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402. Joint use of cardio-embolic and bleeding risk scores in elderly patients with atrial fibrillation

Author

Marcucci, M, Nobili, A, Tettamanti, M, Iorio, A, Pasina, L, Djade, Cd, Franchi, C, Marengoni, A, Salerno, F, Corrao, S, Violi, F, Mannucci, Pm, Reposi, Investigators, Pier, Mm, Spirito, V, Noce, D, Bonazzi, J, Lombardo, R, Sparacio, E, Alborghetti, S, De Vittorio, L, Prisco, D, Silvestri, E, Cenci, C, Barnini, T, Delitala, G, Carta, S, Atzori, S, Guarnieri, G, Zanetti, M, Spalluti, A, Serra, Mg, Bleve, Ma, Vanoli, M, Grignani, G, Casella, G, Gasbarrone, L, Maniscalco, G, Gunelli, M, Tirotta, D, Brucato, A, Ghidoni, S, Di Corato, P, Bernardi, M, Li Bassi, S, Santi, L, Agnelli, G, Marchesini, E, Mannarino, E, Lupattelli, G, Rondelli, P, Paciullo, F, Fabris, F, Carlon, M, Turatto, F, Baroni, Mc, Zardo, M, Manfredini, R, Molino, C, Pala, M, Fabbian, F, Nuti, R, Valenti, R, Ruvio, M, Cappelli, S, Paolisso, G, Rizzo, Mr, Laieta, Mt, Salvatore, T, Sasso, Fc, Utili, R, Durante Mangoni, E, Pinto, D, Olivieri, O, Stanzial, Am, Fellin, R, Volpato, S, Fotini, S, Barbagallo, M, Dominguez, L, Plances, L, D'Angelo, D, Rini, G, Mansueto, P, Pepe, I, Licata, G, Calvo, L, Valenti, M, Borghi, C, Strocchi, E, Rinaldi, Er, Zoli, M, Fabbri, E, Magalotti, D, Auteri, A, Pasqui, Al, Puccetti, L, Pasini, Fl, Capecchi, Pl, Bicchi, M, Sabbà, C, Vella, Fs, Marseglia, A, Luglio, Cv, Palasciano, G, Modeo, Me, Aquilino, A, Raffaele, P, Pugliese, S, Capobianco, C, Postiglione, A, Barbella, Mr, De Stefano, F, Fenoglio, L, Brignone, C, Bracco, C, Giraudo, A, Musca, G, Cuccurullo, O, Cricco, L, Fiorentini, A, Cappellini, Md, Fabio, G, Seghezzi, S, De Amicis MM, Fargion, S, Bonara, P, Bulgheroni, M, Lombardi, R, Magrini, F, Massari, F, Tonella, T, Peyvandi, F, Tedeschi, A, Rossio, R, Moreo, G, Ferrari, B, Roncari, L, Monzani, V, Savojardo, V, Folli, C, Magnini, M, Mari, D, Dionigi Rossi, P, Damanti, S, Prolo, S, Lilleri, Ms, Micale, G, Podda, M, Selmi, C, Meda, F, Accordino, S, Conca, A, Monti, V, Corazza, Gr, Miceli, E, Lenti, Mv, Padula, D, Balduini, Cl, Bertolino, G, Provini, S, Quaglia, F, Murialdo, G, Bovio, M, Dallegri, F, Ottonello, L, Quercioli, A, Barreca, A, Secchi, Mb, Ghelfi, D, Chin, Ws, Carassale, L, Caporotundo, S, Sofia, L, Anastasio, L, Carbone, M, Traisci, G, De Feudis, L, Di Carlo, S, Guagnano, Mt, Sestili, S, Bergami, E, Rizzioli, E, Cagnoni, C, Bertone, L, Manucra, A, Buratti, A, Tognin, T, Liberato, Nl, Bernasconi, G, Nardo, B, Bianchi, Gb, Giaquinto, S, Benetti, G, Quagliolo, M, Centenaro, Gr, Purrello, Francesco, Di Pino, A, Piro, Salvatore, Mancuso, G, Calipari, D, Bartone, M, Gullo, F, Cortellaro, M, Magenta, M, Perego, F, Meroni, Mr, Cicardi, M, Magenta, Ag, Sacco, A, Bonelli, A, Dentamaro, G, Rozzini, R, Falanga, L, Giordano, A, Perin, Pc, Lorenzati, B, Gruden, G, Bruno, G, Montrucchio, G, Greco, E, Tizzani, P, Fera, G, Di Luca ML, Renna, D, Perciccante, A, Coralli, A, Tassara, R, Melis, D, Rebella, L, Menardo, G, Bottone, S, Sferrazzo, E, Ferri, C, Striuli, R, Scipioni, R, Salmi, R, Gaudenzi, P, Gamberini, S, Ricci, F, Morabito, C, Fava, R, Semplicini, A, Gottardo, L, Vendemiale, G, Serviddio, G, Forlano, R, Bolondi, L, Rasciti, L, Serio, I, Masala, C, Mammarella, A, Raparelli, V, Rossi Fanelli, F, Delfino, M, Amoroso, A, Basili, S, Perri, L, Serra, P, Fontana, V, Falcone, M, Landolfi, R, Grieco, A, Gallo, A, Zuccalà, G, Franceschi, F, De Marco, G, Chiara, C, Marta, S, Bellusci, M, Setti, D, Pedrazzoli, F, Romanelli, G, Pirali, C, Amolini, C, Rosei, Ea, Rizzoni, D, Castoldi, L, Picardi, A, Gentilucci, Uv, Mazzarelli, C, Gallo, P, Guasti, L, Castiglioni, L, Maresca, A, Squizzato, A, Contini, S, Molaro, M, Annoni, G, Zazzetta, Mc, Bertolotti, M, Scotto, Cm, Ferri, Ma, Veltri, F, Arturi, F, Succurro, E, Sesti, G, Gualtieri, U, Perticone, F, Sciacqua, A, Quero, M, Bagnato, C, Loria, P, Becchi, Ma, Martucci, G, Fantuzzi, A, Maurantonio, M, Corinaldesi, R, De Giorgio, R, Serra, M, Grasso, V, Ruggeri, E, Carozza, Lm, Pignatti, F., Maura Marcuccia, Alessandro Nobili, Mauro Tettamanti, Alfonso Iorio, Luca Pasina, Codjo D. Djade, Carlotta Franchi, Alessandra Marengoni, Francesco Salerno, Salvatore Corrao, Francesco Violi, Pier Mannuccio Mannucci, REPOSI Investigators1 […, Corinaldesi Roberto, Strocchi Enrico, Borghi Claudio, Bolondi Luigi, Zoli Marco, De Giorgio Roberto, Bernardi Mauro, …], Marcucci, Maura, Nobili, Alessandro, Tettamanti, Mauro, Iorio, Alfonso, Pasina, Luca, Djade, Codjo D., Franchi, Carlotta, Marengoni, Alessandra, Salerno, Francesco, Corrao, Salvatore, Violi, Francesco, Mannucci, Pier o, Zanetti, Michela, Investigators, Reposi, Marcucci, M, Nobili, A, Tettamanti, M, Iorio, A, Pasina, L, Djade, Cd, Franchi, C, Marengoni, A, Salerno, F, Corrao, S, Violi, F, Mannucci, Pm, Reposi, Investigator, Postiglione, Alfredo, PAGANO LEONETTI GIANNI MANNUCCI, Paolo, Pier, Mannuccio, Rizzo, Mr, Djade, C, Mannucci, P, and Annoni, G

