@article{milind_preuss_haber_ananda_mukherjee_john_shapley_logsdon_crane_carter_2020, title={Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology}, volume={16}, ISSN={["1553-7404"]}, DOI={10.1371/journal.pgen.1008775}, abstractNote={Late-Onset Alzheimer’s disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10−8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.}, number={6}, journal={PLOS GENETICS}, author={Milind, Nikhil and Preuss, Christoph and Haber, Annat and Ananda, Guruprasad and Mukherjee, Shubhabrata and John, Cai and Shapley, Sarah and Logsdon, Benjamin A. and Crane, Paul K. and Carter, Gregory W.}, year={2020}, month={Jun} }
 @article{iweala_hardy_choudhary_wang_addison_milind_orgel_kulis_urban_nagler_et al._2019, title={Epigenetic Dysfunction in T cells is Associated with Enhanced Type-2 and Blunted Regulatory Immunity}, volume={143}, ISSN={["1097-6825"]}, DOI={10.1016/j.jaci.2018.12.627}, abstractNote={Epigenetic alterations partly mediated by histone H3 lysine 27 (H3K27) demethylase UTX are critical for humoral and cellular immunity against chronic viral infections. Whether UTX-modulated epigenetic changes impact type 2 immunity in allergic sensitization and type 2/regulatory immunity associated with chronic helminth infection is unclear. We used mice with UTX-deficient T cells (UTX-TCD) to assess whether T cell-specific UTX expression affects 1) IgE production following subcutaneous sensitization to galactose-alpha-1,3-galactose (alpha-gal) and 2) the immunosuppressive effects of preexisting intestinal helminth infection on antibody responses to intramuscular vaccination. We sensitized wildtype (WT) C57Bl/6J or UTX-TCD mice 3 times at 1 to 2-week intervals with 50 micrograms of lone star tick (Amblyomma americanum)-derived salivary gland extract (TSGE). We examined polyclonal and antigen-specific IgE and CD4+T cell responses 2 weeks after the last subcutaneous injection. In separate experiments, WT and UTX-TCD mice were infected or not with the mouse intestinal parasitic nematode Heligmosomoides polygyrus bakeri and vaccinated intramuscularly twice at 1-week intervals with chicken-egg ovalbumin adsorbed to alum (OVA-alum). Polyclonal and antigen-specific IgE and IgG1 responses were assessed. Without UTX expression in T cells, TSGE injection enhanced polyclonal IgE production and CD4+IL4+Th2 cell frequency despite reduced CD4+T cell frequency. Polyclonal IgE production was preserved during chronic intestinal helminth infection, but Th2-skewed OVA-specific IgG1 responses to OVA-alum vaccination were not significantly reduced. Our results suggest that epigenetic factors like UTX in T cells may regulate cellular and humoral immunity associated with type 2 and immunoregulatory responses during allergic sensitization and helminth infection.}, number={2}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={Iweala, Onyinye I. and Hardy, Lakeya C. and Choudhary, Shailesh and Wang, Hsing-Hui and Addison, Claire T. and Milind, Nikhil and Orgel, Kelly A. and Kulis, Michael D., Jr. and Urban, Joseph F., Jr. and Nagler, Cathryn R. and et al.}, year={2019}, month={Feb}, pages={AB205–AB205} }