While an enormous number of genetic variants have been associated with risk for human disease, how these variants affect gene expression in various cell types remains largely unknown. To address this gap as it relates to immune cells, as well as to identify which immune cell types are most susceptible to the effects of disease- risk variants, the DICE (Database of Immune Cell Expression, Expression quantitative trait loci (eQTLs) and Epigenomics) project was established in 2014, funded by the current R24 resource grant (R24AI108564). Our current datasets reveal the effects of disease risk-associated SNPs on common immune cell types (http://dice- database.org). However, this dataset is far from complete; the effects of disease-risk variants on several very important but rare and/or difficult to isolate cells, such as circulating innate immune cells and tissue-resident immune cells, have yet to be studied. Having accomplished the aims of the first DICE grant, we now propose to build on our findings through the following specific aims:
In Aim 1, we will expand eQTL analysis to (A) Rare circulating immune cell types such as dendritic cells, innate lymphoid cells (ILCs), invariant NKT cells, gdT cells and CD4-CTL subsets, isolated from banked cryopreserved leukapheresis samples (>100) collected via the DICE project, (B) circulating immune cells activated ex vivo, and (C) Tissue-resident memory (TRM) T cell types such as CD8+ TRM, CD4+ TRM and tissue-resident NK cells isolated from lung tissue samples of 100 subjects to map tissue-specific immune eQTLs tissue-resident immune cell types.
In Aim 2, we will define long-range enhancer-promoter 3D interactions in immune cell types to predict functionally important non-coding GWAS SNPs.
In Aim 3, we will expand our existing website (http://dice-database.org) to make current and newly generated experimental data and analysis tools available to the community.

Public Health Relevance

/RELEVANCE For many human diseases, large-scale genomic studies have identified common genetic variants that occur more frequently in people with cardiovascular, autoimmune, inflammatory and infectious diseases, diabetes and asthma than in those without these diseases. Here we propose to understand how these variants cause susceptibility to disease, focusing on diseases related to the immune system, and use this information to find novel therapeutic targets for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Resource-Related Research Projects (R24)
Project #
2R24AI108564-05
Application #
9793021
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Breen, Joseph J
Project Start
2014-08-01
Project End
2024-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schmiedel, Benjamin J; Singh, Divya; Madrigal, Ariel et al. (2018) Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell 175:1701-1715.e16
Lee, Alexandra J; Chang, Ivan; Burel, Julie G et al. (2018) DAFi: A directed recursive data filtering and clustering approach for improving and interpreting data clustering identification of cell populations from polychromatic flow cytometry data. Cytometry A 93:597-610
Youhanna Jankeel, Diana; Cayford, Justin; Schmiedel, Benjamin Joachim et al. (2018) An Integrated and Semiautomated Microscaled Approach to Profile Cis-Regulatory Elements by Histone Modification ChIP-Seq for Large-Scale Epigenetic Studies. Methods Mol Biol 1799:303-326
Patil, Veena S; Madrigal, Ariel; Schmiedel, Benjamin J et al. (2018) Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Sci Immunol 3:
Burel, Julie G; Qian, Yu; Lindestam Arlehamn, Cecilia et al. (2017) An Integrated Workflow To Assess Technical and Biological Variability of Cell Population Frequencies in Human Peripheral Blood by Flow Cytometry. J Immunol 198:1748-1758
Schmiedel, Benjamin Joachim; Seumois, Grégory; Samaniego-Castruita, Daniela et al. (2016) 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nat Commun 7:13426