Subjects
Registrie, Male, Embolism, Atrial fibrillation, Bleeding risk, Cardioembolic risk, Elderly, Prediction guides, Thromboprophylaxis, Aged, 80 and over, Anticoagulants, Atrial Fibrillation, Female, Hemorrhage, Humans, Logistic Models, Platelet Aggregation Inhibitors, Retrospective Studies, Stroke, Warfarin, Registries, Risk Assessment, Internal Medicine, Retrospective Studie, aritmia, bleeding risk score, atrial fibrillation, Aged, 80 and over, Aspirin, education.field_of_study, Elderly, Atrial fibrillation, Prediction guides, Bleeding risk, Cardioembolic risk, Thromboprophylaxis, Cardiovascular disease, cardio-embolic score, Platelet aggregation inhibitor, cardio-embolic scores, bleeding risk scores, elderly, Risk assessment, medicine.drug, Human, medicine.medical_specialty, Logistic Model, Population, CARDIOEMBOLIC RISK, NO, BLEEDING RISK, Internal medicine, medicine, Prediction guide, education, ELDERLY, business.industry, Platelet Aggregation Inhibitor, Settore MED/09 - MEDICINA INTERNA, Anticoagulant, Retrospective cohort study, medicine.disease, Surgery, Thromboprophylaxi, business
Abstract

Background Scores for cardio-embolic and bleeding risk in patients with atrial fibrillation are described in the literature. However, it is not clear how they co-classify elderly patients with multimorbidity, nor whether and how they affect the physician's decision on thromboprophylaxis. Methods Four scores for cardio-embolic and bleeding risks were retrospectively calculated for ≥ 65 year old patients with atrial fibrillation enrolled in the REPOSI registry. The co-classification of patients according to risk categories based on different score combinations was described and the relationship between risk categories tested. The association between the antithrombotic therapy received and the scores was investigated by logistic regressions and CART analyses. Results At admission, among 543 patients the median scores (range) were: CHADS22 (0-6), CHA2DS2-VASc 4 (1-9), HEMORR2HAGES 3 (0-7), HAS-BLED 2 (1-6). Most of the patients were at high cardio-embolic/high-intermediate bleeding risk (70.5% combining CHADS2and HEMORR2HAGES, 98.3% combining CHA2DS2-VASc and HAS-BLED). 50-60% of patients were classified in a cardio-embolic risk category higher than the bleeding risk category. In univariate and multivariable analyses, a higher bleeding score was negatively associated with warfarin prescription, and positively associated with aspirin prescription. The cardio-embolic scores were associated with the therapeutic choice only after adjusting for bleeding score or age. Conclusion REPOSI patients represented a population at high cardio-embolic and bleeding risks, but most of them were classified by the scores as having a higher cardio-embolic than bleeding risk. Yet, prescription and type of antithrombotic therapy appeared to be primarily dictated by the bleeding risk. © 2013 European Federation of Internal Medicine.

