MicroRNAs may be biomarkers in hereditary angioedema
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Key takeaways:
- 56 microRNAs were upregulated and 64 were downregulated in hereditary angioedema.
- Two microRNAs were differentially expressed in mild and severe disease.
- SERPING1 includes six candidate microRNAs.
MicroRNAs may indicate patients who have hereditary angioedema along with different phenotypes of the disease, according to a study published in Annals of Allergy, Asthma & Immunology.
Also, post-transcriptional gene regulation may have an impact on hereditary angioedema (HAE) development, Timothy Craig, DO, clinical researcher, department of medicine, pediatrics and biomedical sciences, Pennsylvania State University, and colleagues wrote.
The cross-sectional, case-control study involved 15 patients who did not have HAE (average age, 40.7 years; 87% female; 87% white), 11 with mild HAE (average age, 26.3 years; 54% female; 91% white) and 19 with severe HAE (average age, 30.5 years; 79% female; 79% white).
The researchers classified mild HAE as fewer than six attacks a year and severe HAE as more than one attack a month. The mild group experienced a median of 0.58 attacks a month, and the severe group experienced a median of three attacks a month.
Analysis of plasma collected from participants indicated 120 microRNAs with different expression in patients with HAE, compared with the group that did not have HAE (adjusted P < .05), including 56 downregulated and 64 upregulated microRNAs.
Receiver operating characteristic analysis performed to determine which microRNAs were the best indicators of patients with and without HAE indicated four with the best areas under the curve (AUCs), the researchers wrote: miR-30d-5p (AUC, 0.912), mir-150-3p (AUC, 0.893), Let-7i-5p (AUC, 0.883) and miR-148-3p (AUC, 0.873).
Also, a cluster analysis of microRNA expression in the patients with HAE found two distinct clusters, the researchers wrote, with cluster 1 reporting 1.6 ± 2.1 attacks per month and cluster 2 reporting 3.8 ± 4.1 attacks per month.
There were no differences in age, sex, race, BMI or severity between the clusters, the researchers wrote, adding that these patterns may help identify or characterize different disease phenotypes.
The researchers also found that miR-99b-5p and miR-127-3p were the only microRNAs with any difference in expression between the groups with mild or severe HAE (adjusted P < .05).
Specifically, miR-99b-5p was undetectable in 10 of 11 patients in the mild group but found in 16 of 19 patients in the severe group, the researchers wrote, indicating that it may have the most promise as a potential biomarker.
Additionally, pathway analysis uncovered 11 microRNAs that mapped to the adherens junction pathway, which is related to the regulation of vascular permeability. Six of these microRNAs were upregulated, and five were downregulated.
Prediction analysis found 54 candidate microRNAs that the researchers called potential targets of SERPING1, which is an individual gene involved in HAE pathogenesis, and that were differentially expressed between the patients who did and who did not have HAE.
Two of these microRNAs bind to SERPING1 mRNA, the researchers wrote, and many of the microRNAs in this group had good predictive potential to differentiate between patients who did and did not have HAE.
Also, 12 of the 20 microRNAs with the highest AUC on ROC analysis were predicted targets of SERPING1, including miR-30D-5p, which had the highest AUC. SERPING1 may produce six candidate microRNAs as well, the researchers wrote, including miR-326 and miR-6073, which are predicted to regulate the gene and could have an autoregulatory role.
KLK1 is another gene involved in HAE pathogenesis, but none of the candidate microRNAs were predicted to regulate it. But miR-4448 was predicted to interact with BKRB2, which also is involved in HAE pathogenesis.
Analysis additionally found 23 candidate microRNAs that could regulate the high molecular weight isoform of KNG1, another gene involved in HAE pathogenesis, with 13 of them able to regulate SERPING1 as well.
The two microRNAs that were differentially expressed between the groups with mild and severe HAE were not predicted to target these four genes, but they did map to the adherens junctions Kyoto Encyclopedia of Genes and Genomes pathway.
In patients with severe HAE, miR-99b-5p was upregulated and predicted to regulate three genes in the adherens junction pathway, and miR-127-3p was downregulated and predicted to regulate LM07 in the same pathway.
Noting the different expressions of microRNAs between patients with and without HAE, the researchers wrote, post-transcriptional gene regulation may impact disease development and explain why patients with similar genotypes may have different clinical findings.
With better genomic characterization, the researchers wrote, physicians may be able to identify patients who may benefit from prophylactic treatment, gene therapy or even CRISPR gene editing, improving clinical outcomes and quality of life.
However, the researchers also called for additional studies with larger sample sizes to determine the function of these microRNAs and whether they can be used as biomarkers for the disease and its clinical outcomes.