Characterization of caffeine response regulatory variants in vascular endothelial cells

  1. Carly Boye
  2. Cynthia A Kalita
  3. Anthony S Findley
  4. Adnan Alazizi
  5. Julong Wei
  6. Xiaoquan Wen
  7. Roger Pique-Regi
  8. Francesca Luca  Is a corresponding author
  1. Wayne State University, United States
  2. University of Michigan-Ann Arbor, United States

Abstract

Genetic variants in gene regulatory sequences can modify gene expression and mediate the molecular response to environmental stimuli. In addition, genotype-environment interactions (GxE) contribute to complex traits such as cardiovascular disease. Caffeine is the most widely consumed stimulant and is known to produce a vascular response. To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants. We identified 665 variants with allelic effects on gene regulation and 29 variants that regulate the gene expression response to caffeine (GxE, FDR<10%). When overlapping our GxE results with eQTLs colocalized with CAD and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine. Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption.

Data availability

FASTQ files and read count data are available at the GEO accession number GSE221514

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Carly Boye

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Cynthia A Kalita

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Anthony S Findley

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9922-3076
  4. Adnan Alazizi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Julong Wei

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaoquan Wen

    Department of Biostatistics, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Roger Pique-Regi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1262-2275
  8. Francesca Luca

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    For correspondence
    fluca@wayne.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8252-9052

Funding

National Institute of General Medical Sciences (R01GM109215)

  • Roger Pique-Regi
  • Francesca Luca

National Institute of Environmental Health Sciences (R01ES033634)

  • Xiaoquan Wen
  • Roger Pique-Regi
  • Francesca Luca

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen CJ Parker, University of Michigan, United States

Version history

  1. Received: November 30, 2022
  2. Accepted: February 8, 2024
  3. Accepted Manuscript published: February 9, 2024 (version 1)

Copyright

© 2024, Boye et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Carly Boye
  2. Cynthia A Kalita
  3. Anthony S Findley
  4. Adnan Alazizi
  5. Julong Wei
  6. Xiaoquan Wen
  7. Roger Pique-Regi
  8. Francesca Luca
(2024)
Characterization of caffeine response regulatory variants in vascular endothelial cells
eLife 13:e85235.
https://doi.org/10.7554/eLife.85235

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https://doi.org/10.7554/eLife.85235