Disease-modifying factors in hereditary angioedema: an RNA expression-based screening

Abstract

BackgroundHereditary Angioedema due to C1-Inhibitor deficiency (HAE types I and II) is a monogenic disease characterized by sudden, self-limited episodes of cutaneous and mucosal swelling due to local deregulation of vascular permeability. Despite its monogenic pattern of inheritance, HAE exhibits great clinical variability and low genotype/phenotype correlation among those affected, which ultimately hinders therapeutic approach and probably underlies yet unknown genetic and environmental factors.MethodsWe studied whole-genome RNA expression of PBMCs in three HAE type-I families (accounting for 40 individuals), 24 of which carry the same R472X mutation in the C1-Inhibitor gene and show large variability in terms of disease expression. Those included in this study were analyzed according to the presence of mutation and/or clinical symptoms.ResultsInstead of a single, common disease-associated expression pattern, we found different transcriptome signatures in two of the families studied. In one of them (referred to as DR family), symptoms correlate with the upregulation of 35 genes associated to the biological response to viral infections (including RSADs, OAS, MX and ISG pathway members) and immune response. In another pedigree (Q family), disease manifestation is linked to the upregulation of 43 genes with diverse functions, including transcription and protein folding. Moreover, symptoms-free members of the Q pedigree display relatively higher expression of 394 genes with a wide diversity of functions.ConclusionWe found no evidence for a common altered PBMC expression pattern linked to HAE symptoms in the three families analyzed. All the data considered, differential gene expression in PBMCs do not seem to play a significant role in the predisposition or protection against HAE in the basal -between crises- conditions analyzed. Although the RNA expression pattern associated to the response to viral infections observed in the DR family supports the idea of infectious diseases as a modifying factor for HAE severity, large-scale studies would be needed to statistically associate such expression pattern to the development of this rare disease.

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

“…Several reasons for SERPING1 allelic heterogeneity have been developed by Germenis and Speletas (). A deeper knowledge of transcriptome signatures (López‐Lera, Cabo, Garrido, Dopazo, & López‐Trascasa, ) is expected to be gained in the coming years, with a contribution of epigenetic elements, gene–gene or gene–environment that regulate gene expression and biological processes, as recently suggested by Maia et al (). This important issue will lead to a better understanding of C1‐INH‐HAE pathophysiology and interpretation of genetics of C1‐INH‐HAE.…”

Neutrophils Are Dysregulated in Patients with Hereditary Angioedema Types I and II in a Symptom-Free Period

“…Changes in neutrophil activation markers were detected mostly during HAE attacks in previous studies [17, 24, 25]. Regarding symptom-free periods, only single cytokines related to neutrophil activation (IL-8, IL-17) have been described as upregulated in individual patients so far [24, 26].…”

Genetic variants of SERPING1 gene in Polish patients with hereditary angioedema due to C1 inhibitor deficiency

“…However, the frequency of this polymorphism is quite high in the general population (according to Ensembl database, the frequency of variant c.1438A is 27%, rs4926). Until now, this polymorphism has not been related to C1-INH-HAE (ClinVar: RCV000288563.1, RCV000616583.1 -clinical significance: benign), but there may be preliminary observation indicating the predisposition of people with this variant to C1-INH-HAE type I unrelated to the presence of disease-associated variants in encoding sequence of the SER-mRNA transcription or secretion of C1-INH in the serum, or may decrease the catabolism of aC1-INH elevated usually in patients with C1-INH-HAE [35,41].…”