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Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension.

ABSTRACT: Inflammatory cell infiltrates are a prominent feature of aberrant vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that immune effector cells contribute to disease progression. Genome-wide blood expression profiling studies have attempted to better define this inflammatory component of PAH pathobiology but have been hampered by small sample sizes, methodological differences, and very little gene-level reproducibility. The current meta-analysis (seven studies; 156 PAH patients/110 healthy controls) was performed to assess the comparability of data across studies and to possibly derive a generalizable transcriptomic signature. Idiopathic (IPAH) compared with disease-associated PAH (APAH) displayed highly similar expression profiles with no differentially expressed genes, even after substantially relaxing selection stringency. In contrast, using a false discovery rate of ?1% and I² < 40% (low-to-moderate heterogeneity across studies) both IPAH and APAH differed markedly from healthy controls with the combined PAH cohort yielding 1,269 differentially expressed, unique gene transcripts. Bioinformatic analyses, including gene-set enrichment, which uses all available data independent of gene selection thresholds, identified interferon, mammalian target of rapamycin/p70S6K, stress kinase, and Toll-like receptor signaling as enriched mechanisms within the PAH gene signature. Enriched biological functions and diseases included tumorigenesis, autoimmunity, antiviral response, and cell death consistent with prevailing theories of PAH pathogenesis. Although otherwise indistinguishable, APAH (predominantly PAH due to systemic sclerosis) had a somewhat stronger interferon profile than IPAH. Meta-analysis defined a robust and generalizable transcriptomic signature in the blood of PAH patients that can help inform the identification of biomarkers and therapeutic targets.

SUBMITTER: Elinoff JM

PROVIDER: S-EPMC6985867 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Project description:BackgroundThe role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) remains to be fully elucidated. This study evaluated the expression profile of miRNAs in the lung tissue of patients with SSc-PAH.MethodsLung tissue samples were collected from 3 SSc-PAH patients and 4 healthy controls. A small RNA high throughput sequence approach was used for screening the differentially expressed miRNAs in the lung tissue samples. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 4 highly significant differentially expressed miRNAs. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for mRNAs were performed using the R package clusterProfiler software.ResultsA total of 82 upregulated miRNAs and 35 downregulated miRNAs were detected in the lung tissues of patients with SSc-PAH compared with healthy controls. GO enrichment analysis demonstrated that the upregulated target genes were closely involved in biological processes such as nervous system development, anatomical structure morphogenesis, system development, cellular macromolecule metabolic processes, and cellular processes. The downregulated target genes were involved in the plasma membrane bound cell projection morphogenesis and the regulation of macromolecule metabolic processes. The KEGG enrichment analysis showed that the upregulated genes were associated with important pathways involved in cancer biology, and the target genes of the downregulated miRNAs were involved in axon guidance. High throughput sequencing and qRT-PCR revealed that hsa-miR-205-5p and hsa-miR-539-3p were differentially expressed in SSc-PAH tissue. The target genes of hsa-miR-205-5p and hsa-miR-539-3p, IRF1and ADCYAP1, respectively, were verified using the high throughput dataset GSE48149.ConclusionsmiRNAs may play an important role in the pathogenesis of SSc-PAH, and hsa-miR-205-5p and hsa-miR-539-3p may be potential therapeutic targets in patients with SSc-PAH.

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Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension.

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