Elevated VRK2 expression promotes the onset and progression of bronchiectasis

Abstract Background Today, the prevalence of bronchiectasis is on the rise worldwide and ranks third among chronic respiratory diseases, yet there is currently no standard treatment. Exploring new drug targets based on a patient’s genetic profile provides new directions to further address the current challenges of bronchiectasis. Methods First, we used the cis-expression quantitative trait locus (cis-eQTL) data of druggable genes from blood samples as the exposure factor and the genome-wide association study (GWAS) data of bronchiectasis as the outcome to perform two-sample Mendelian randomization (MR) analysis. Next, we conducted colocalization and summary-data-based MR (SMR) analyses to validate the selected drug target genes. Finally, we collected peripheral blood samples from healthy individuals and untreated bronchiectasis patients for RT-qPCR validation of the genes identified in the previous analysis. The gene expression levels were also correlated with age, sex, BMI, smoking status, BACI score, BSI score, and E-FACED score. Results According to the MR analysis, the expression of the ACVR2A, DDR1, and VRK2 genes is associated with an increased risk of bronchiectasis, while the expression of the EFTUD2, CASP9, SCD5, ACLY, SOD2, TNFRSF4, XCL2, and SRPK1 genes is associated with a decreased risk of bronchiectasis. The odds ratio (OR) values range from 0.59 to 1.54, and the false discovery rate (FDR) is < 0.05. Colocalization analysis suggests that bronchiectasis may share causal variants with ACVR2A and VRK2, with posterior probabilities of 92.24% for ACVR2A and 78.38% for VRK2. The SMR analysis and HEIDI test results show that the beta value for VRK2 in the SMR test is 0.78 ( P = 0.004), and the P -value in the heterogeneity in dependent instruments (HEIDI) test is > 0.05. Subsequently, peripheral blood samples from 51 bronchiectasis patients and 33 healthy controls were collected to validate the expression of VRK2. RT-qPCR results revealed that, compared to the control group, the expression level of VRK2 was significantly higher in the bronchiectasis group ( P < 0.05). No significant differences in VRK2 expression were observed in patients with different age groups, genders, BMI, smoking statuses, or E-FACED scores. In contrast, patients with severe BSI classification and a BACI score of medium to high risk exhibited increased VRK2 expression in peripheral blood ( P < 0.05). Conclusions High expression of VRK2 is associated with a higher risk of bronchiectasis and higher BSI and BACI, suggesting its potential as a risk factor for the development and progression of bronchiectasis.