Genetics of thrombotic thrombocytopenic purpura: systematic review in immune and congenital thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severe deficiency of the metalloprotease ADAMTS13. TTP has 2 subtypes: immune (iTTP) and congenital (cTTP). Autoimmune mechanisms underlie iTTP; however, the genetic factors influencing disease risk, relapse risk, and response to treatment are incompletely understood. In cTTP, although variants are described throughout the ADAMTS13 gene, the effect of many of these variants is uncertain. We conducted a comprehensive literature review of both iTTP and cTTP, incorporating findings from genome-wide association studies, case-control studies, registry publications, and population-level databases. In iTTP, 9 studies have investigated the effect of HLA alleles, with HLA-DRB1∗11 most consistently associated with an increased risk, and HLA-DRB1∗04 with protection. However, effect sizes varied across ancestral populations, as we highlight in a meta-analysis of available studies. Beyond the HLA locus, a genome-wide association study in iTTP patients with European ancestry identified a locus on chromosome 3 (rs9884090) associated with a reduced iTTP risk. In cTTP, we identified 364 variants within the literature, the majority (199, 54.7%) being missense variants within coding regions. Although variants are located across the gene, the highest density of variants was observed within exon 7 (32 variants, 8.8% of the total), corresponding to the metalloprotease domain. Finally, analysis of population-level constraint data from gnomAD offered additional insight into the tolerance of ADAMTS13 to variation. Together, these findings highlight the complexity of the genetic factors influencing TTP, and the value of combining clinical information and population data to increase understanding of the disease.