Journal of Clinical Medicine (Oct 2020)
The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians
- Ilaria Mancini,
- Elisa Giacomini,
- Silvia Pontiggia,
- Andrea Artoni,
- Barbara Ferrari,
- Emanuela Pappalardo,
- Roberta Gualtierotti,
- Silvia Maria Trisolini,
- Saveria Capria,
- Luca Facchini,
- Katia Codeluppi,
- Erminia Rinaldi,
- Domenico Pastore,
- Simona Campus,
- Cinzia Caria,
- Aldo Caddori,
- Daniela Nicolosi,
- Gaetano Giuffrida,
- Vanessa Agostini,
- Umberto Roncarati,
- Clara Mannarella,
- Alberto Fragasso,
- Gian Marco Podda,
- Simone Birocchi,
- Anna Maria Cerbone,
- Antonella Tufano,
- Giuseppe Menna,
- Michele Pizzuti,
- Michela Ronchi,
- Alessandro De Fanti,
- Sergio Amarri,
- Marzia Defina,
- Monica Bocchia,
- Silvia Cerù,
- Salvatore Gattillo,
- Frits R. Rosendaal,
- Flora Peyvandi
Affiliations
- Ilaria Mancini
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy
- Elisa Giacomini
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy
- Silvia Pontiggia
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Andrea Artoni
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Barbara Ferrari
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Emanuela Pappalardo
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy
- Roberta Gualtierotti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy
- Silvia Maria Trisolini
- Hematology, Department of Translational and Precision Medicine, “Sapienza” University of Rome, 00161 Rome, Italy
- Saveria Capria
- Hematology, Department of Translational and Precision Medicine, “Sapienza” University of Rome, 00161 Rome, Italy
- Luca Facchini
- Hematology Unit, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
- Katia Codeluppi
- Hematology Unit, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
- Erminia Rinaldi
- Hematology Unit, A. Perrino Hospital, 72100 Brindisi, Italy
- Domenico Pastore
- Hematology Unit, A. Perrino Hospital, 72100 Brindisi, Italy
- Simona Campus
- Pediatric Unit, Ospedale Microcitemico, 09121 Cagliari, Italy
- Cinzia Caria
- Internal Medicine Unit, S.S. Trinità Hospital, 09121 Cagliari, Italy
- Aldo Caddori
- Internal Medicine Unit, S.S. Trinità Hospital, 09121 Cagliari, Italy
- Daniela Nicolosi
- Hematology Division, Department of Clinical and Molecular Biomedicine, University of Catania, 95123 Catania, Italy
- Gaetano Giuffrida
- Hematology Division, Department of Clinical and Molecular Biomedicine, University of Catania, 95123 Catania, Italy
- Vanessa Agostini
- U.O. Medicina Trasfusionale, IRCCS—Ospedale Policlinico San Martino, 16132 Genova, Italy
- Umberto Roncarati
- U.O. Immunoematologia e Medicina Trasfusionale/Officina Trasfusionale, Cesena e Forlì, 47521 Cesena, Italy
- Clara Mannarella
- Hematology Unit, Madonna delle Grazie Hospital, 75100 Matera, Italy
- Alberto Fragasso
- Hematology Unit, Madonna delle Grazie Hospital, 75100 Matera, Italy
- Gian Marco Podda
- U.O. Medicina III, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
- Simone Birocchi
- U.O. Medicina III, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
- Anna Maria Cerbone
- Department of Clinical Medicine and Surgery, AOU Federico II, 80131 Naples, Italy
- Antonella Tufano
- Department of Clinical Medicine and Surgery, AOU Federico II, 80131 Naples, Italy
- Giuseppe Menna
- Department of Oncology, AORN Santobono-Pausilipon, 80122 Naples, Italy
- Michele Pizzuti
- Hematology Unit, AO San Carlo, 85100 Potenza, Italy
- Michela Ronchi
- Internal Medicine Unit, Department of Medicine, Lugo Hospital, Lugo, 48022 Ravenna, Italy
- Alessandro De Fanti
- Departmental Simple Unit of Pediatric Rheumatology, AUSL-IRCSS Reggio Emilia, 42123 Reggio Emilia, Italy
- Sergio Amarri
- Paediatrics Unit, AUSL-IRCSS Reggio Emilia, 42123 Reggio Emilia, Italy
- Marzia Defina
- Department of Medical, Surgery and Neuroscience, Hematology Unit, Azienda Ospedaliera Universitaria Senese, Università degli Studi di Siena, 53100 Siena, Italy
- Monica Bocchia
- Department of Medical, Surgery and Neuroscience, Hematology Unit, Azienda Ospedaliera Universitaria Senese, Università degli Studi di Siena, 53100 Siena, Italy
- Silvia Cerù
- Hematology Unit, Santa Chiara Hospital, 38122 Trento, Italy
- Salvatore Gattillo
- Immuno-Hematology and Transfusion Medicine Unit, San Raffaele Hospital, 20132 Milan, Italy
- Frits R. Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Flora Peyvandi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy
- DOI
- https://doi.org/10.3390/jcm9103379
- Journal volume & issue
-
Vol. 9,
no. 10
p. 3379
Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30–50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β −3.34, 95%CI −6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.
Keywords