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
C-reactive protein: a critical update
Pepys, M. B., & Hirschfield, G. M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318921 · Cited by 3,436
The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis
Chrousos, G. P. (1992) · JAMA · doi:10.1001/jama.1992.03480090092034 · Cited by 2,689
Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V, Yudkin, J. S., Humphries, S., & Woo, P. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2629 · Cited by 2,243
Searching for genetic determinants in the new millennium
Risch, N. J. (2000) · Nature · doi:10.1038/35015718 · Cited by 1,839
Gene–environment interactions in psychiatry: joining forces with neuroscience
Caspi, A., & Moffitt, T. E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1925 · Cited by 1,300
Age-Associated Increased Interleukin-6 Gene Expression, Late-Life Diseases, and Frailty
Ershler, W. B., & Keller, E. T. (2000) · Annual Review of Medicine · doi:10.1146/annurev.med.51.1.245 · Cited by 1,282
Sapolsky, R. M. (1994) · W.H. Freeman eBooks · Cited by 1,212
Social ties and health: The benefits of social integration
Seeman, T. E. (1996) · Annals of Epidemiology · doi:10.1016/s1047-2797(96)00095-6 · Cited by 1,137
Self-citation(2000) · doi:10.1093/oso/9780195083316.001.0001 · Cited by 1,069
Lachenbruch, P. A., McCullagh, P., & Nelder, J. A. (1990) · Biometrics · doi:10.2307/2532465 · Cited by 947
A mechanism converting psychosocial stress into mononuclear cell activation
Bierhaus, A., Wolf, J., Andrassy, M., Rohleder, N., Humpert, P. M., Petrov, D., Ferstl, R., von Eynatten, M., Wendt, T., Rudofsky, G., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0438019100 · Cited by 927
The Hopkins Symptom Checklist (HSCL)
Derogatis, L. R., Lipman, R. S., Rickels, K., UHLENHUTH, E. H., & Covi, L. (2015) · Modern problems of pharmacopsychiatry/Modern trends in pharmacopsychiatry · doi:10.1159/000395070 · Cited by 895
RefSeq and LocusLink: NCBI gene-centered resources
Pruitt, K. D. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.137 · Cited by 884
Disease and disadvantage in the United States and in England
Banks, J., Marmot, M., Oldfield, Z., & Smith, J. P. (2006) · JAMA · doi:10.1001/jama.295.17.2037 · Cited by 807
Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation
Terry, C., Loukaci, V., & Green, F. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000379200 · Cited by 803
Strategy for Investigating Interactions Between Measured Genes and Measured Environments
Moffitt, T. E., Caspi, A., & Rutter, M. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.5.473 · Cited by 784
Social regulation of gene expression in human leukocytes
Cole, S. W., Hawkley, L. C., Arevalo, J. M., Sung, C. Y., Rose, R. M., & Cacioppo, J. T. (2007) · Genome Biology · doi:10.1186/gb-2007-8-9-r189 · Cited by 745
Self-citationZhang, D.-H., Cohn, L. E., Ray, P., Bottomly, K., & Ray, A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21597 · Cited by 665
Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health
Meaney, M. J., Szyf, M., & Seckl, J. R. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.05.003 · Cited by 661
Elevated inflammation levels in depressed adults with a history of childhood maltreatment
Danese, A., Moffitt, T. E., Pariante, C. M., Ambler, A., Poulton, R., & Caspi, A. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.4.409 · Cited by 641
Socioeconomic Status Is Associated With Stress Hormones
Cohen, S., Doyle, W. J., & Baum, A. (2006) · Psychosomatic Medicine · doi:10.1097/01.psy.0000221236.37158.b9 · Cited by 639
Berkman, L. F., Seeman, T. E., Albert, M., Blazer, D. G., Kahn, R. L., Mohs, R. C., Finch, C. E., Schneider, E. L., Cotman, C. W., McClearn, G. E., et al. (1993) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(93)90112-e · Cited by 499
Self-citationWhy Zebras Don't Get Ulcers: An Updated Guide to Stress, Stress Related Diseases, and Coping
Sapolsky, R. M. (1998) · Medical Entomology and Zoology · Cited by 445
Lee, H. J., Takemoto, N., Kurata, H., Kamogawa, Y., Miyatake, S., O'Garra, A., & Arai, N. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.1.105 · Cited by 393
Acute mental stress elicits delayed increases in circulating inflammatory cytokine levels
STEPTOE, A., WILLEMSEN, G., OWEN, N., FLOWER, L., & MOHAMED-ALI, V. (2001) · Clinical Science · doi:10.1042/cs1010185 · Cited by 354
Taylor, S. E., Lehman, B. J., Kiefe, C. I., & Seeman, T. E. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.016 · Cited by 296
Self-citationSocial stress induces glucocorticoid resistance in macrophages
Stark, J. L., Avitsur, R., Padgett, D. A., Campbell, K. A., Beck, F. M., & Sheridan, J. F. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.6.r1799 · Cited by 295
Self-citationPerturbing the organism: the biology of stressful experience
(1993) · Choice Reviews Online · doi:10.5860/choice.30-2669 · Cited by 285
Transcriptional Regulation in Eukaryotes: Concepts, Strategies and Techniques
Carey, M., & Smale, S. T. (2000) · Cited by 253
Regulatory polymorphisms underlying complex disease traits.
