MicroRNA Markers for Acute Respiratory Distress Syndrome and Shared Genetic Architecture of Asthma With Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals From UK Biobank
CitationZhu, Zhaozhong. 2017. MicroRNA Markers for Acute Respiratory Distress Syndrome and Shared Genetic Architecture of Asthma With Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals From UK Biobank. Doctoral dissertation, Harvard T.H. Chan School of Public Health.
AbstractMicroRNAs (miRNAs) mediate inflammation and infection, common manifestations of acute respiratory distress syndrome (ARDS). I proposed to examine whether miRNAs from whole blood serve as potential diagnostic or prognostic biomarkers for ARDS. This nested case-control study (N=530) included 2 cohorts of ARDS patients and critically ill at-risk controls. Whole blood miRNAs were profiled and logistic regression analyses or survival analysis were performed to identify miRNA correlations with ARDS. Receiver operating characteristic (ROC) analysis was used for evaluating miRNA diagnostic performance along with the Lung Injury Prediction Score (LIPS). ARDS patient whole blood miRNA profiling revealed that miR-181a and miR-92a were risk biomarkers of ARDS, whereas miR-424 was a protective biomarker. Addition of these miRNAs increased the risk diagnosis of ARDS from LIPS. We also built a miRNA classifier for predicting ARDS 28-day mortality. In addition, I also did a genome-wide cross trait analysis of 112,000 individuals from UK Biobank to investigate shared genetic architecture of asthma with allergic diseases. Clinical and epidemiological data suggest that asthma and allergic diseases, such as allergic rhinitis and eczema, are associated. One hypothesis to account for the relationship is that these diseases share a common genetic etiology. Heritability has been estimated at high level for asthma and allergic diseases, which suggests that the genetic contribution to them can be significant. We analyzed genome-wide single-nucleotide polymorphism (SNP) data for the asthma and allergic diseases in 35,783 cases and 76,768 controls of European ancestry. We used a logistic regression, linkage disequilibrium score regression, cross trait meta-analysis and GETx tissue enrichment analysis in this study. We have found a strong genetic correlation between asthma and allergic diseases (Rg=0.75, P=6.84×10-62). Cross trait analysis and identified 90 loci. GTEx tissue enrichment analysis showed shared genetic loci between asthma and allergic diseases were enriched in skin and esophageal tissue. Our GWAS study has highlighted shared genetic pathway in immune and inflammatory systems and skin/esophageal tissue by asthma and allergic diseases. This work should support the idea that common patterns of association between asthma and allergy implicate shared biological processes and advance understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.
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