Project description:We undertook transcriptome profiling with RNA-sequencing of scalp skin from seven cases of European ancestry and seven matched controls.
Project description:Genome-wide association studies (GWAS) have identified hundreds of genetic risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in coronary artery disease (CAD). However, non-European populations are underrepresented in GWAS and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotype information to identify quantitative trait loci (QTL) for gene expression and splicing in coronary arteries obtained from 138 ancestrally diverse Americans.
Project description:Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer's disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2,500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.
Project description:Systemic lupus erythematosus (SLE) is a heterogeneous disease which leads to different levels of serum autoantibodies to RNA-binding proteins (anti-RBP) and interferon-α (IFN-α), which plays an important pathogenic role in SLE, between European-American (EA) and African-American (AA) patients. We aimed to explore how IFN-related gene expression pathways differ in patients according to their ancestry and anti-RBP profile Whole blood from 33 female SLE patients and 16 matched controls from EA and AA ancestral backgrounds was analyzed through Affymetrix Gene 1.0 ST gene expression arrays and the data were further studied through Ingenuity Pathways Analysis for canonical pathway comparison. An independent replication cohort of more than 100 SLE patient samples and 30 controls was used to test the hypotheses generated by the microarray data, using qPCR to quantify gene expression.
Project description:Fibroblast responses to injury are shaped by cytokine signaling and macrophage activation, yet the extent to which these pathways vary across individuals, and how ancestry associated immune differences influence fibrosis risk, remains poorly understood. Here, we developed a poly(ethylene glycol) (PEG)-based hydrogel microphysiological system to model fibroblast-macrophage interactions following oxidative stress and integrate donor-specific immune signals using matched macrophages and serum. Circulating monocytes from individuals of self-reported African American ancestry exhibited higher expression of CCL4 and increased serum IL10, whereas those from European ancestry donors showed elevated OXER1 expression. Within the hydrogel, oxidative stress reduced fibroblast number while inducing Ki67 and p16. Exogenous TGFbeta1 enhanced fibroblast survival and collagen 3 production but did not independently increase alpha smooth muscle actin (alphaSMA). Anti-inflammatory macrophages promoted fibroblast activation through mechanisms resistant to TGFbeta receptor inhibition. Incorporating donor-derived macrophages and serum revealed that cultures from individuals of European ancestry demonstrated higher fibroblast alphaSMA and p16 expression, despite lower systemic IL10 levels. Pharmacologic inhibition of IL10 further increased alphaSMA, particularly in European ancestry derived cultures, identifying IL10 as a key protective signal limiting fibroblast activation. This hydrogel system provides a platform for dissecting inter-individual immune variation and identifying mechanisms underlying ancestry associated fibrosis risk.
Project description:Genome-wide association study performed on the EPICOLON2 cohort, comprising colorectal cancer cases and matched controls of Spanish origin.