Knight, J. C. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0603-7 · Cited by 246
Combinations of biomarkers predictive of later life mortality
Gruenewald, T. L., Seeman, T. E., Ryff, C. D., Karlamangla, A. S., & Singer, B. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606215103 · Cited by 242
Self-citationDepression, social support, and beta-adrenergic transcription control in human ovarian cancer
Lutgendorf, S. K., DeGeest, K., Sung, C. Y., Arevalo, J. M., Penedo, F., Lucci, J., Goodheart, M., Lubaroff, D., Farley, D. M., Sood, A. K., et al. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2008.04.155 · Cited by 215
Self-citationSocial Ties and Support and Neuroendocrine Function: the MacArthur Studies of Successful Aging
Seeman, T. E., Berkman, L. F., Blazer, D. G., & Rowe, J. W. (1994) · Annals of Behavioral Medicine · doi:10.1093/abm/16.2.95 · Cited by 210
Self-citationThe Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Lifespans
Finch, C. E. (2007) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) · Cited by 194
The Peripheral Kinetics of Norepinephrine in Depressive Illness
Esler, M. (1982) · Archives of General Psychiatry · doi:10.1001/archpsyc.1982.04290030035006 · Cited by 194
Social Regulation of Human Gene Expression
Cole, S. W. (2009) · Current Directions in Psychological Science · doi:10.1111/j.1467-8721.2009.01623.x · Cited by 187
Self-citationSocioeconomic status and C-reactive protein levels in the US population: NHANES IV
Alley, D. E., Seeman, T. E., Kim, J. K., Karlamangla, A. S., Hu, P., & Crimmins, E. M. (2005) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2005.10.003 · Cited by 186
Self-citationExpression-based monitoring of transcription factor activity: the TELiS database
Cole, S. W., Yan, W., Galic, Z., Arevalo, J., & Zack, J. A. (2005) · Bioinformatics · doi:10.1093/bioinformatics/bti038 · Cited by 185
Self-citationSloan, E. K., Capitanio, J. P., Tarara, R. P., Mendoza, S. P., Mason, W. A., & Cole, S. W. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1247-07.2007 · Cited by 170
Self-citationRobinson, G. E. (2004) · Science · doi:10.1126/science.1095766 · Cited by 161
Interleukin-6 -174G-->C polymorphism is associated with improved outcome in high-risk breast cancer.
DeMichele, A. M., Martin, A.-M., Mick, R., Gor, P. P., Wray, L., Klein-Cabral, M., Athanasiadis, G., Colligan, T., Stadtmauer, E. A., & Weber, B. (2003) · PubMed · Cited by 155
Interleukin-6 Promoter Haplotypes and Interleukin-6 Cytokine Responses
Rivera-Chávez, F. A., Hybki, D. P., Barber, R. C., & O’Keefe, G. E. (2003) · Shock · doi:10.1097/00024382-200309000-00004 · Cited by 141
Siegel, M. D., Zhang, D.-H., Ray, P., & Ray, A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.41.24548 · Cited by 138
Chen, C.-H., Zhang, D.-H., LaPorte, J. M., & Ray, A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.10.5597 · Cited by 136
Hudson, T. J. (2003) · Nature Genetics · doi:10.1038/ng0403-439 · Cited by 108
Regulatory SNPs in complex diseases: their identification and functional validation
Prokunina‐Olsson, L., & Alarcón-Riquelme, M. E. (2004) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399404007690 · Cited by 108
The importance and identification of regulatory polymorphisms and their mechanisms of action
Buckland, P. R. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2005.10.004 · Cited by 107
Tremblay, J., & Viger, R. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213149200 · Cited by 98
Catecholamines stimulate interleukin-6 synthesis in rat cardiac fibroblasts.
Bürger, A., Benicke, M., Deten, A., & Zimmer, H.-G. (2001) · American Journal of Physiology. Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.1.h14 · Cited by 91
Gene therapy for severe combined immune deficiency
Qasim, W., Gaspar, H. B., & Thrasher, A. (2004) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399404007884 · Cited by 52
Protein Kinase A Regulates GATA-3-Dependent Activation of IL-5 Gene Expression in Th2 Cells
Klein‐Hessling, S., Jha, M. K., Santner‐Nanan, B., Berberich‐Siebelt, F., Baumruker, T., Schimpl, A., & Serfling, E. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.6.2956 · Cited by 50
Janicki‐Deverts, D., Cohen, S., Adler, N. E., Schwartz, J. E., Matthews, K. A., & Seeman, T. E. (2007) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3180f60645 · Cited by 49
Self-citationBriest, W., Rassler, B., Deten, A., Leicht, M., Morwinski, R., Neichel, D., Wallukat, G., Ziegelhöffer, T., & Zimmer, H.-G. (2003) · Pflügers Archiv · doi:10.1007/s00424-003-1043-x · Cited by 36
Norepinephrine-induced expression of cytokines in isolated biventricular working rat hearts
Briest, W., Elsner, C., Hemker, J., Müller-Strahl, G., & Zimmer, H. (2003) · Molecular and Cellular Biochemistry · doi:10.1023/a:1022861609896 · Cited by 12
Potential regulatory SNPs in promoters of human genes: A systematic approach
Stepanova, M. S., Tyazhelova, T. V., Скоблов, М. Ю., & Baranova, A. V. (2006) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2006.03.007 · Cited by 12
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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“This adrenergic signaling cascade suppresses transcription of antiviral type I IFN genes (Cole et al. 1998) and upregulates transcription of the proinflammatory immune response genes IL1B, TNF, and IL6, leading to increases in systemic inflammatory activity (Cole et al. 2010).”
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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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