Stubbs, Matthew James; (2021) Characterisation of Immune Thrombotic Thrombocytopenic Purpura utilising deep phenotyping and genotyping via genome wide association study. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Immune Thrombotic Thrombocytopenic Purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system microthrombus formation. It has specific HLA associations. We used genome-wide association studies to investigate whether iTTP patients are genetically distinct from controls. We examined two iTTP patient cohorts against controls, following standardised genome-wide quality control procedures for SNPs (>3million) and imputed HLA types. Associations were functionally investigated using expression quantitative trait loci (eQTL), motif binding prediction software, and by electrophoretic mobility shift assay (EMSA). Potential proteinprotein interactions were identified in-silico using Mast-Meme. We identified a novel locus on chromosome 3 (rs9884090, p-value of 5.22x10-10, OR0.40) associated with reduced risk of developing iTTP in the UK discovery cohort. Independent HLA signals were also detected, confirming known iTTP HLA associations. Meta-analysis,including the French replication cohort, strengthened the significance of statistical associations. The haploblock containing rs9884090 is associated with reduced POGLUT1 expression (eQTL P<0.05), and a potential causative variant (rs71767581) was identified and validated (by EMSA) within the POGLUT1 promotor. POGLUT1 in-silico modelling suggested POGLUT1 may bind ADAMTS13 TSP domains at O-glycosylation sites (TSP3:S757, TSP6:S1008, TSP7:S1027). The novel locus identified is associated with reduced risk of developing iTTP, conferring protection with an incidence of 8% of cases versus 19% in controls. Reduced POGLUT1 expression may contribute to iTTP by post-transcriptionally modifying key iTTP targets, which may include ADAMTS13, or alternative targets such as NOTCH proteins. POGLUT1 is a glycosyltransferase known to glycosylate EGF-domains, and POGLUT1 may potentially bind TSP domains within ADAMTS13, in addition to other potential targets. This work directly implicates POGLUT1 in iTTP pathophysiology.

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