Published
2013

403. Comparison of Disease Clusters in Two Elderly Populations Hospitalized in 2008 and 2010

Author

Marengoni, A, Nobili, A, Pirali, C, Tettamanti, M, Pasina, L, Salerno, F, Corrao, S, Iorio, A, Marcucci, M, Franchi, C, Mannucci, Pm, Reposi, Investigators, Pier Mannucci, M, Spirito, V, Noce, D, Bonazzi, J, Lombardo, R, Sparacio, E, Alborghetti, S, De Vittorio, L, Djade, Cd, Paolisso, G, Rizzo, Mr, Laieta, Mt, Roberto, T, Persico, Marcello, Salvatore, T, Sasso, Fc, Utili, R, Durante Mangoni, E, Pinto, D, Fenoglio, L, Brignone, C, Bracco, C, Gasbarrone, L, Porcari, P, Famularo, G, Sajeva, Mr, Maniscalco, G, Gunelli, M, Tirotta, D, Realdi, G, Baritussio, A, Frassoni, F, Delsignore, R, Baroni, Mc, Zardo, M, Volpato, S, Fotini, S, Manfredini, R, Longhini, C, Molino, C, Incasa, E, Guarnieri, G, Zanetti, M, Spalluti, A, Rini, G, Mansueto, P, Pepe, I, Licata, G, Calvo, L, Valenti, M, Tuttolomondo, A, Di Sciacca, R, Antonaci, S, Vella, F, Marseglia, A, Centonze, V, Modeo, Me, Palasciano, G, Pugliese, S, Capobianco, C, Murialdo, G, Bovio, M, Pasini, Fl, Capecchi, Pl, Bicchi, M, Nuti, R, Valenti, R, Capodarca, C, Auteri, A, Pasqui, Al, Puccetti, L, Olivieri, O, Stanzial, Am, Agnelli, G, Macura, A, Mannarino, E, Lupattelli, G, Rondelli, P, Serra, Mg, Musca, G, Cuccurullo, O, Cappellini, Md, Fabio, G, Motta, I, Cantoni, F, Fargion, S, Bonara, P, Bulgheroni, M, Magrini, F, Massari, F, Tonella, T, Peyvandi, F, Tedeschi, A, Rossio, R, Moreo, G, Ferrari, B, Roncari, L, Monzani, V, Savojardo, V, Folli, C, Mari, D, Rossi, Pd, Ziglioli, E, Vergani, C, Lilleri, Ms, Podda, M, Selmi, C, Meda, F, Cazzaniga, M, Monti, V, Balduini, Cl, Bertolino, G, Dezzani, L, Cavallo, P, Corazza, Gr, Miceli, E, Secchi, Mb, Wu, Sc, Balsamo, C, Anastasio, L, Sofia, L, Carbone, M, Bertucci, L, Valentia, V, Traisci, G, De Feudis, L, Bergami, E, Rizzioli, E, Cagnoni, C, Bertone, L, Manucra, A, Ronchi, E, Buratti, A, Tognin, T, Bertolini, D, Liberato, Nl, Bernasconi, G, Nardo, B, Venco, A, Guasti, L, Maroni, L, Castiglioni, L, Vanoli, M, Grignani, G, Casella, G, Mancuso, G, Tavella, R, Persico, R, Cicardi, M, Sandrone, G, Cortellaro, M, Magenta, M, Perego, F, Meroni, Mr, Rozzini, R, Falanga, L, Giordano, A, Menardo, G, Bottone, S, Sferrazzo, E, Tassara, R, Melis, D, Rebella, L, Ferri, C, Striuli, R, Scipioni, R, Salmi, R, Gaudenzi, P, Di Todaro, F, Nielsen, I, Giusto, L, Semplicini, A, Gottardo, L, Delitala, G, Carta, S, Atzori, S, Rosei, Ea, Rizzoni, D, Castoldi, L, Altomare, E, Serviddio, G, Salvatore, S, Fera, G, Di Luca ML, Renna, D, Picardi, A, Mazzarelli, C, Gentilucci, Uv, De Vincentis, A, Hila, D, Bernardi, M, Li Bassi, S, Santi, L, Masala, C, Mammarella, A, Raparelli, V, Rossi Fanelli, F, Delfino, M, Amoroso, A, Serra, P, Fontana, V, Falcone, M, Violi, F, Basili, S, Perri, L, Silveri, Ng, De Marco, G, Giupponi, B, Landolfi, R, Grieco, A, Gallo, A, Perticone, F, Sciacqua, A, Quero, M, Bagnato, C, Loria, P, Ballestri, S, Becchi, Ma, Bellettini, E, Bolondi, L, Rasciti, L, Serio, I, Gualandi, S, Romanelli, G, Bonometti, F, Carulli, N, Rondinella, S, Giannico, I, Dallegri, F, Ottonello, L, Quercioli, A, Barreca, A, Sacco, A, Bonelli, A, Dentamaro, G, Micale, G, Delitalia, G, Deidda, S, Cuccuru, Lm, Benetti, G, Quagliolo, M, Centenaro, Gr, Perciccante, A, Coralli, A, Morabito, C, Fava, R, Macchini, L, Realdi, A, Cricco, L, Fiorentini, A, Tofi, C., Marengoni A, Nobili A, Pirali, C, Tettamanti, M, Pasina, L, Salerno, F, Corrao, S, Iorio, A, Marcucci, M, Franchi, C, Mannucci, Pm, Investigators, Reposi, Zanetti, Michela, Marengoni, A., Nobili, A., Pirali, C., Tettamanti, M., Pasina, L., Salerno, F., Corrao, S., Iorio, A., Marcucci, M., Franchi, C., Mannucci, P. M, Rizzo, Mr, Marengoni A, Nobili A, Pirali C, Tettamanti M, Pasina L, Salerno F, Corrao S, Iorio A, Marcucci M, Franchi C, Mannucci PM, REPOSI Investigators [.., Bernardi M, Bolondi L, ], Mannucci, P., and Mansueto, P.

