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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):574-582
Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
Matthew J. Stubbs,1,2 Paul Coppo,3 Chris Cheshire,2 Agnès Veyradier,4 Stephanie Dufek,2 Adam P. Levine,2 Mari Thomas,1,5 Vaksha Patel,2 John O. Connolly,2 Michael Hubank,6 Ygal Benhamou,3 Lionel Galicier,3 Pascale Poullin,3 Robert Kleta,2# Daniel P. Gale,2# Horia Stanescu2# and Marie A. Scully1,5#
1Hemostasis Research Unit, ULC, London, UK; 2Department of Renal Medicine, UCL, London, UK; 3Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, Paris, France; 4Department d’Hematologie, Centre de Référence des Microangiopathies Thrombotiques, Hôpital Lariboisière, Paris, France; 5National Institute for Health Research Cardiometabolic Programme, UCLH/UCL Cardiovascular BRC, London, UK and 6Clinical Genomics, Royal Marsden Hospital, London, UK.
#RK, DPG, HS and MAS contributed equally as co-senior authors.
ABSTRACT
Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 defi- ciency causing multi-system micro-thrombi formation, and has spe- cific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically dis- tinct associations in iTTP. We compared two iTTP patient cohorts with controls, following standardized genome-wide quality control proce- dures for single-nucleotide polymorphisms and imputed HLA types. Associations were functionally investigated using expression quantita- tive trait loci (eQTL), and motif binding prediction software. Independent associations consistent with previous findings in iTTP were detected at the HLA locus and in addition a novel association was detect- ed on chromosome 3 (rs9884090, P=5.22x10-10, odds ratio 0.40) in the UK discovery cohort. Meta-analysis, including the French replication cohort, strengthened the associations. The haploblock containing rs9884090 is associated with reduced protein O-glycosyltransferase 1 (POGLUT1) expression (eQTL P<0.05), and functional annotation suggested a poten- tial causative variant (rs71767581). This work implicates POGLUT1 in iTTP pathophysiology and suggests altered post-translational modifica- tion of its targets may influence disease susceptibility.
Introduction
Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare, life-threatening illness, with an annual incidence of approximately 6/million, and with an untreat- ed mortality approaching 90% (10-20% with prompt intervention). It can affect patients of any age, but often affects young adults (30-40 years) and is more com- mon in women.1 The initial diagnosis of TTP is based on clinical suspicion, but ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity <10 IU/dL confirms the diagnosis. Severe deficiency of ADAMTS13 results in failure to cleave ultra-large von Willebrand Factor multi- mers (UL-VWF), crucial for normal hemostatic function and proteolytic regulation of VWF. ADAMTS13 deficiency in immune TTP (iTTP) is mediated through immunoglobulin G (IgG) autoantibodies.2,3 The precipitant of the disease in most cases is unclear.4
As with many autoimmune diseases, human leukocyte antigen (HLA) type is associated with the risk of developing iTTP, with HLA-DRB1*11, HLA-DQB1*03 and HLADRB3* increasing risk, and HLA-DRB1*04 and HLA-DRB4 (HLA-DR53) being protective in Europeans.5,6,7 No genetic risk factors outside the HLA genes have previously been shown to be associated with iTTP.
Platelet Biology & its Disorders
Correspondence:
MATTHEW JAMES STUBBS
m.stubbs@doctors.org.uk
Received: October 21, 2020. Accepted: February 2, 2021. Pre-published: February 18, 2021.
https://doi.org/10.3324/haematol.2020.274639 ©2022 Ferrata Storti Foundation
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