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

Alberto López-Lera,Ana Dopazo,Sofía Garrido,Fátima Cabo,Margarita López-Trascasa

doi:10.1186/1750-1172-8-77

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.

Highlights

Hereditary Angioedema (HAE, OMIM#106100) is a rare genetic condition characterised by the occurrence of severely incapacitating episodes of edema affecting mucosal and submucosal layers
800 ng of total RNA from patients and controls, were reverse transcribed using T7 promoter primer and the Moloney murine leukemia virus (MMLV) reverse transcriptase (RT). cDNA was converted to anti-sense RNA by using T7 RNA polymerase which amplifies target material simultaneously incorporating cyanine 3 (Cy3)-labeled CTP
Microarray results For the evaluation of the results, a threshold of Fold Change (FC):2 was used in order to provide a conservative foundation for further interpretations

Summary

Introduction

Hereditary Angioedema (HAE, OMIM#106100) is a rare genetic condition characterised by the occurrence of severely incapacitating episodes of edema affecting mucosal and submucosal layers. Inheritance of the disease is autosomal dominant due to deleterious mutations in the serpin (Serum protease inhibitor) C1-Inhibitor (C1-INH) (HAE types I and II) or gain-of-function mutations in the gene coding for the coagulation Factor XII (FXII) (HAE type III or oestrogen-related HAE) [2] Both genetic alterations cause uncontrolled activation of the contact and kinin-forming cascades, as evidenced by the extensive activation of the factor XII–dependent pathways and bradykinin release observed in HAE patients’ plasmas [3,4]. Patients with HAE carrying the same mutation exhibit large variability of symptoms’ frequency and severity, even among siblings Such variability hinders therapeutic assessment and probably underlies yet unknown genetic and environmental factors. Despite its monogenic pattern of inheritance, HAE exhibits great clinical variability and low genotype/phenotype correlation among those affected, which hinders therapeutic approach and probably underlies yet unknown genetic and environmental factors

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