Subjects
Registrie, Male, Aging, Cirrhosis, Settore MED/09 - Medicina Interna, Time Factors, hispitalization, Gerontology, aging populations, atterns of multimorbidity, diseases in the elderly population, Health care, 80 and over, Prevalence, Chronic diseases, Cluster analysis, Hospitalized elderly, Registries, aging population, Aged, 80 and over, education.field_of_study, Settore MED/45 - Scienze Infermieristiche Generali, Cliniche E Pediatriche, Hospitalization, Italy, elderly, disease clusters, Female, hospitalized, Human, medicine.medical_specialty, Time Factor, Anemia, MULTIMORBIDITY, Population, MEDLINE, Malignancy, Diabetes mellitus, Internal medicine, medicine, Multimorbidity, Humans, education, Aged, Chronic Disease, Cluster Analysis, Geriatrics and Gerontology, Cluster Analysi, business.industry, medicine.disease, Physical therapy, disease cluster, business
Abstract

Background: As chronicity represents one of the major challenges in the healthcare of aging populations, the understanding of how chronic diseases distribute and co-occur in this part of the population is needed. Objectives: The aims of this study were to evaluate and compare patterns of diseases identified with cluster analysis in two samples of hospitalized elderly. Methods: Data were obtained from the multicenter ‘Registry Politerapie SIMI (REPOSI)' that included people aged 65 or older hospitalized in internal medicine and geriatric wards in Italy during 2008 and 2010. The study sample from the first wave included 1,411 subjects enrolled in 38 hospitals wards, whereas the second wave included 1,380 subjects in 66 wards located in different regions of Italy. To analyze patterns of multimorbidity, a cluster analysis was performed including the same diseases (19 chronic conditions with a prevalence >5%) collected at hospital discharge during the two waves of the registry. Results: Eight clusters of diseases were identified in the first wave of the REPOSI registry and six in the second wave. Several diseases were included in similar clusters in the two waves, such as malignancy and liver cirrhosis; anemia, gastric and intestinal diseases; diabetes and coronary heart disease; chronic obstructive pulmonary disease and prostate hypertrophy. Conclusion: These findings strengthened the idea of an association other than by chance of diseases in the elderly population.

Published
2013

405. Differential diagnosis between type 2A and 2B von Willebrand disease in a child with a previously undescribed de novo mutation.

Author

Pagliari, M. T., Baronciani, L., Stufano, F., Colpani, P., Siboni, S. M., and Peyvandi, F.

Subjects
DIFFERENTIAL diagnosis, VON Willebrand disease, VON Willebrand disease treatment, ENZYME-linked immunosorbent assay, BLOOD platelets, PATIENTS
Abstract

The article discusses the differential diagnosis between type 2A and 2B von Will brand disease in a child. It mentions the development of a ristocetin- independent ELISA method using a recombinant gain- of- function GPIbα to evaluate the platelet dependent VWF activity. It also mentions the International Society On Thrombosis And Haemostasis- Bleeding Assessment Tool.

Published
2018
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407. Factor XIII deficiency diagnosis: Challenges and tools.

Author

Karimi, M., Peyvandi, F., Naderi, M., and Shapiro, A.

Subjects
*HEMORRHAGIC diseases, *ALGORITHMS, *CLINICAL pathology, *GENETIC testing, *DIAGNOSIS
Abstract

Abstract: Factor XIII deficiency (FXIIID) is a rare hereditary bleeding disorder arising from heterogeneous mutations, which can lead to life‐threatening hemorrhage. The diagnosis of FXIIID is challenging due to normal standard coagulation assays requiring specific FXIII assays for diagnosis, which is especially difficult in developing countries. This report presents an overview of FXIIID diagnosis and laboratory methods and suggests an algorithm to improve diagnostic efficiency and prevent missed or delayed FXIIID diagnosis. Assays measuring FXIII activity: The currently available assays utilized to diagnose FXIIID, including an overview of their complexity, reliability, sensitivity, and specificity, as well as mutational analysis are reviewed. The use of a FXIII inhibitor assay is described. Diagnostic tools in FXIIID: Many laboratories are not equipped with quantitative FXIII activity assays, and if available, limitations in lower activity ranges are important to consider. Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries. To minimize the number of patients with undiagnosed FXIIID, test quality should be improved in less well‐equipped laboratories. Common country‐specific mutations may facilitate diagnosis through targeted genetic analysis in reference laboratories in suspected cases. However, genetic analysis may not be feasible in every country and may miss spontaneous mutations. Centralized FXIII activity measurements should also be considered. An algorithm for diagnosis of FXIIID including different approaches dependent upon laboratory capability is proposed. [ABSTRACT FROM AUTHOR]

Published
2018
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408. Acquired Von Willebrand syndrome and response to desmopressin.

