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ResearchIn-Press PreviewEndocrinologyGeneticsMetabolism Open Access | 10.1172/JCI190180

The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis

Hima Bindu Durumutla,1 April Haller,2 Greta Noble,1 Ashok Daniel Prabakaran,1 Kevin McFarland,1 Hannah Latimer,1 Akanksha Rajput,1 Olukunle Akinborewa,1 Bahram Namjou-Khales,3 David Y. Hui,2 and Mattia Quattrocelli1

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Durumutla, H. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Haller, A. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Noble, G. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Prabakaran, A. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by McFarland, K. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Latimer, H. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Rajput, A. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Akinborewa, O. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Namjou-Khales, B. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Hui, D. in: PubMed | Google Scholar

1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

2Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, United States of America

3Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Quattrocelli, M. in: PubMed | Google Scholar |

Published July 1, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190180.
Copyright © 2025, Durumutla et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 1, 2025 - Version history
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Abstract

Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene en-coding the GR, rs6190, associated with increased cholesterol in women according to UK Biobank and All Of Us datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) re-ceptors respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein frac-tions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corti-costerone and testosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mu-tant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.

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graphical abstract
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Version history
  • Version 1 (July 1, 2025): In-Press Preview
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