, S, Pittman, C, Luttrell, L, Lopes-Virella, M, Johnson, M, Gunyou, K, Bergenstal, R, Vittetoe, B, Sivitz, W, Flaherty, N, Bantle, J, Hitt, S, Goldstein, D, Hainsworth, D, Cimino, L, Orchard, T, Wigley, C, Dagogo-Jack, S, Strowig, S, Raskin, P, Barnie, A, Zinman, B, Fahlstrom, R, Palmer, J, Harth, J, Driscoll, M, Mcdonald, C, Lipps Hagan, J, May, M, Levandoski, L, White, N, Gatcomb, P, Tamborlane, W, Adelman, D, Colson, S, Molitch, M, Lorenzi, G, Mudaliar, S, Johnsonbaugh, S, Miller, R, Canady, J, Schade, D, Bernal, Ml, Malone, J, Morrison, A, Martin, C, Herman, W, Pop-Busui, R, Cowie, C, Leschek, E, Cleary, P, Lachin, J, Braffett, B, Steffes, M, Arends, V, Blodi, B, Danis, R, Lawrence, D, Wabers, H, Soliman, E, Zhang, Zm, Campbell, C, Hensley, S, Keasler, L, Mark, M, Albertini, M, Boustany, C, Ehlgen, A, Gerl, M, Huber, J, Schölch, C, Zimdahl-Gelling, H, Groop, L, Agardh, E, Ahlqvist, E, Ajanki, T, Al Maghrabi, N, Almgren, P, Apelqvist, J, Bengtsson, E, Berglund, L, Björckbacka, H, Blom-Nilsson, U, Borell, M, Burström, A, Cilio, C, Cinthio, M, Dreja, K, Dunér, P, Engelbertsen, D, Fadista, J, Gomez, M, Goncalves, I, Hedblad, B, Hultgårdh, A, Johansson, Me, Kennbäck, C, Kravic, J, Ladenvall, C, Lernmark, Å, Lindholm, E, Ling, C, Luthman, H, Melander, O, Neptin, M, Nilsson, J, Nilsson, P, Nilsson, T, Nordin, G, Orho-Melander, M, Ottoson-Laakso, E, Persson, A, Persson, M, Persson, Må, Postma, J, Pranter, E, Rattik, S, Sterner, G, Tindberg, L, Wigren, M, Zetterqvist, A, Åkerlund, M, Ostling, G, Kanninen, T, Ahonen-Bishopp, A, Eliasson, A, Herrala, T, Tikka-Kleemola, P, Hamsten, A, Betsholtz, C, Björkholm, A, Foroogh, F, Genové, G, Gertow, K, Gigante, B, He, B, Leander, K, Mcleod, O, Nastase-Mannila, M, Patrakka, J, Silveira, A, Strawbridge, R, Tryggvason, K, Vikström, M, Ohrvik, J, Österholm, Am, Thorand, B, Gieger, C, Grallert, H, Ludwig, T, Nitz, B, Schneider, A, Wang-Sattler, R, Zierer, A, Remuzzi, G, Benigni, A, Donadelli, R, Lesti, Md, Noris, M, Perico, N, Perna, A, Piras, R, Ruggenenti, P, Rurali, E, Dunger, D, Chassin, L, Dalton, N, Deanfield, J, Horsford, J, Rice, C, Rudd, J, Walker, N, Whitehead, K, Wong, M, Colhoun, H, Adams, F, Akbar, T, Belch, J, Deshmukh, H, Dove, F, Ellingford, A, Farran, B, Ferguson, M, Henderson, G, Houston, G, Khan, F, Leese, G, Liu, Y, Livingstone, S, Looker, H, Mccann, M, Mcgurnaghan, S, Morris, A, Newton, D, Pearson, E, Reekie, G, Smith, N, Shore, A, Aizawa, K, Ball, C, Bellenger, N, Casanova, F, Frayling, T, Gates, P, Gooding, K, Hattersley, A, Ling, R, Mawson, D, Shandas, R, Strain, D, Thorn, C, Smith, U, Hammarstedt, A, Häring, H, Pedersen, O, Sesti, G, Fagerholm, E, Toppila, I, Valo, E, Salomaa, V, Havulinna, A, Kristiansson, K, Okamo, P, Peltola, T, Perola, M, Pietilä, A, Ripatti, S, Taimi, M, Ylä-Herttuala, S, Babu, M, Dijkstra, M, Gurzeler, E, Huusko, J, Kholová, I, Merentie, M, Poikolainen, M, Mccarthy, M, Groves, C, Juliusdottir, T, Karpe, F, Lagou, V, Rayner, W, Robertson, N, van Zuydam, N, Cobelli, C, Di Camillo, B, Finotello, F, Sambo, F, Toffolo, G, Trifoglio, E, Bellazzi, R, Barbarini, N, Bucalo, M, Larizza, C, Magni, P, Malovini, A, Marini, S, Mulas, F, Quaglini, S, Sacchi, L, Vitali, F, Ferrannini, E, Boldrini, B, Kozakova, M, Mari, A, Morizzo, C, Mota, L, Natali, A, Palombo, C, Venturi, E, Walker, M, Patrono, C, Pagliaccia, F, Rocca, B, Nuutila, P, Haukkala, J, Knuuti, J, Roivainen, A, Saraste, A, Mckeague, P, Colombo, M, Steckel-Hamann, B, Bokvist, K, Shankar, S, Thomas, M, Gan, Lm, Heinonen, S, Jönsson-Rylander, Ac, Momo, R, Schnecke, V, Unwin, R, Walentinsson, A, Whatling, C, Nogoceke, E, Pacheco, Gd, Formentini, I, Schindler, T, Tortoli, P, Bassi, L, Boni, E, Dallai, A, Guidi, F, Lenge, M, Matera, R, Ramalli, A, Ricci, S, Viti, J, Jablonka, B, Crowther, D, Gassenhuber, J, Hess, S, Hubschle, T, Juretschke, Hp, Rutten, H, Sadowski, T, Wohlfart, P, Brosnan, J, Clerin, V, Fauman, E, Hyde, C, Malarstig, A, Pullen, N, Tilley, M, Tuthill, T, Vangjeli, C, Linda T, Ziemek D., Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ronald C W, Ma, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin N A, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, Mccarthy, Mark, I, Palombo, Carlo, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Nefrologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Tiinamaija Tuomi Research Group, Endokrinologian yksikkö, Per Henrik Groop / Principal Investigator, Leif Groop Research Group, HUS Abdominal Center, HUS Internal Medicine and Rehabilitation, and Lee Kong Chian School of Medicine (LKCMedicine)

