title: Immunochip analysis identifies novel susceptibility loci in the human leukocyte antigen region for acquired thrombotic thrombocytopenic purpura.
abstract: Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case-control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02-3.27, P = 1.64 × 10-14). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10-5to 7.60 × 10-5). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10-19). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease.
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, Milan, Italy.
authors.forename: I
authors.identifier: 0000-0002-5059-5212
authors.initials: I
authors.lastname: Mancini
authors.affiliation: Genetics Department, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Pappalardo
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cairo
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, Milan, Italy.
authors.forename: M M
authors.initials: MM
authors.lastname: Gorski
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Casoli
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Ferrari
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Alberti
authors.affiliation: Hemostasis Department and Hemophilia Center, Blood Transfusion Institute of Serbia, Belgrade, Serbia.
authors.forename: D
authors.initials: D
authors.lastname: Mikovic
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Noris
authors.affiliation: Genetics Department, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, Milan, Italy.|Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen
keywords: SNPs; genetic association studies; genetic predisposition to disease; human leukocyte antigen; risk factors; thrombotic thrombocytopenic purpura