112 research outputs found
Sensitization To Dust Mite And Dog Independently Predict Asthma Severity In African Caribbean Asthmatics From Barbados
No full textFilaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis
No full textBackground: Atopic dermatitis (AD; eczema) is characterized by a widespread abnormality in cutaneous barrier function and propensity to inflammation. Filaggrin is a multifunctional protein and plays a key role in skin barrier formation. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a highly significant risk factor for atopic disease, but the molecular mechanisms leading to dermatitis remain unclear. Objective: We sought to interrogate tissue-specific variations in the expressed genome in the skin of children with AD and to investigate underlying pathomechanisms in atopic skin. Methods: We applied single-molecule direct RNA sequencing to analyze the whole transcriptome using minimal tissue samples. Uninvolved skin biopsy specimens from 26 pediatric patients with AD were compared with site-matched samples from 10 nonatopic teenage control subjects. Cases and control subjects were screened for FLG genotype to stratify the data set. Results: Two thousand four hundred thirty differentially expressed genes (false discovery rate, P <.05) were identified, of which 211 were significantly upregulated and 490 downregulated by greater than 2-fold. Gene ontology terms for "extracellular space" and "defense response" were enriched, whereas "lipid metabolic processes" were downregulated. The subset of FLG wild-type cases showed dysregulation of genes involved with lipid metabolism, whereas filaggrin haploinsufficiency affected global gene expression and was characterized by a type 1 interferon-mediated stress response. Conclusion: These analyses demonstrate the importance of extracellular space and lipid metabolism in atopic skin pathology independent of FLG genotype, whereas an aberrant defense response is seen in subjects with FLG mutations. Genotype stratification of the large data set has facilitated functional interpretation and might guide future therapy development.</p
[[alternative]]Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes (Nature, (2020), 586, 7831, (763-768), 10.1038/s41586-020-2819-2)
No full text[[abstract]]In this Article, Abhishek Niroula should have been listed as an author, with the affiliations: Broad Institute of MIT and Harvard, Cambridge, MA, USA; and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. They performed additional bioinformatic analyses (see ‘Author contributions’). The original Article has been corrected online. *A list of authors and their affiliations appears online
A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample
No full textRationale: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
Objectives: To comprehensively analyse previously reported genetic associations with lung function measures, and to
investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.
Methods: We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/210 kb), after conducting a
systematic review of the literature in the PubMed database for genetic association studies reporting lung function
associations.
Results: The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.361025. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.8161025), CNTN5 (P = 4.3761024), and TRPV4 (P = 1.5861023). Among eversmokers, SERPINA1 showed the most significant association with FEV1 (P = 8.4161025), followed by PDE4D (P = 1.2261024). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.3861024), and ESR1 (P = 5.4261024) among ever-smokers.
Conclusions: Polymorphisms spanning previously associated lung function genes did not show strong evidence for
association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may
affect FEV1 among smokers in the general population
Serum Macrophage Migration Inhibitory Factor (MIF) Is Increased In Patients With Pulmonary Arterial Hypertension
No full textPrevalence of Actionable Exposures to Pharmacogenetic Medications Among Solid Organ Transplant Recipients in a Population-Scale Biobank
No full textBackground/Objectives: Solid organ transplant (SOT) recipients are exposed to multiple medications, many of which have pharmacogenetic (PGx) prescribing recommendations. This study leveraged data from a population-scale biobank and an enterprise data warehouse to determine the prevalence of actionable exposures to PGx medications among kidney, heart, and lung transplant recipients during the first six months post-transplant. Methods: We conducted a retrospective analysis of adult SOT patients with genetic data available from the Colorado Center for Personalized Medicine (CCPM) biobank and clinical data from Health Data Compass (HDC). We evaluated 29 variants in 13 pharmacogenes and 42 Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B medications (i.e., sufficient evidence to recommend at least one prescribing action based on genetics). The primary outcome was actionable exposure to a PGx medication (i.e., actionable phenotype and a prescription for an affected PGx medication). Results: The study included 358 patients. All patients were prescribed at least one PGx medication, and 49.4% had at least one actionable exposure to a PGx medication during the first six months post-transplant. The frequency of actionable exposure was highest for tacrolimus (15.4%), followed by proton pump inhibitors (PPIs) (15.1%) and statins (12.8%). Statin actionable exposures significantly differed by transplant type, likely due to variations in prescribing patterns and actionable phenotypes for individual statins. Conclusions: Our findings highlight the potential clinical utility of PGx testing among SOT patients. Further studies are needed to address the impact on clinical outcomes and the optimal timing of PGx testing in the SOT population
Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms Are Associated With Favorable Hemodynamic Indices In Pulmonary Arterial Hypertension
No full textPolymorphisms In IL33 Gene Are Associated With Hemodynamic Measurements In Patients With Scleroderma-Associated Pulmonary Arterial Hypertension
No full textAfrican and non-African admixture components in African Americans and an African Caribbean population
No full textJournal of Allergy and Clinical Immunology
No full textTexto completo. Acesso restrito. p. 53Rationale
ST2 (IL1RL1), is an IL1 family receptor that mediates important effectors of Th2 functions. Its soluble form (sST2) neutralizes its ligand, IL-33, by acting as a decoy receptor. Serum sST2 has been used as a biomarker for disease severity and outcome for multiple inflammatory and lung diseases, including atopic asthma. We undertook a targeted deep resequencing of ST2 gene in 241 samples of African ancestry to identify ST2variants controlling serum sST2 levels.
Methods
Serum sST2 concentration was measured by ELISA, and resequencing of ∼50kb (chr2:102922962-102973497) encompassing the ST2gene was performed using Illumina's HiSeq2000. Single-variant tests for all common variants (MAF≥5%) were performed using linear regression assuming an additive model on log serum total ST2 considering age, gender and the first two principal components on a pre-existing genome-wide association panel of ancestry informative markers to adjust for admixture.
Results
A total of 565 ST2 variants were identified, 192 of which had a MAF≥5% including 3 coding synonymous and 6 missense variants. In the sST2 level analysis, ten SNPs in strong linkage disequilibrium yielded p-value less than 10-3; a single common haplotype (frequency=65%) across all 10 SNPs yielded an overall p-value = 0.0002 and was negatively associated with sST2 levels (β = -0.09).
Conclusions
Sequencing ST2 gene revealed a novel haplotype influencing sST2 levels in individuals of African ancestry, including 5 variants mapping to intron 1 and 5 mapping to the 5’ region of ST2. Further work is ongoing to fully explore this association in an additional 400 subjects of African ancestry.Salvado
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