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Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to invest...

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Autores principales: Stubbs, Matthew J., Coppo, Paul, Cheshire, Chris, Veyradier, Agnès, Dufek, Stephanie, Levine, Adam P., Thomas, Mari, Patel, Vaksha, Connolly, John O., Hubank, Michael, Benhamou, Ygal, Galicier, Lionel, Poullin, Pascale, Kleta, Robert, Gale, Daniel P., Stanescu, Horia, Scully, Marie A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883548/
https://www.ncbi.nlm.nih.gov/pubmed/33596643
http://dx.doi.org/10.3324/haematol.2020.274639
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author Stubbs, Matthew J.
Coppo, Paul
Cheshire, Chris
Veyradier, Agnès
Dufek, Stephanie
Levine, Adam P.
Thomas, Mari
Patel, Vaksha
Connolly, John O.
Hubank, Michael
Benhamou, Ygal
Galicier, Lionel
Poullin, Pascale
Kleta, Robert
Gale, Daniel P.
Stanescu, Horia
Scully, Marie A.
author_facet Stubbs, Matthew J.
Coppo, Paul
Cheshire, Chris
Veyradier, Agnès
Dufek, Stephanie
Levine, Adam P.
Thomas, Mari
Patel, Vaksha
Connolly, John O.
Hubank, Michael
Benhamou, Ygal
Galicier, Lionel
Poullin, Pascale
Kleta, Robert
Gale, Daniel P.
Stanescu, Horia
Scully, Marie A.
author_sort Stubbs, Matthew J.
collection PubMed
description Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically distinct associations in iTTP. We compared two iTTP patient cohorts with controls, following standardized genome-wide quality control procedures for single-nucleotide polymorphisms and imputed HLA types. Associations were functionally investigated using expression quantitative 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 detected 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 potential causative variant (rs71767581). This work implicates POGLUT1 in iTTP pathophysiology and suggests altered post-translational modification of its targets may influence disease susceptibility.
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spelling pubmed-88835482022-03-18 Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura Stubbs, Matthew J. Coppo, Paul Cheshire, Chris Veyradier, Agnès Dufek, Stephanie Levine, Adam P. Thomas, Mari Patel, Vaksha Connolly, John O. Hubank, Michael Benhamou, Ygal Galicier, Lionel Poullin, Pascale Kleta, Robert Gale, Daniel P. Stanescu, Horia Scully, Marie A. Haematologica Article Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically distinct associations in iTTP. We compared two iTTP patient cohorts with controls, following standardized genome-wide quality control procedures for single-nucleotide polymorphisms and imputed HLA types. Associations were functionally investigated using expression quantitative 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 detected 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 potential causative variant (rs71767581). This work implicates POGLUT1 in iTTP pathophysiology and suggests altered post-translational modification of its targets may influence disease susceptibility. Fondazione Ferrata Storti 2021-02-18 /pmc/articles/PMC8883548/ /pubmed/33596643 http://dx.doi.org/10.3324/haematol.2020.274639 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Stubbs, Matthew J.
Coppo, Paul
Cheshire, Chris
Veyradier, Agnès
Dufek, Stephanie
Levine, Adam P.
Thomas, Mari
Patel, Vaksha
Connolly, John O.
Hubank, Michael
Benhamou, Ygal
Galicier, Lionel
Poullin, Pascale
Kleta, Robert
Gale, Daniel P.
Stanescu, Horia
Scully, Marie A.
Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title_full Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title_fullStr Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title_full_unstemmed Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title_short Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
title_sort identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883548/
https://www.ncbi.nlm.nih.gov/pubmed/33596643
http://dx.doi.org/10.3324/haematol.2020.274639
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