Publications

Background: In view of the large heterogeneity in the clini- cal presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made to- wards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kalli- krein 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 sig- nificantly 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% low- er 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 dis- ease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity.