Germline mutations in the alternative pathway of complement predispose to HELLP syndrome
| Autor: | Solange N. Eloundou, Samuel A. Merrill, Shruti Chaturvedi, Karin J. Blakemore, Andrea C. Baines, Igor Makhlin, Jagar Jasem, Xuan Yuan, Arthur J. Vaught, Robert A. Brodsky, C. John Sperati, Evan M. Braunstein |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult medicine.medical_specialty HELLP Syndrome Adolescent HELLP syndrome Thrombotic thrombocytopenic purpura 030204 cardiovascular system & hematology 03 medical and health sciences Young Adult 0302 clinical medicine Germline mutation Pregnancy Risk Factors Internal medicine Atypical hemolytic uremic syndrome medicine Genetic predisposition Complement C3b Inactivator Proteins Humans Genetic Predisposition to Disease Prospective Studies Germ-Line Mutation Aged Atypical Hemolytic Uremic Syndrome Analysis of Variance Complement Inactivator Proteins Hematology Purpura Thrombotic Thrombocytopenic business.industry Case-control study General Medicine Blood Proteins Middle Aged medicine.disease Hemolysis 030104 developmental biology Case-Control Studies Immunology Female Clinical Medicine business |
| Popis: | BACKGROUND. HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a severe variant of hypertensive disorders of pregnancy affecting approximately 1% of all pregnancies, and has significant maternal and fetal morbidity. Previously, we showed that upregulation of the alternative pathway of complement (APC) plays a role in HELLP syndrome. We hypothesize that HELLP syndrome follows a 2-hit disease model similar to atypical hemolytic uremic syndrome (aHUS), requiring both genetic susceptibility and an environmental risk factor. Our objective was to perform a comparative analysis of the frequency of APC activation and germline mutations in affected women and to create a predictive model for identifying HELLP syndrome. METHODS. Pregnant women with HELLP syndrome, and healthy controls after 23 weeks of gestation were recruited, along with aHUS and thrombotic thrombocytopenic purpura participants. We performed a functional assay, the mHam, and targeted genetic sequencing in all groups. RESULTS. Significantly more participants with rare germline mutations in APC genes were present in the HELLP cohort compared with controls (46% versus 8%, P = 0.01). In addition, significantly more HELLP participants were positive for the mHam when compared with controls (62% versus 16%, P = 0.009). Testing positive for both a germline mutation and the mHam was highly predictive for the diagnosis of HELLP syndrome. CONCLUSION. HELLP syndrome is characterized by both activation of the APC and frequent germline mutations in APC genes. Similar to aHUS, treatment via complement inhibition to mitigate maternal and fetal morbidity and mortality may be possible. FUNDING. National Heart Lung and Blood Institute grants T32HL007525 and R01HL133113. |
| Databáze: | OpenAIRE |
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