The DOI matches its Crossref record; 65 of the 66 references it cites were found in a registry or an index.
Computational identification of gene–social environment interaction at the human IL6 locus
Open accessAbstract
To identify genetic factors that interact with social environments to impact human health, we used a bioinformatic strategy that couples expression array–based detection of environmentally responsive transcription factors with in silico discovery of regulatory polymorphisms to predict genetic loci that modulate transcriptional responses to stressful environments. Tests of one predicted interaction locus in the human IL6 promoter (SNP rs1800795) verified that it modulates transcriptional response to β-adrenergic activation of the GATA1 transcription factor in vitro. In vivo validation studies confirmed links between adverse social conditions and increased transcription of GATA1 target genes in primary neural, immune, and cancer cells. Epidemiologic analyses verified the health significance of those molecular interactions by documenting increased 10-year mortality risk associated with late-life depressive symptoms that occurred solely for homozygous carriers of the GATA1-sensitive G allele of rs1800795. Gating of depression-related mortality risk by IL6 genotype pertained only to inflammation-related causes of death and was associated with increased chronic inflammation as indexed by plasma C-reactive protein. Computational modeling of molecular interactions, in vitro biochemical analyses, in vivo animal modeling, and human molecular epidemiologic analyses thus converge in identifying β-adrenergic activation of GATA1 as a molecular pathway by which social adversity can alter human health risk selectively depending on individual genetic status at the IL6 locus.
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In the citing paper
“This adrenergic signaling cascade suppresses transcription of antiviral type I IFN genes”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“high levels of social-environmental stress were associated with increased mortality risk for rs1800795 G homozygotes; C allele carriers, in contrast, exhibited no increases in mortality risk under high levels of stress”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“a regulatory SNP in the human IL6 promoter, that moderate inflammatory responses to social stress”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“the effect of this SNP on mortality was completely attenuated when the survival analyses adjusted for levels of CRP”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“this effect amounted to a 2.8-year shorter average life span for persons who were homozygous for the G allele”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“the effect of this genotype on mortality risk was entirely specific to inflammation-related causes of death (e.g., cardiovascular and neurodegenerative diseases)”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“SNS activation enhances transcription of proinflammatory immune response genes (S. W. Cole et al., 2010; Grebe et al., 2010), which increases systemic inflammatory activity that aids in combating bacteria and other extracellular pathogens”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as S. W. Cole et al., 2010
In the citing paper
“SNS activation of the CTRA is mediated in large part by β-adrenergic receptors, which stimulate transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), GATA, and cAMP response element-binding protein (CREB) to selectively up-regulate transcription of proinflammatory genes (e.g., IL6 [19]) while simultaneously inhibiting the activity of transcription”
From Human Social Genomics (2014) · cites this paper as [19]
Citations
Cites
The CES-D Scale: A Self-Report Depression Scale for Research in the General Population
Radloff, L. S. (1977) · Applied Psychological Measurement · doi:10.1177/014662167700100306 · Cited by 53,267
(2005) · Springer eBooks · doi:10.1007/0-387-27255-0_9 · Cited by 20,333
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
dbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502
Acute-Phase Proteins and Other Systemic Responses to Inflammation
Gabay, C., & Kushner, I. (1999) · New England Journal of Medicine · doi:10.1056/nejm199902113400607 · Cited by 6,734
Cox, D. R., & Oakes, D. (2018) · Chapman & Hall/CRC eBooks · doi:10.1201/9781315137438 · Cited by 6,269
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 5,429
C-reactive protein: a critical update
Pepys, M. B., & Hirschfield, G. M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18921 · Cited by 4,694
Affective Neuroscience: The Foundations of Human and Animal Emotions
Panksepp, J. (1998) · doi:10.1093/oso/9780195096736.001.0001 · Cited by 4,428
Breslow, N. E., Cox, D. R., & Oakes, D. (1985) · Biometrics · doi:10.2307/2530888 · Cited by 4,381
Research works printed but not linked: 2
- LM Hernandez DG Blazer (National Academies Press Washington DC 2006).
- dbSNP 2009 rs1800795 dbSNP Database Record http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1800795. Last accessed October 7 2009.
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Metadata
- Authors
- Cole, S. W., Arevalo, J. M. G., Takahashi, R., Sloan, E. K., Lutgendorf, S. K., Sood, A. K., Sheridan, J. F., & Seeman, T. E.
- Affiliations
- Department of Medicine and
- University of California, Los Angeles (US)
- University of Iowa (US)
- The University of Texas MD Anderson Cancer Center (US)
- The Ohio State University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-02-22
- Volume
- 107
- Issue
- 12
- Pages
- 5681-5686
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2851818
- OpenAlex
- W2133353372
- Cited by
- 256
- References
- 66
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 13 · 2021: 6 · 2020: 15 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 14 · 2015: 19 · 2014: 36 · 2013: 20 · 2012: 23
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG028748, AG107265, P60AG010415, AG010415, P30AG028748)
- National Institute of Mental Health (MH046801, R01MH046801)
- National Cancer Institute (CA 109298, R01CA110793, CA 110793, R01CA109298, R01CA116778, R01CA104825, CA-116778)
- National Institute of Allergy and Infectious Diseases (R01AI052737, AI052737)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- gene-environment interaction, rs1800795, beta-adrenergic signaling, social adversity, depression, mortality risk, chronic inflammation, C-reactive protein, regulatory polymorphisms
- MeSH terms
- Base Sequence, DNA, Humans, Models, Genetic, Promoter Regions, Genetic, Social Environment, Stress, Psychological, Sympathetic Nervous System, Transcription Factors, Transcriptional Activation, Interleukin-6, Molecular Epidemiology, Computational Biology, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, RNA, Small Interfering, GATA1 Transcription Factor
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