Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset

Abstract

Background: In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype. Methods: We studied 249 C1-INH-HAE patients from 114 European families, and we explored possible associations of C1-INH-HAE clinical features with carriage of KLKB1-428G/A, combined or not with that of the functional F12-46C/T polymorphism. Results: Carriers of the G allele of the KLKB1-428G/A polymorphism exhibited a significantly delayed disease onset (i.e., by 4.1 years [p < 0.001], depending on the zygocity status), while carriers of both the KLKB1-428G/A and the F12-46C/T polymorphism displayed an 8.8-year delay in disease onset (p < 0.001) and a 64% lower probability of needing long-term prophylactic treatment (p = 0.019). Conclusions: These findings support our initial hypothesis that functional alterations in genes of proteins involved in bradykinin metabolism and function affect the clinical phenotype and possibly contribute to the pathogenesis of C1-INH-HAE. Given that an earlier onset of symptoms is inversely correlated with the subsequent course of the disease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity.

On the pathogenicity of the plasminogen K330E mutation for hereditary angioedema

“…went back to their whole‐exome sequencing data to investigate the possible co‐segregation of gene variants encoding for other proteins of the contact system that may affect either the expression of the disease or its clinical phenotype. In support of this hypothesis is our finding that the F12 ‐46C/T and the KLKB1 ‐S143N functional variants are associated with the clinical severity of HAE due to C1‐INH deficiency …”

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

“…On one hand, we found a significant over-representation of the C allele and the CC genotype in the studied patients ( Figure 1 ), which is in line with previous studies implicating c.-4T>C in HAE-C1INH. 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 ).…”

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

“…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. 26 The traditional view of genetic diseases as monogenic or multifactorial is no longer supported and requires a different way of thinking towards factors that modify gene expression and clinical phenotype.…”

“…The T allele is acknowledged to affect the translation efficiency of the gene and results in low plasma levels of FXII activity and antigen . In addition, other common variants within different genes involved in the kallikrein kinin system have been suggested to modulate the occurrence of the disease …”