Genetic variants contribute to modulation of renal function in patients with immune thrombotic thrombocytopenic purpura

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2024-07-16 DOI:10.1016/j.bvth.2024.100019

Wenjing Cao , Malay K. Basu , Elizabeth Staley , X. Long Zheng

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Abstract

Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13. However, the contribution of genetic variations that may modulate its clinical presentations remains unknown. This study aimed to determine the potential contribution of variants in the genes associated with coagulation, complement activation or regulation, and platelet activation to pathophysiology of iTTP. Multicenter case series, whole-exome sequencing, and bioinformatic approaches were used. We focused on analysis of 20 genes that are involved in regulation of coagulation (eg, ADAMTS13, THBD, MMACHC, INF2, and PLG), complement activation (eg, C3, C3AR1, C5, CFB, CFH, CFI, C4BPA, CD46 [MCP], CD59, and CFHR1-CFHR5), and platelet activation (eg, DGKE) from 40 adult patients with iTTP. Multiple genetic variations were identified in 12 of 20 genes of interest. More than 80% of patients harbored genetic variants in CFI, CFH, C5, and ADAMTS13; 15% to 55% of patients had variants in C3, INF2, CFHR5, and PLG; and <10% of patients had variants in CD46, C3AR1, DGKE, and THBD. Of these, the variants in C5 are associated with a more favorable renal function, whereas the variants in DGKE are associated with more persistently elevated creatinine levels. These results demonstrate that 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.

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基因变异有助于调节免疫性血小板减少性紫癜患者的肾功能

摘要免疫性血栓性血小板减少性紫癜（iTTP）是一种潜在的致命性血液疾病，由针对 ADAMTS13 的自身抗体引起。然而，遗传变异对其临床表现的影响仍不清楚。本研究旨在确定与凝血、补体激活或调节以及血小板激活相关的基因变异对 iTTP 病理生理学的潜在影响。研究采用了多中心病例系列、全外显子组测序和生物信息学方法。我们重点分析了 40 名 iTTP 成年患者中参与凝血调节（如 ADAMTS13、THBD、MMACHC、INF2 和 PLG）、补体激活（如 C3、C3AR1、C5、CFB、CFH、CFI、C4BPA、CD46 [MCP]、CD59 和 CFHR1-CFHR5）和血小板激活（如 DGKE）的 20 个基因。在 20 个相关基因中的 12 个基因中发现了多种基因变异。80%以上的患者存在CFI、CFH、C5和ADAMTS13基因变异；15%至55%的患者存在C3、INF2、CFHR5和PLG基因变异；10%的患者存在CD46、C3AR1、DGKE和THBD基因变异。其中，C5 的变异与较好的肾功能有关，而 DGKE 的变异与较持续的肌酐水平升高有关。这些结果表明，参与凝血、补体和血小板活化的基因变异在 iTTP 患者中很常见，这可能会导致严重 ADAMTS13 缺乏引起的 iTTP 表型改变或易患 iTTP。

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Blood Vessels, Thrombosis & Hemostasis

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