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

Abstract

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.

Biomarkers in Hereditary Angioedema

“…1 Biomarkers in hereditary angioedema-future applications and research directions. NPV/PPV, negative/positive predictive value; HAE, hereditary angioedema; miRNA, micro RNA showed higher PKa-like activity and exhibited more severe and frequent manifestations of the disease [129].…”

Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency

“…An additional variant was found in this family: NM_000505.3:c.-4T>C;rs1801020 polymorphism in the F12 gene that has been recognized as a disease modifier in families with HAE-C1-INH 32 and with HAE with a gain of function of factor XII (HAE-FXII). 33 …”

In Silico Analysis and In-depth Assessment of a Female Patient with a Missense Mutation in the F12 Gene Associated with Hereditary Angioedema Symptoms: A Case Study

“…The F12 gene, spanning approximately 12 kbp and consists of 14 exons, some of which encode functional domains. The exon-intron organization of the gene is similar to that observed in the serine protease activator of plasminogen gene family rather than in the blood coagulation factor gene family [48,49]. The F12 protein circulates in the blood as a single-chain zymogen, which transforms into a twochain serine protease with a heavy chain (F12a) and a light chain.…”