The functional promoter <i>F12</i>‐46C/T variant predicts the asymptomatic phenotype of C1‐INH‐HAE

Rijavec, Matija; Košnik, Mitja; Andrejević, Slađana; Karadža-Lapić, Ljerka; Grivčeva-Panovska, Vesna; Korošec, Peter

doi:10.1111/cea.13470

Cited by 14 publications

(11 citation statements)

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“…In European HAE-C1INH cohorts, the c.-4TC genotype is associated with a delayed disease onset and a lesser need for long-term prophylaxis (Bors et al, 2013;Gianni et al, 2017;Liu et al, 2019). Similarly, studies performed by Rijavec and colleagues have found a significant association of the c.-4T allele with an asymptomatic phenotype in HAE-C1INH (Rijavec et al, 2019).…”

Section: Discussionmentioning

confidence: 82%

“…In a study involving 152 European patients, those carriers of the T allele were shown to exhibit a significantly delayed disease onset and did not need long-term treatment ( Speletas et al, 2015 ). Accordingly, a recent study on southeastern European population has demonstrated that the C allele is overrepresented in HAE-C1INH patients while the T allele is associated to an asymptomatic course of the disease ( Rijavec et al, 2019 ). Of note, haplotype analysis by Cichon et al (2006) and Firinu et al (2015) has shown that the c.1032C>A (p.Thr328Lys) variant originated in an extended haplotype presenting a C allele at c.-4 position and is therefore a high-expression allele.…”

Section: Introductionmentioning

confidence: 99%

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The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

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Background Hereditary 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. Objectives To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients. Methods The 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. Results The 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. Conclusion The 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.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

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“…In HAE patients carrying a SERPING1 mutation, the F12 functional promoter polymorphism-46C/T modulates the age of onset of symptoms and the penetrance of the disease, the TT genotype being significantly associated with a 7-year delay and a 25-fold lower risk of developing symptoms. 23,24 The T allele is acknowledged to affect the translation efficiency of the gene and results in low plasma levels of FXII activity and antigen. 25 In addition, other common variants within different genes involved in the kallikrein kinin system have been suggested to modulate the occurrence of the disease.…”

Section: From Genotype To Phenotype: a Complex Relationshipmentioning

confidence: 99%

“…Indeed, besides known mutations causing the FXII‐HAE, F12 also harbours a gene variant that modulates the HAE phenotype. In HAE patients carrying a SERPING1 mutation, the F12 functional promoter polymorphism‐46C/T modulates the age of onset of symptoms and the penetrance of the disease, the TT genotype being significantly associated with a 7‐year delay and a 25‐fold lower risk of developing symptoms . The T allele is acknowledged to affect the translation efficiency of the gene and results in low plasma levels of FXII activity and antigen .…”

Section: Lightening the Dark Side Of The Pathogenesismentioning

confidence: 99%

Hereditary angioedema: Looking for bradykinin production and triggers of vascular permeability

Margaglione

D’Apolito

Santocroce

et al. 2019

Clin Experimental Allergy

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Since the Osler's identification of the inherited nature of hereditary angioedema, a huge array of information was collected on pathogenetic mechanisms of the disease. Over the last years, information grew fast, and mutations in different genes, in addition to C1‐inhibitor, were found to be causative. All types are inherited as autosomal‐dominant traits with incomplete penetrance and little or no genotype‐phenotype correlation. As a result, the clinical expression is characterized by a large heterogeneity. The acknowledgement of mechanisms leading to heterogeneity of the clinical phenotype is likely to provide important information not only for a better understanding of the pathogenesis but also for therapy. Regardless of which gene is mutated, similar pathways seem to play a pivotal role, triggering the up‐regulation of contact activation system/kallikrein kinin system and giving rise to an unbalanced increase of bradykinin. However, notwithstanding the increase of bradykinin in bloodstream, the phenomenon is localized and no general vascular leakage and oedema is recognized. Thus, it is conceivable that there exist one or more localized factors that stimulate the production of bradykinin, which does not become a systemically event. Uncovering of these factors may shed lights on the missing part of the pathogenesis of hereditary angioedema. The present review, collecting information on pathogenesis from biochemical and genetics investigations, tries to provide a comprehensive view of the pathogenesis of hereditary angioedema. This can allow for a better understanding of the disease and lead to focused investigations that can further improve our knowledge.

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“…Other less frequent types of HAE, formerly called Type III, are characterized by a family history of nonmast-cell dependent angioedema, with normal C1-INH serum levels and activity (Cicardi et al, 2016;Duffey & Firszt, 2015;Ghazi & Andrew Grant, 2013). Mutations in the F12 gene (FXII-HAE, the most frequent), angiopoietin-1 (ANGPT1), and plasminogen (PLG) have been described; however, in most patients, no gene mutations have been found and pathogenesis remains unknown (Bork, Wulff, Witzke, & Hardt, 2015;Germenis & Speletas, 2016;Maurer et al, 2018;Rijavec et al, 2019). C1-INH is a serine protease inhibitor (SERPIN) that regulates different pathways of inflammation and the coagulation system.…”

Section: Introductionmentioning

confidence: 99%

Self‐administration of icatibant in acute attacks of Type I hereditary angioedema: A case report and review of hereditary angioedema

Piras

Alves

Gonçalo

2019

Dermatologic Therapy

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Hereditary angioedema (HAE) is a rare group of genetic disease characterized by non‐itchy swelling of subcutaneous and submucosal tissues of the extremities, genitalia, gastrointestinal tract, and upper airways, which can be life threatening. Moreover, unpredictability and recurrence of HAE attacks significantly affect patients' quality of life. Short‐ and long‐term prophylaxis is used to decrease the severity and frequency of attacks, but during severe or potentially severe acute episodes, treatment with C1‐INH replacement or icatibant is mandatory. Icatibant is a selective bradykinin B2 receptor antagonist that has been licensed for self‐administration at home, resulting in earlier treatment of the attack and quicker recovery, less emergency admittance with a significant improvement of patients' quality of life, and decrease of health care costs. The authors present a case of a young woman, affected by Type I HAE, who has been successfully treated with icatibant on demand at home, resulting in reduction of emergency admissions and improvement of quality of life. The authors also review the different types HAE, their clinical aspects, diagnosis, and management.

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The functional promoter F12‐46C/T variant predicts the asymptomatic phenotype of C1‐INH‐HAE

Cited by 14 publications

References 14 publications

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

Hereditary angioedema: Looking for bradykinin production and triggers of vascular permeability

Self‐administration of icatibant in acute attacks of Type I hereditary angioedema: A case report and review of hereditary angioedema

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