AUTHOR=Corvillo Fernando , Morena-Barrio María Eugenia de la , Marcos-Bravo Carmen , López-Trascasa Margarita , Vicente Vicente , Emsley Jonas , Caballero Teresa , Corral Javier , López-Lera Alberto 

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

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.01033

DOI=10.3389/fgene.2020.01033

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>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&gt;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.</p></sec><sec><title>Objectives</title><p>To assess the influence of the c.-4T&gt;C polymorphism on disease expression in 39 Spanish HAE-FXII index patients.</p></sec><sec><title>Methods</title><p>The c.-4T&gt;C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by <xref ref-type="bibr" rid="B13">Cumming et al. (2003)</xref> 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.</p></sec><sec><title>Results</title><p>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%) (<italic>p</italic> = 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) (<italic>p</italic> = 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; <italic>p</italic> = 0.006) but not the degree of estrogen dependence or time until remission.</p></sec><sec><title>Conclusion</title><p>The c.-4T&gt;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.</p></sec>