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BackgroundEffector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively. However, it is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival.MethodsThe interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients.ResultsAmong the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20-0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19-0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135).ConclusionsBRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.

INTRODUCTION: The development and progression of Alzheimer's disease (AD) is a complex process, during which genetic influences on phenotypes may also change. Incorporating longitudinal phenotypes in genome‐wide association studies (GWAS) could unmask these genetic loci. METHODS: We conducted a longitudinal GWAS using a varying coefficient test to identify age‐dependent single nucleotide polymorphisms (SNPs) in AD. Data from 1877 Alzheimer's Neuroimaging Data Initiative participants, including impairment status and amyloid positron emission tomography (PET) scan standardized uptake value ratio (SUVR) scores, were analyzed using a retrospective varying coefficient mixed model association test (RVMMAT). RESULTS: RVMMAT identified 244 SNPs with significant time‐varying effects on AD impairment status, with 12 SNPs on chromosome 19 validated using National Alzheimer's Coordinating Center data. Age‐stratified analyses showed these SNPs' effects peaked between 70 and 80 years. Additionally, 73 SNPs were linked to longitudinal amyloid accumulation changes. Pathway analyses implicated immune and neuroinflammation‐related disruptions. DISCUSSION: Our findings demonstrate that longitudinal GWAS models can uncover time‐varying genetic signals in AD. Highlights: Identify time‐varying genetic effects using a longitudinal GWAS model in AD.Illustrate age‐dependent genetic effects on both diagnoses and amyloid accumulation.Replicate time‐varying effect of APOE in a second dataset. [ABSTRACT FROM AUTHOR]

Background: Epigenome-wide association studies (EWAS) have identified CpG sites associated with HIV infection in blood cells in bulk, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. In this study, we aim to identify differentially methylated CpG sites for HIV infection in immune cell types: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes. Methods: Applying a computational deconvolution method, we performed a cell-type based EWAS for HIV infection in three independent cohorts (Ntotal = 1,382). DNA methylation in blood or in peripheral blood mononuclear cells (PBMCs) was profiled by an array-based method and then deconvoluted by Tensor Composition Analysis (TCA). The TCA-computed CpG methylation in each cell type was first benchmarked by bisulfite DNA methylation capture sequencing in a subset of the samples. Cell-type EWAS of HIV infection was performed in each cohort separately and a meta-EWAS was conducted followed by gene set enrichment analysis. Results: The meta-analysis unveiled a total of 2,021 cell-type unique significant CpG sites for five inferred cell types. Among these inferred cell-type unique CpG sites, the concordance rate in the three cohorts ranged from 96% to 100% in each cell type. Cell-type level meta-EWAS unveiled distinct patterns of HIV-associated differential CpG methylation, where 74% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of unique HIV-associated CpG sites (N = 1,624) compared to any other cell type. Genes harboring significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CD4+ T-cells: NLRC5, CX3CR1, B cells: IFI44L, NK cells: IL12R, monocytes: IRF7), and in oncogenesis (e.g. CD4+ T-cells: BCL family, PRDM16, monocytes: PRDM16, PDCD1LG2). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis that were enriched among interferon-α and -γ, TNF-α, inflammatory response, and apoptotic pathways. Conclusion: Our findings uncovered computationally inferred cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding HIV pathogenesis. Author summary: The host epigenome (i.e., the DNA methylome) plays a pivotal role in HIV-1 viral integration, maintenance, and activation or silencing. Epigenome-wide association studies have identified many DNA methylation CpG sites in bulk cells associated with HIV infection, which offer an aggregated view of the average DNA methylation across cell types. To understand the effect of DNA methylation on chronic HIV infection at the cell-type level, we applied a computational method to deconvolute DNA methylation from blood bulk cells into five cell types: CD4+ T cell, CD8+ T cell, B cell, Nature Killer cell, and Monocytes and conducted an epigenome-wide analysis for HIV infection in each inferred cell type. Our results show that most of the HIV infection associated CpG sites are unique to each cell type. The largest number of significant CpG sites for HIV infection are from inferred CD4+ T cells. Significant CpG sites are located on genes that are enriched in interferon-α and -γ pathways, which are known to be key players in HIV infection. The findings help us understand the cellular relationship between DNA methylation and HIV infection. [ABSTRACT FROM AUTHOR]

Background: In light of previous studies that profiled breed-specific traits or used genome-wide association studies to refine loci associated with characteristic morphological features in dogs, the field has gained tremendous genetic insights for known dog traits observed among breeds. Here we aim to address the question from a reserve perspective: whether there are breed-specific genotypes that may underlie currently unknown phenotypes. This study provides a complete set of breed-specific genetic signatures (BSGS). Several novel BSGS with significant protein-altering effects were highlighted and validated. Results: Using the next generation whole-genome sequencing technology coupled with unsupervised machine learning for pattern recognitions, we constructed and analyzed a high-resolution sequence map for 76 breeds of 412 dogs. Genomic structures including novel single nucleotide polymorphisms (SNPs), SNP clusters, insertions, deletions (INDELs) and short tandem repeats (STRs) were uncovered mutually exclusively among breeds. We also partially validated some novel nonsense variants by Sanger sequencing with additional dogs. Four novel nonsense BSGS were found in the Bernese Mountain Dog, Samoyed, Bull Terrier, and Basset Hound, respectively. Four INDELs resulting in either frame-shift or codon disruptions were found in the Norwich Terrier, Airedale Terrier, Chow Chow and Bernese Mountain Dog, respectively. A total of 15 genomic regions containing three types of BSGS (SNP-clusters, INDELs and STRs) were identified in the Akita, Alaskan Malamute, Chow Chow, Field Spaniel, Keeshond, Shetland Sheepdog and Sussex Spaniel, in which Keeshond and Sussex Spaniel each carried one amino-acid changing BSGS in such regions. Conclusion: Given the strong relationship between human and dog breed-specific traits, this study might be of considerable interest to researchers and all. Novel genetic signatures that can differentiate dog breeds were uncovered. Several functional genetic signatures might indicate potentially breed-specific unknown phenotypic traits or disease predispositions. These results open the door for further investigations. Importantly, the computational tools we developed can be applied to any dog breeds as well as other species. This study will stimulate new thinking, as the results of breed-specific genetic signatures may offer an overarching relevance of the animal models to human health and disease. [ABSTRACT FROM AUTHOR]