Author

Biguzzi, E., Siboni, S. M., and Peyvandi, F.

Subjects
DESMOPRESSIN, THALIDOMIDE, INTRAVENOUS immunoglobulins, HYPOTHYROIDISM, CARDIOVASCULAR diseases, AUTOIMMUNE diseases, THERAPEUTICS
Abstract

The article discusses how desmopressin (DDAVP), high dose intravenous immunoglobulins and thalidomide can be used for the treatment of patients with Acquired Von Willebrand Syndrome (AVWS) and severe bleeding. According to the author, such therapeutic approaches can be used to eradicate the AVWS in patients suffering from hypothyroidism, cardiovascular diseases and autoimmune diseases.

Published
2018
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409. A comparative evaluation of a new fully automated assay for von Willebrand factor collagen binding activity to an established method.

Author

Stufano, F., Baronciani, L., Cozzi, G., Peyvandi, F., Mane‐Padros, D., and Faraudo, S.

Subjects
VON Willebrand disease, VON Willebrand factor, ENZYME-linked immunosorbent assay, COLLAGEN, RISTOCETIN, PEPTIDES, CHEMILUMINESCENCE assay
Abstract

Introduction: Laboratory diagnosis of von Willebrand disease (VWD) is made by the measurement of von Willebrand factor (VWF) protein level and its activities. Current VWF activity tests include ristocetin cofactor and collagen binding (VWF:CB) assays. Aim: We have undertaken an evaluation of a new fully automated VWF:CB assay relative to an established enzyme‐linked immunosorbent assay (ELISA) method. Methods: The two analytical systems operate with different detection principles: a chemiluminescent method performed on ACL AcuStar Analyzer (the former) and a colorimetric ELISA by Asserachrom Stago (the latter) (type III collagen from human placenta). The HemosIL AcuStar VWF:CB assay is a chemiluminescent 2‐step immunoassay that uses magnetic particles coated with a type III collagen triple‐helical peptide. VWF:CB levels were determined in 50 healthy subjects and 100 VWD patients (22 type 1, 73 type 2 and 5 type 3). Results: Eleven VWD samples reported VWF:CB values below the lower detection limit of one or both methods. The new method showed a good correlation with the ELISA method (r > .9, mean bias 3.85 IU/dL) in both healthy and VWD samples. One of 150 samples gave inconsistent results using the two assays, leading to an uncertain diagnosis of VWD type 1 (ELISA method) or type 2 MCB (fully automated method). Conclusion: The new assay is rapid and simple to use, with its ready‐to‐use reagent cartridges. This VWF:CB assay, in addition to the measurement of VWF:Ag and VWF:RCo made on the same platform, gives additional information for the diagnosis of VWD in both nonspecialized and reference laboratories. [ABSTRACT FROM AUTHOR]

Published
2018
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410. Ageing successfully with haemophilia: A multidisciplinary programme.

Author

Boccalandro, E., Mancuso, M. E., Pisaniello, D. M., Santagostino, E., Peyvandi, F., Mannucci, P. M., Riva, S., Ronchetti, F., Solimeno, L. P., and Pasta, G.

Subjects
HEMOPHILIA, HEMOPHILIACS, AGING, MUSCULOSKELETAL diseases in old age, DISABILITIES, PHYSICAL therapists
Abstract

Introduction: Persons with haemophilia (PWH) born before the middle 1970s have spent a substantial part of their lives without the benefits of replacement therapy, that became available on a relative large scale only during the 1970s. As a consequence, this group of PWH, although still relatively young, suffers from musculoskeletal and functional problems that are typical of old people. Methods: We report herewith the short‐term results of a project based upon a multidisciplinary training programme led by a physiotherapist and an occupational therapist, that was implemented over a period of 12 months in 40 patients with severe or moderate hemophilia A or B born before the middle 1970s and regularly followed‐up at a comprehensive haemophilia treatment centre in Italy. The project was aimed to provide information and skills in order to empower the older PWH carrying physical handicaps and functional limitations that had resulted from the inadequate management in their early ages, and to enable them to cope more efficiently with their crippling disease and prevent further disabilities. Results and Conclusions: The comparison of the data obtained before and after the 12‐month programme found marginal improvements, but the purpose of this programme was indeed to offer a blueprint for the future. In this respect, the level of satisfaction for the programme was very high and we expect that it will be implemented long‐term by our older PWH. [ABSTRACT FROM AUTHOR]

Published
2018
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412. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis

