Genetic Variants Contribute to Modulation of Renal Function in Patients with Immune Thrombotic Thrombocytopenic Purpura

• Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) exhibit various degrees of renal insufficiency.

• We found that genetic variations in complement C5 and diacylglycerol kinase epsilon (DGKE) modify the renal presentation in iTTP.

Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13. However, genetic variations that may contribute to modulation of its clinical presentations remain unknown. The present study aims to determine the potential contribution of variants in the genes associated with coagulation, complement activation or regulation, and platelet activation to pathophysiology of iTTP. Multi-center case series, whole exome sequencing (WES), and bioinformatic approaches were employed. We focused on analysis of 20 genes that are involved in regulation of coagulation (e.g., ADAMTS13, THBD, MMACHC, INF2, and PLG), complement activation (e.g., C3, C3AR1, C5, CFB, CFH, CFI, C4BPA, CD46 or MCP, CD59, CFHR1-CFHR5), and platelet activation (e.g., DGKE) from 40 adult patients with iTTP. Multiple genetic variations were identified in 12 of 20 genes of interest. More than 80% patients harbored genetic variants in CFI, CFH, C5, and ADAMTS13, 15-55% patients had variants in C3, INF2, CFHR5, and PLG, and <10% patients had variants in CD46, C3AR1, DGKE, and THBD. Of these, the variants in C5 are associated with a more favorable renal function, while the variants in DGKE are associated with more persistently elevated creatinine levels. Conclusions: These results demonstrate that genetic variants in the genes involved in coagulation, complement, and platelet activation are common in patients with iTTP, which may contribute to phenotypical modulations of or predispose to iTTP resulting from severe ADAMTS13 deficiency.