First, NVP-BKM120 we applied two scoring systems: one recently described by Cumming et al. , the second modified by using a quantitative determination of attack frequency and a more complex definition of symptom severity, not only reflecting the body site affected (Table 1). Next, we separately sorted the patients according to particular disease manifestations such as disease course in relation to laryngeal oedema or ileus occurrence, need for hospitalization, frequency of episodes and age of disease onset, all of them known to appear independently (Table 2). It should be emphasized that all phenotypic data were related to the period without treatment to avoid misclassification becasue of
prophylactic treatment. However, worsening of a disease course in young patients later in life could not be considered in our study. Making an effort to minimize confusion caused by this factor along with the risk of falsely asymptomatic patients included into the study, we performed analyses only in individuals older than 12 years. HAE is a rare condition and a limited number of patients were available for analysis, so we decided to examine, in addition to a group of unrelated patients, a larger group of all affected persons. We assumed that such an analysis might be of value because substantial variability of disease phenotype occurs among members of
the same family [2, 6]. Bradykinin currently has the most evidence for a role as a primary oedema mediator in HAE. Thus, while looking for factors that modify the clinical manifestation of oedema, we decided to primarily analyse genes that code for proteins with a possible direct influence on bradykinin action, such as Sotrastaurin the BDKR1, BDKR2 and ACE gene. Earlier, we did not confirm a supposed influence of the BDKR2 gene variant with 9 bp deletion in the first exon in our group of patients [14, 15]. In this study, we focused on polymorphisms −58c/t and 181c/t in BDKR2, −699c/g and 1098g/c in BDKR1, and I/D in the ACE gene. Other researchers have shown that
promoter variants −58c and −699c in the BDKR2 and BDKR1 gene, respectively, increased transcription of these genes in comparison with variants −58t and −699g [16, 21]. We assumed that higher expression of bradykinin receptors not could represent higher susceptibility to oedema development. Another polymorphism in the BDKR1 gene, 1098g/c, located in the 3′ untranslated region, might have an influence on mRNA stability . The D variant in the 16th exon of the ACE gene was shown to increase degradation of bradykinin compared to variant I . Thus, we might suggest a hypothesis that oedemas will develop more frequently in I variant carriers. An alternative hypothesis might be that oedema manifestation is enhanced by the D variant in cases when up-regulation of bradykinin receptors becasue of lower bradykinin concentration is predominant. Nevertheless, our results did not support any of above-mentioned hypotheses.