Adaptive variation regulates the expression of the human SGK1 gene in response to stress
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The Serum and Glucocorticoid-regulated Kinase1 (SGK1) gene is a target of the glucocorticoid receptor (GR) and is central to the stress response in many human tissues. Because environmental stress varies across habitats, we hypothesized that natural selection shaped the geographic distribution of genetic variants regulating the level of SGK1 expression following GR activation. By combining population genetics and molecular biology methods, we identified a variant (rs9493857) with marked allele frequency differences between populations of African and European ancestry and with a strong correlation between allele frequency and latitude in worldwide population samples. This SNP is located in a GR-binding region upstream of SGK1 that was identified using a GR ChIP-chip. SNP rs9493857 also lies within a predicted binding site for Oct1, a transcription factor known to cooperate with the GR in the transactivation of target genes. Using ChIP assays, we show that both GR and Oct1 bind to this region and that the ancestral allele at rs9493857 binds the GR-Oct1 complex more efficiently than the derived allele. Finally, using a reporter gene assay, we demonstrate that the ancestral allele is associated with increased glucocorticoid-dependent gene expression when compared to the derived allele. Our results suggest a novel paradigm in which hormonal responsiveness is modulated by sequence variation in the regulatory regions of nuclear receptor target genes. Identifying such functional variants may shed light on the mechanisms underlying inter-individual variation in response to environmental stressors and to hormonal therapy, as well as in the susceptibility to hormone-dependent diseases.
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A key gene involved in mediating these effects shows evidence of recent adaptive variation across human populations.
“Interestingly, a key gene involved in mediating these effects shows evidence of recent adaptive variation across human populations [52].”
From Human Social Genomics (2014) · cites this paper as [52]
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Self-citationvan Zuiden, M., Geuze, E., Willemen, H. L. D. M., Vermetten, E., Maas, M., Amarouchi, K., Kavelaars, A., & Heijnen, C. J. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.10.026 · Cited by 201 · see citing works
Spatial patterns of variation due to natural selection in humans
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The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum
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Self-citationSerum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth
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Therapeutic potential of serum and glucocorticoid inducible kinase inhibition
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Genetics of glucocorticoid regulation and posttraumatic stress disorder -what do we know?
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Genetic analysis of reproductive traits and antibody response in a PRRS outbreak herd1
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Genotype × environment interactions in gene regulation and complex traits
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Multiple Functional Variants in cis Modulate PDYN Expression
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SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α
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Genetic, Functional and Molecular Features of Glucocorticoid Receptor Binding
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Human Expression QTLs Are Enriched in Signals of Environmental Adaptation
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miR-16-2-3p enhances glucocorticoid sensitivity in ulcerative colitis by targeting CREB1 and NF-κB1
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Nutritional Aspects of the Mosaic of Rheumatic Autoimmune Diseases a Recipe for Therapy?
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An adaptive interaction between cell type and metabolism drives ploidy evolution in a wild yeastPreprint
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Age-related microbiome metabolites alter RNA splicing and chromatin accessibility in the brainPreprint
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Self-citationThe Role of Glucocorticoid Receptor in the Racial/Ethnic Disparity of Aggressive Breast Cancer
Al‐Alem, U. (2015) · Figshare
Transcriptional Effects of Heroin and Methamphetamine in the Striatum
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- Authors
- Luca, F., Kashyap, S., Southard, C., Zou, M., Witonsky, D., Di Rienzo, A., & Conzen, S. D.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Conzen, Suzanne D.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-05-22
- Volume
- 5
- Issue
- 5
- Pages
- e1000489
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2679193
- OpenAlex
- W2058917347
- Cited by
- 45
- References
- 92
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- University of Chicago (cc-by)
- Funders
- American Heart Association
- University of Chicago (P30 CA014599)
- Wellcome Trust (068545/Z/02), G0000934, 068545)
- National Institutes of Health (G0000934)
- Medical Research Council (G0000934)
- National Cancer Institute (R01CA089208, P50CA125183, P30CA014599)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056670)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- SGK1, glucocorticoid receptor, OCT1, single nucleotide polymorphisms, glucocorticoid response element, transcriptional regulation, natural selection, allele frequency variation, latitude, stress response
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Alleles, Base Sequence, Binding Sites, Cell Line, DNA, Enhancer Elements, Genetic, Female, Gene Frequency, Humans, Neurosecretory Systems, Receptors, Glucocorticoid, Stress, Physiological, Genetic Variation, Signal Transduction, Gene Expression, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Black People, White People, Octamer Transcription Factor-1
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