The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant
BackgroundHereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management...
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2020.01033/full |
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| author | Fernando Corvillo Fernando Corvillo María Eugenia de la Morena-Barrio María Eugenia de la Morena-Barrio Carmen Marcos-Bravo Margarita López-Trascasa Margarita López-Trascasa Vicente Vicente Vicente Vicente Jonas Emsley Teresa Caballero Teresa Caballero Teresa Caballero Javier Corral Javier Corral Alberto López-Lera Alberto López-Lera |
| author_facet | Fernando Corvillo Fernando Corvillo María Eugenia de la Morena-Barrio María Eugenia de la Morena-Barrio Carmen Marcos-Bravo Margarita López-Trascasa Margarita López-Trascasa Vicente Vicente Vicente Vicente Jonas Emsley Teresa Caballero Teresa Caballero Teresa Caballero Javier Corral Javier Corral Alberto López-Lera Alberto López-Lera |
| author_sort | Fernando Corvillo |
| collection | DOAJ |
| description | BackgroundHereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency.ObjectivesTo assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients.MethodsThe c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate.ResultsThe c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) (p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) (p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission.ConclusionThe c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease. |
| first_indexed | 2024-12-21T03:40:55Z |
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| language | English |
| last_indexed | 2024-12-21T03:40:55Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-8c501be6821e43969c9be71be3b16b1b2022-12-21T19:17:14ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-09-011110.3389/fgene.2020.01033550064The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys VariantFernando Corvillo0Fernando Corvillo1María Eugenia de la Morena-Barrio2María Eugenia de la Morena-Barrio3Carmen Marcos-Bravo4Margarita López-Trascasa5Margarita López-Trascasa6Vicente Vicente7Vicente Vicente8Jonas Emsley9Teresa Caballero10Teresa Caballero11Teresa Caballero12Javier Corral13Javier Corral14Alberto López-Lera15Alberto López-Lera16Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHospital La Paz Institute for Health Research (IdiPaz), Madrid, SpainCentre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHematology and Medical Oncology Department, University Hospital Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, IMIB-Arrixaca, Murcia, SpainAllergy Department, University Hospital Complex of Vigo, Hospital Meixoeiro, Vigo, SpainHospital La Paz Institute for Health Research (IdiPaz), Madrid, SpainFaculty of Medicine, Autonomous University of Madrid, Madrid, SpainCentre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHematology and Medical Oncology Department, University Hospital Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, IMIB-Arrixaca, Murcia, SpainCentre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United KingdomCentre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHospital La Paz Institute for Health Research (IdiPaz), Madrid, SpainAllergy Department, La Paz University Hospital, Madrid, SpainCentre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHematology and Medical Oncology Department, University Hospital Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, IMIB-Arrixaca, Murcia, SpainCentre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, SpainHospital La Paz Institute for Health Research (IdiPaz), Madrid, SpainBackgroundHereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency.ObjectivesTo assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients.MethodsThe c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate.ResultsThe c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) (p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) (p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission.ConclusionThe c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.https://www.frontiersin.org/article/10.3389/fgene.2020.01033/fullhereditary angioedemahereditary angioedema with normal C1-Inhibitorhereditary angioedema due to FXII mutationsF12 genegenetic disease-modifier |
| spellingShingle | Fernando Corvillo Fernando Corvillo María Eugenia de la Morena-Barrio María Eugenia de la Morena-Barrio Carmen Marcos-Bravo Margarita López-Trascasa Margarita López-Trascasa Vicente Vicente Vicente Vicente Jonas Emsley Teresa Caballero Teresa Caballero Teresa Caballero Javier Corral Javier Corral Alberto López-Lera Alberto López-Lera The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant Frontiers in Genetics hereditary angioedema hereditary angioedema with normal C1-Inhibitor hereditary angioedema due to FXII mutations F12 gene genetic disease-modifier |
| title | The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant |
| title_full | The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant |
| title_fullStr | The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant |
| title_full_unstemmed | The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant |
| title_short | The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant |
| title_sort | fxii c 4t c polymorphism as a disease modifier in patients with hereditary angioedema due to the fxii p thr328lys variant |
| topic | hereditary angioedema hereditary angioedema with normal C1-Inhibitor hereditary angioedema due to FXII mutations F12 gene genetic disease-modifier |
| url | https://www.frontiersin.org/article/10.3389/fgene.2020.01033/full |
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