OC 04.5 - Immune Medicated Thrombotic Thrombocytopenic Purpura relapse is associated with HLA-DRB1*15:01

Saturday, July 9, 2022

2:00 PM – 2:15 PM

Location: ICC Capital Suite Room 14-16

Presentation Format: In-Person

Presenting Author(s)

Matthew J. Stubbs, MBChB, PhD

Consultant Haematologist
University College London Hospitals NHS Foundation Trust
London, England, United Kingdom

Co-Author(s)

Andrew J. Doyle, MBChB MRCP FRCPath

Consultant Haematologist
Guy's & St Thomas' NHS Foundation Trust
London, England, United Kingdom
CC

Chris Cheshire

Post-Doctoral Scientist
University College London
London, England, United Kingdom
AL

Adam P. Levine

Specialist Registrar
University College London
London, England, United Kingdom
Mari Thomas, MD, PhD

Consultant Haematologist
University College Hospitals London NHS Foundation Trust
London, England, United Kingdom
JW

John-Paul Westwood

Consultant Haematologist
University College London Hospitals NHS Foundation Trust
London, England, United Kingdom
RK

Robert Kleta

Director of Division of Medicine
University College London
London, England, United Kingdom
DG

Daniel P. Gale

Professor of Nephrology
University College London
London, England, United Kingdom
HS

Horia Stanescu

Senior Lecturer
University College London
London, England, United Kingdom
Marie Scully, MD

Professor of Haemostasis and Thrombosis
Department of Haematology, University College London Hospitals, London, UK
London, England, United Kingdom

Background: Despite significant advances in immune Thrombotic Thrombocytopenic Purpura (iTTP) care relapses occur in 30-50% of patients. This causes significant morbidity and mortality, and the aetiology remains poorly understood.

Aims: We undertook HLA and genome-wide analysis to identify genetic associations for iTTP relapse.

Methods: 155 iTTP patients (44 relapsed, 111 non-relapsed) of European genetic ancestry were genotyped at 3,649,347 Single Nucleotide Polymorphisms genome-wide. HLA imputation was performed using SNP2HLA (V1.0.3, European reference panel). Relapse data from the UK TTP registry (defined as ADAMTS13 relapse or clinical relapse) were used to identify iTTP relapse associations.

Results: Among 25 Class-II HLA types tested, HLA-DRB1*15:01 was identified as being associated with iTTP disease relapse (P=0.0008, see Table 1). HLA-DQB1*06:02 and HLA-DQA1*01:02, which are in linkage disequilibrium with HLA-DRB1*15:01, also showed evidence of association.

HLA-DRB1*11:01 and HLA-DQA1*03:01 (associated with risk of iTTP) were not associated with disease relapse (P=0.97 and 0.94 respectively). Genome-wide association analysis revealed that no genetic markers outside HLA region were significantly associated with iTTP relapse.

Conclusion(s): Here we demonstrate HLA-DRB1*15:01 being associated with iTTP relapse for the first time, but not HLA-DRB1*11:01. HLA-DRB1*11:01 is well established in iTTP risk, with functional studies demonstrating that this allele is associated with ADAMTS13 presentation in addition to autoreactive CD4+ Th-cells. HLA-DRB1*15:01 is associated with several other autoimmune conditions (notably multiple sclerosis and SLE). Subsequent functional studies in MS implicate HLA-DRB1*15:01 in autoreactive T-cell activity and antigen presentation, and it is possible that similar mechanisms are also important in iTTP relapse. This work has identified HLA-DRB1*15:01 as a means to potentially individualise monitoring to reduce relapse risk, in addition to increasing understanding of the pathophysiology in iTTP relapse.