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 RoncaratiClara 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

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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.

Original languageEnglish
Article number3379
JournalJournal of Clinical Medicine
Issue number10
Publication statusPublished - Oct 21 2020


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