Meta-analysis links HLA alleles and ADAMTS13 variants to thrombotic thrombocytopenic purpura risk

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Journal of thrombosis and haemostasis : JTH Published May 9, 2026 Medically reviewed May 9, 2026 Study authors: Carter Matthew A, Scully Marie PubMed ↗ DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider that HLA-DRB1*11 and *04 are associated with iTTP risk and protection, respectively, but associations vary by ancestry.

This systematic review and meta-analysis examined genetic variants associated with immune thrombotic thrombocytopenic purpura (iTTP) and congenital thrombotic thrombocytopenic purpura (cTTP). The analysis focused on HLA alleles, ADAMTS13 variants, and genome-wide association study loci. The population included patients with iTTP and cTTP, with some studies limited to European ancestry for GWAS.

Key findings include that HLA-DRB1*11 was the most consistently associated allele with increased iTTP risk, while HLA-DRB1*04 was associated with protection. A locus on chromosome 3 (rs9884090) was associated with reduced iTTP risk. For cTTP, 364 ADAMTS13 variants were identified, of which 199 (54.7%) were missense, with the highest density in exon 7 (32 variants, 8.8%).

The authors note that effect sizes varied across ancestral populations, and the certainty of many ADAMTS13 variant associations is uncertain. The study emphasizes that these are associations, not causal relationships, and effect sizes should not be generalized across populations.

Clinically, these findings may inform genetic risk assessment, but the associative nature and population variability limit direct practice application. Further research is needed to clarify causal mechanisms and validate findings in diverse populations.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedMay 2026

PMID41692098

View Original Abstract ↓

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.