Subjects
0301 basic medicine, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Type 2 diabetes, Bioinformatics, Kidney Failure, 0302 clinical medicine, Genome-wide analysis, 80 and over, Diabetic Nephropathies, Renal Insufficiency, Chronic, Genome-wide analysis, Type 2 Diabetes, Aged, 80 and over, RISK, INSULIN-RESISTANCE, diabetes, Diabetes, STAGE RENAL-DISEASE, Single Nucleotide, Middle Aged, Type 2 Diabetes, SUSCEPTIBILITY GENES, Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, OBESITY, BIOLOGICAL PATHWAYS, nephropathy, Medical genetics, Type 2, kidney, medicine.medical_specialty, Diabetic Nephropathies/epidemiology, Settore BIO/14 - FARMACOLOGIA, Renal Insufficiency, Chronic/complications, NEPHROPATHY, SNP, 030209 endocrinology & metabolism, Nephropathy, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Journal Article, Diabetes Mellitus, Internal Medicine, medicine, Medicine [Science], Polymorphism, Diabetic Kidney Disease, METAANALYSIS, Genetic heterogeneity, business.industry, Diabetes Mellitus, Type 2/complications, association, Case-control study, nutritional and metabolic diseases, Kidney Failure, Chronic/complications, FAT DISTRIBUTION, medicine.disease, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Microalbuminuria, genetic, business
Abstract

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore)

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