Ontology highlight
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PROVIDER: PRJNA1270980 | ENA |
REPOSITORIES: ENA
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Project description:Background: Genetic control of gene expression in asthma-related tissues is not well-characterized, particularly for African-ancestry populations, limiting advancement in our understanding of the increased prevalence and severity of asthma in those populations. Objective: To create novel transcriptome prediction models for asthma tissues (nasal epithelium and CD4+ T cells) and apply them in transcriptome-wide association study to discover candidate asthma genes. Methods: We developed and validated gene expression prediction databases for unstimulated CD4+ T cells and nasal epithelium using an elastic net framework. Combining these with existing prediction databases (N=51), we performed TWAS of 9,284 individuals of African-ancestry to identify tissue-specific and cross-tissue candidate genes for asthma. Results: Novel databases for CD4+ T cells and nasal epithelial gene expression prediction contain 8,351 and 10,296 genes, respectively, including four asthma loci (SCGB1A1, MUC5AC, ZNF366, LTC4S) not predictable with existing public databases. Prediction performance was comparable to existing databases and was most accurate for populations sharing ancestry with the training set (e.g. African ancestry). From transcriptome-wide association study, we identified 17 candidate causal asthma genes (adjusted P<0.1), including genes with tissue-specific (IL33 in nasal epithelium) and cross-tissue (CCNC and FBXW7) effects. Conclusions: Expression of IL33, CCNC, and FBXW7 may affect asthma risk in African ancestry populations by mediating inflammatory responses. The addition of CD4+ T cell and nasal epithelium prediction databases to the public sphere will improve ancestry representation and power to detect novel gene-trait associations from transcriptome-wide association study.
2025-09-09 | GSE301390 | GEO
Project description:Background: Asthma, a complex chronic lung disease affecting the airways, has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omics signatures of asthma risk in the nasal epithelium focusing on populations of African ancestry. Methods: DNA methylation (DNAm) quantification was performed using Illumina’s Infinium MethylationEPIC array® using genomic DNA from nasal airway epithelial cells collected across the 4 US recruitment sites (Baltimore, Chicago, Denver, and Washington DC) for 331 subjects (N=149 asthma cases, N= 182 never asthmatic controls). We performed association analysis to identify eQTMs (CpG-gene associations) for DEGs limiting to CpGs ≤5kb from the transcription start site or within enhancer regions identified through promoter-capture HiC in bronchial epithelial cells. CpGs from significant eQTMs (p<0.05) were tested for differential methylation by asthma (DMCs) to assess the relative contribution of expression and methylation in asthma risk. All models were fully adjusted for ancestry, sampling site, and appropriate latent factors. Findings: Multi-omic analysis identified FKBP5 as a key contributor to asthma risk, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. FKBP5 is a co-chaperone of glucocorticoid receptor signaling and known to be involved in drug response in asthma. Interpretation: Our analyses reveal genes and networks in asthma that are differentially expressed in nasal epithelium of current asthma cases of African ancestry in CAAPA. Importantly, this work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.
2023-12-23 | GSE250513 | GEO
Project description:Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma (ULM) tissues combined resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.
2022-02-16 | PXD029323 | Pride
Project description:Background: Asthma, a complex chronic lung disease affecting the airways, has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omics signatures of asthma risk in the nasal epithelium focusing on populations of African ancestry. Methods: RNASeq data were generated from nasal epithelium in subjects recruited from up to 7 sites (Baltimore, Washington DC, Chicago, Denver, Salvador Brazil, Barbados, and Nigeria). Current asthma cases (N=253) were compared to never-asthma controls (N=283) to identify differentially expressed genes (DEGs; q <0.05). Network analyses were performed with Ingenuity Pathway Analysis (IPA; DEGs with q<0.05) and weighted gene co-expression network analysis (WGCNA; DEGs with q<0.15). All models were fully adjusted for ancestry, sampling site, and appropriate latent factors. Findings: CAAPA represents diversity across the African Diaspora with a wide range of continental African ancestry (9%-100%). We identified 389 DEGs; the top DEG, FN1, was downregulated in asthma cases (q=3.26x10-9) and encodes fibronectin which plays a role in wound healing. Others in the top 10 DEGs have high relevance for asthma: SNTG2 (q = 1.12x10-4) is the target of multiple miRNAs related to asthma; PPP1R9A expression (q=7.60x10-5) was previously determined to be influenced by IL-13 in mouse lung; and SPTBN1 (q=1.12x10-4) plays a key role in mediating TGFβ signaling. IPA revealed networks with upstream regulators relevant for immune response (IL4; p=7.25x10-10 and TGFβ1; p=5.47x10-8) and drug response (dexamethasone; p=4.31x10-10 and fluticasone propionate; p=9.42x10-8). Among asthma cases, genes regulated by dexamethasone and fluticasone propionate were not associated with inhaled corticosteroid medication use. The top three WGCNA modules implicate networks related to immune response (CEACAM5; p=9.62x10-16 and CPA3; p=2.39x10-14) and wound healing (FN1; p=7.63x10-9). Multi-omic analysis identified FKBP5 as a key contributor to asthma risk, whereby the association between nasal epithelium gene expression is mediated through methylation and is associated with increased use of inhaled corticosteroids. FKBP5 is a co-chaperone of glucocorticoid receptor signaling and known to be involved in drug response in asthma. Interpretation: Our analyses reveal genes and networks in asthma that are differentially expressed in nasal epithelium of asthma cases of African ancestry in CAAPA. Importantly, this work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.
