The Contribution of Functional Polymorphismsof the Contact Activation System (F12-46C/T and KLKB1-428G/A) to the Clinical Phenotype of Hereditary Angioedema
Introduction. Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by episodic local swelling involving subcutaneous or submucous tissue in different parts of the body, including limbs, face, and throat. The disease can be potentially life-threatening when swelling obstructs the airway. Purpose. To study the contribution of the functional polymorphisms F12-46C/T and KLKB1-428G/A to the clinical phenotype of C1-INH-HAE in a cohort of patients from the Republic of Belarus. Materials and methods. The study included 73 patients; 63 patients (37 women) of them had a manifestation of the disease (type I, n=48; type II, n=15). The detection of polymorphisms F12-46C/T and KLKB1-428G/A was performed with Sanger sequencing. The statistical analysis was conducted to search for the patterns between the presence of the T and/or G alleles and the age of onset and severity of the disease. Results. We examined 73 C1-INH-HAE patients for the F12-46C/T and KLKB1-428G/A. In 63 patients with clinical manifestation of the disease, the median age of disease onset was 12.1 years (min 1, max 43), and the median severity was 6 out of 10. The presence of the T allele (homozygous and heterozygous) was significantly associated with a delay in disease onset by 5 years, but we didn’t find such association with the presence of the G allele. Also, we didn’t find any association with the presence of the G or T allele with the clinical severity score. Without statistically significant evidence, patients carrying both polymorphisms exhibited an 8.5-year delay in disease onset, if compared to the carries of the corresponding wild types (p=0.12). Conclusions. These findings demonstrate that C1-INH-HAE represents a much more extended genetic dependence than just because of mutations in the SERPING1 gene, since functional alterations in the genes encoding proteins other than the C1 inhibitor and involved in bradykinin metabolism can affect the clinical phenotype and possibly contribute to the pathogenesis of C1- INH-HAE.