Author

Stahl, E. A., Wegmann, D., Trynka, G., Gutierrez Achury, J., Do, R., Voight, B. F., Kraft, P., Chen, R., Kallberg, H. J., F. A. S., Replication, D. G., Consortium, M. a., Genetics, M. I., Kathiresan, S., Wijmenga, C., Gregersen, P. K., Alfredsson, L., Siminovitch, K. A., Worthington, J., P. I. W., Raychaudhuri, S., Plenge, R. M., Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Fox, Cs, Franklin, Cs, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam RM, van Haeften TW, van Herpt, T, van Vliet Ostaptchouk JV, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, Fs, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, Js, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn CM, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Kathiresan, S, Williams, G, Nathan, Dm, Macrae, Ca, O'Donnell, Cj, Ardissino, D, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, Flavio Luciano, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Mannucci, Pm, Schwartz, Sm, Siscovick, Ds, Yee, J, Friedlander, Y, Elosua, R, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Salomaa, V, Havulinna, As, Peltonen, L, Melander, O, Berglund, G, Hirschhorn, Jn, Asselta, R, Duga, S, Spreafico, M, Musunuru, K, Purcell, S, Surti, A, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, Gabriel, Sb, Stahl, Ea, Wegmann, D, Trynka, G, Gutierrez achury, J, Do, R, Voight, Bf, Kraft, P, Che, R, Kallberg, H, Kurreeman, F, Diabetes Genetics Replication And Meta analysis Consortium: Myocardial Infarction Genetics, Consortium, Casari, GIORGIO NEVIO, Kathiresan, S, Wijmenga, C, Gregersen, Pk, Alfredsson, L, Siminovitch, Ka, Worthington, J, De Bakker, Pi, Raychaudhuri, S, Plenge, Rm, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Multifactorial Inheritance, SUSCEPTIBILITY LOCI, GENETIC SUSCEPTIBILITY, Genome-wide association study, Single-nucleotide polymorphism, Disease, HEART-DISEASE, Biology, VARIANTS, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, COMMON SNPS, Missing heritability problem, MISSING HERITABILITY, Rheumatoid, Genetic model, Genetic predisposition, Diabetes Mellitus, Humans, genetics, Genetic Predisposition to Disease, Human height, Polymorphism, GENOME-WIDE ASSOCIATION, Arthritis, genetics, Bayes Theorem, Cardiovascular Diseases, genetics, Case-Control Studies, Celiac Disease, genetics, Diabetes Mellitus, Type 2, genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genetics, CELIAC-DISEASE, Bayes Theorem, RISK LOCI, Genetic architecture, Celiac Disease, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Genetic Loci, Case-Control Studies, HUMAN HEIGHT, Genome-Wide Association Study
Abstract

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.

Published
2012

413. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders

Author

Peyvandi, F., Palla, R., Menegatti, M., Siboni, S.M., Halimeh, S., Faeser, B., Pergantou, H., Platokouki, H., Giangrande, P., Peerlinck, K., Celkan, T., Ozdemir, N., Bidlingmaier, C., Ingerslev, J., Giansily-Blaizot, M., Schved, J.F., Gilmore, R., Gadisseur, A., Benedik-Dolnicar, M., Kitanovski, L., Mikovic, D., Musallam, K.M., Rosendaal, F.R., En Rbd Grp, and European Network of Rare Bleeding Disorders

Subjects
Male, Turkey, Cross-sectional study, Fibrinogen, Gastroenterology, Severity of Illness Index, Risk Factors, Registries, Young adult, Child, bleeding episode, Factor X Deficiency, Blood coagulation test, Aged, 80 and over, coagulant activity, Hematology, Blood Coagulation Disorders, Middle Aged, Afibrinogenemia, Blood Coagulation Factors, Europe, Coagulation, Predictive value of tests, Child, Preschool, Female, Blood Coagulation Tests, medicine.symptom, medicine.drug, Adult, medicine.medical_specialty, Adolescent, phenotype, Hemorrhage, Asymptomatic, Risk Assessment, Young Adult, Rare Diseases, Predictive Value of Tests, Internal medicine, Severity of illness, medicine, Humans, Blood Coagulation, rare bleeding disorder, Aged, business.industry, Infant, Factor XIII Deficiency, Surgery, Cross-Sectional Studies, Linear Models, Human medicine, business, Biomarkers
Abstract

Background: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. Objectives: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. Patients/Methods: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. Results: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1); FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. Conclusions: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.

Published
2012

415. Coagulation Factor Activity Level and Clinical Bleeding Severity in Rare Bleeding Disorders: Results Foam the European Network of Rare Bleeding Disorders (EN-RBD)

Author

Peyvandi, F., Palla, R., Menegatti, M., Siboni, S.M., Halimeh, S., Faeser, B., Pergantou, H., Platokouki, H., Giangrande, P., Peerlink, K., Celkan, T., Ozdemir, N., Bidlingmaier, C., Ingerslev, J., Giansily-Blaizot, M., Schved, J.F., Gilmore, R., Gadisseur, A.P., Benedik-Dolnicar, M., Kitanovski, L., Mikovic, D., Musallam, K.M., and Rosendaal, F.R.

Published
2011

417. Central nervous system bleeding in patients with rare bleeding disorders

Author

Siboni, S. M., Zanon, E., Sottilotta, G., Consonni, D., Castaman, G., Mikovic, D., Biondo, F., Tagliaferri, A., Iorio, Alfonso, Mannucci, P. M., and Peyvandi, F.

Subjects
Adult, Male, complications, Adolescent, etiology, Hemorrhage, Young Adult, Rare Diseases, Central Nervous System Diseases, Recurrence, 80 and over, Humans, Preschool, Child, Aged, Proportional Hazards Models, Retrospective Studies, Aged, 80 and over, Incidence, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation Disorders, complications, Central Nervous System Diseases, etiology, Child, Child, Preschool, Female, Hemorrhage, etiology, Humans, Incidence, Infant, Infant, Newborn, Intracranial Hemorrhages, etiology, Male, Middle Aged, Proportional Hazards Models, Rare Diseases, complications, Recurrence, Retrospective Studies, Young Adult, Infant, Newborn, Infant, Blood Coagulation Disorders, Middle Aged, Newborn, Child, Preschool, Female, Intracranial Hemorrhages
Abstract

Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2 years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation.

Published
2011

419. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H. König, I.R. Kathiresan, S. Reilly, M.P. Assimes, T.L. Holm, H. Preuss, M. Stewart, A.F.R. Barbalic, M. Gieger, C. Absher, D. Aherrahrou, Z. Allayee, H. Altshuler, D. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Balmforth, A.J. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Boerwinkle, E. Braund, P.S. Brown, M.J. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Cichon, S. Codd, V. Davies, R.W. Dedoussis, G. Dehghan, A. Demissie, S. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. Mokhtari, N.E.E. Ellis, S.G. Elosua, R. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Folsom, A.R. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gudnason, V. Gulcher, J.R. 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. Kastelein, J.J.P. Khaw, K.-T. Knowles, J.W. Kolovou, G. Kong, A. Laaksonen, R. Lambrechts, D. Leander, K. Lettre, G. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Meitinger, T. Melander, O. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peters, A. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Salomaa, V. Sampietro, M.L. Sandhu, M.S. Schadt, E. Scḧsignfer, A. Schillert, A. Schreiber, S. Schrezenmeir, J. Schwartz, S.M. Siscovick, D.S. Sivananthan, M. Sivapalaratnam, S. Smith, A. Smith, T.B. Snoep, J.D. Soranzo, N. Spertus, J.A. Stark, K. Stirrups, K. Stoll, M. Tang, W.H.W. Tennstedt, S. Thorgeirsson, G. Thorleifsson, G. Tomaszewski, M. Uitterlinden, A.G. Van Rij, A.M. Voight, B.F. Wareham, N.J. Wells, G.A. Wichmann, H.-E. Wild, P.S. Willenborg, C. Witteman, J.C.M. Wright, B.J. Ye, S. Zeller, T. Ziegler, A. Cambien, F. Goodall, A.H. Cupples, L.A. Quertermous, T. Mäsignrz, W. Hengstenberg, C. Blankenberg, S. Ouwehand, W.H. Hall, A.S. Deloukas, P. Thompson, J.R. Stefansson, K. Roberts, R. Thorsteinsdottir, U. O'Donnell, C.J. McPherson, R. Erdmann, J. Samani, N.J.

Subjects
cardiovascular diseases
Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. © 2011 Nature America, Inc. All rights reserved.

Published
2011

420. 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.C. 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.P. 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.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
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 b-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 3 10-4), improved b-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. © 2011 by the American Diabetes Association.

Published
2011

421. 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. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. 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

422. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H, König, Ir, Kathiresan, S, Reilly, Mp, Assimes, Tl, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Balmforth, Aj, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Boerwinkle, E, Braund, Ps, Brown, Mj, 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, Mokhtari, Ne, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Kastelein, Jj, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Laaksonen, R, Lambrechts, D, Leander, K, Lettre, G, Li, M, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Meitinger, T, Melander, O, 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, Peters, A, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Soranzo, N, Spertus, Ja, Stark, K, Stirrups, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Thorleifsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Witteman, Jc, Wright, Bj, Ye, S, Zeller, T, Ziegler, A, Cambien, F, Goodall, Ah, Cupples, La, Quertermous, T, März, W, Hengstenberg, C, Blankenberg, S, Ouwehand, Wh, Hall, As, Deloukas, P, Thompson, Jr, Stefansson, K, Roberts, R, Thorsteinsdottir, U, O'Donnell, Cj, Mcpherson, R, Erdmann, J, the CARDIoGRAM Consortium, Samani, N. J., Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Adult, Male, Multifunction cardiogram, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Genetic determinism, artery disease, Article, Coronary artery disease, Gene Frequency, SDG 3 - Good Health and Well-being, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Allele, Genotyping, Allele frequency, coronary, Alleles, Genetics (clinical), Aged, Genetic association, business.industry, Case-control study, Middle Aged, medicine.disease, coronary artery disease, Large-scale association analysis, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