2023-08-16 | GSE240567 | GEO
Project description:Women of sub-Saharan African descent have disproportionately higher incidence of Triple Negative Breast Cancer (TNBC), and TNBC-specific mortality. Population comparative studies show racial differences in TNBC biology, including higher prevalence of basal-like and Quadruple-Negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily United States (US) populations. Due to heterogenous genetic admixture, and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNAseq on an international cohort of AAs, west and east Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed tumor-associated immunological profiles are distinct in patients of African descent.
2022-11-09 | GSE211167 | GEO
Project description:Consortium on Asthma among African-Ancestry Populations in the Americas (CAAPA)
| PRJNA321780 | ENA
Project description:Consortium on Asthma among African-Ancestry Populations in the Americas (CAAPA)
| PRJNA321779 | ENA
Project description:Variation in gene expression is a fundamental aspect of human phenotypic variation. Several studies have analyzed gene expression levels in populations of different continental ancestry, and concluded that there is variation across populations at a fraction of expressed genes. Here we analyze gene expression levels in African American cell lines, which differ from previously analyzed cell lines in that samples from this population have variable proportions of continental ancestry. We show that for most genes examined, gene expression varies with genetic ancestry. Keywords: Human Gene Expression Study
2008-12-05 | GSE10824 | GEO
Project description:Individuals of African descent in the United States suffer disproportionately from diseases with a metabolic etiology (obesity, metabolic syndrome, and diabetes), and from the pathological consequences of these disorders (hypertension and cardiovascular disease). Using a combination of genetic/genomic and bioinformatics approaches, we identified a large number of genes that were both differentially expressed between American subjects self-identified to be of either African or European ancestry and that also contained single nucleotide polymorphisms that distinguish distantly related ancestral populations. Several of these genes control the metabolism of simple carbohydrates and are direct targets for the SREBP1, a metabolic transcription factor also differentially expressed between our study populations. These data support the concept of stable patterns of gene transcription unique to a geographic ancestral lineage. The coordinated transcriptional adaptation of carbohydrate metabolism to dietary environmental pressures suggests a genetic and transcriptional mechanism for the disproportionate levels of obesity, diabetes, and cardiovascular disease observed in Americans with African ancestry. Keywords: Ancestry-dependent gene expression, functional genomics, personalized medicine, multi-factoral disease, nutrition, diabetes
2009-10-31 | GSE12959 | GEO
Project description:Variation in gene expression is a fundamental aspect of human phenotypic variation. Several studies have analyzed gene expression levels in populations of different continental ancestry, and concluded that there is variation across populations at a fraction of expressed genes. Here we analyze gene expression levels in African American cell lines, which differ from previously analyzed cell lines in that samples from this population have variable proportions of continental ancestry. We show that for most genes examined, gene expression varies with genetic ancestry. Experiment Overall Design: Lymphoblastoid cell lines (LCL) for 60 HapMap CEU, 60 HapMap YRI, and 82 AFA from the Human Variation Panel were obtained from Coriell Cell Repositories. LCLs were grown in culture, total RNA was extracted and hybridized to Affymetrix HG-FOCUS arrays.
2009-01-14 | E-GEOD-10824 | biostudies-arrayexpress