1. The CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011;43:333–338. ### Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants that are associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). The authors state that the current loci discovered in CAD and MI GWAS explain only a small fraction of the heritability of this complex disease. The authors hypothesized that a larger study would provide more power to discover common variants with modest effect sizes. Therefore, they formed the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium, which consisted of data from 14 GWAS of CAD and MI.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 14 GWAS of CAD comprising 22 233 cases and 64 762 control subjects, all of European ancestry. CAD was defined angiographically in a subset (n=7364) and by history in the entire sample. Presence of MI ranged from 48.1% to 100% of each cohort. After the meta-analysis, they genotyped the lead single-nucleotide polymorphisms (SNPs) within the most promising (defined a priori as P 90% power to detect effect sizes observed in the GWAS meta-analysis. Finally, to understand potential mechanisms and intermediate pathways by which novel loci may mediate risk, the authors interrogated 3 genome-wide studies that also assessed gene expression in multiple tissues, using human cell lines, a genome-wide map of allelic expression imbalance, and other human disease traits. ### Principal Findings The analysis of approximately 135 000 individuals more than doubled the number of loci with CAD association, yielding 13 previously unidentified loci and confirming at …

Published
2011

433. Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A

Author

Bafunno, V., Santacroce, R., Chetta, M., D'Andrea, G., Pisanelli, D., Sessa, F., Trotta, T., Tagariello, G., Peyvandi, F., and Margaglione, M.

Subjects
Haemophilia, Hemophilia A, Antibodies, Autoimmune Diseases, Genetic, Gene Frequency, Antigens, CD, Risk Factors, Autoimmune disease, Humans, CTLA-4 Antigen, Antigens, Polymorphism, Factor VIII, Polymorphism, Genetic, Blood Coagulation Factor Inhibitors, Inhibitors, Tumor Necrosis Factor-alpha, Forkhead Transcription Factors, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Exons, Non-Receptor Type 22, CD, Interleukin-10, Italy, Interferon Regulatory Factors, Protein Tyrosine Phosphatase, Polymorphisms
Abstract

One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFalpha, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.

Published
2009

439. Manuale di Ematologia

Author

Corradini, P., Foa, Roberto, Boccadoro, M., Cappellini, M. D., CARLO STELLA, C., Cattaneo, M., Federici, A. B., GAMBACORTI PASSERINI, C., LAMBERTENGHI DELILIERS, G., Mannuccio, P. M., Pane, F., Peyvandi, F., and Pogliani, E. M.

Published
2008

444. New Findings on Inhibitor Development: from Registries to Clinical Studies.

Author

PEYVANDI, F., ETTINGSHAUSEN, C. E., GOUDEMAND, J., JIMÉNEZ-YUSTE, V., SANTAGOSTINO, E., and MAKRIS, M.

Subjects
*BLOOD coagulation factor VIII, *HEMOPHILIA, *HEMOPHILIACS, *IMMUNOLOGICAL tolerance, *PREVENTIVE medicine
Abstract

The high incidence of inhibitors against factor VIII (FVIII) concentrates in patients with haemophilia A has encouraged debate as to whether product-type plays a role. There is debate in the literature as to whether rFVIII concentrates are associated with a higher incidence of inhibitors compared to pdFVIII products. The management of haemophilia in patients with inhibitors includes on-demand/prophylaxis treatment with bypassing agents, and/ or immune tolerance induction (ITI). However, these options create an economic and emotional burden on patients, their families and healthcare practitioners. Although ITI eliminates inhibitors successfully in 60-80% of cases, it is costly. Despite high costs, preliminary data from a decision analytical model have indicated that ITI is economically advantageous compared with on-demand/prophylactic treatment with bypassing agents. In patients with persistent inhibitors and those who are not candidates for ITI or have failed ITI, bleeding-related mortality and morbidity increase and quality of life decreases, compared with non-inhibitor patients. This article provides an update on the risk of inhibitor development and discusses best management approaches for patients with high-risk factors for inhibitor development. [ABSTRACT FROM AUTHOR]

Published
2017
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447. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency

Author

Mariani, G, Herrmann, Fh, Dolce, A, Batorova, A, Etro, Daniela, Peyvandi, F, Wulff, K, Schved, Jf, Auerswald, G, Ingerslev, J, Bernardi, Francesco, and INTERNATIONAL FACTOR VII DEFICIENCY STUDY GROUP

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Adolescent, Genotype, Factor VII Deficiency, Hemorrhage, Gene mutation, Gastroenterology, Asymptomatic, chemistry.chemical_compound, Sex Factors, Polymorphism (computer science), Interquartile range, Internal medicine, medicine, Coagulopathy, Humans, Expressivity (genetics), Child, factor VII deficiency, clinical phenotype, factor VII genotype, Aged, Aged, 80 and over, Factor VII, business.industry, Genetic Variation, Infant, Hematology, Middle Aged, medicine.disease, Phenotype, chemistry, Child, Preschool, Factor Xa, Mutation, Female, medicine.symptom, business
Abstract

SummaryTo investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease char-acterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9–3.8), 83 'moderate' (FVIIc 3%, IQR 1–21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3–31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio =2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125del C) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.

Published
2005

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