Computational identification of gene–social environment interaction at the human IL6 locus

Steven W Cole; Jesusa M. G Arevalo; Rie Takahashi; Erica K Sloan; Susan K Lutgendorf; Anil K Sood; John F Sheridan; Teresa E Seeman

doi:10.1073/pnas.0911515107

Back

Computational identification of gene–social environment interaction at the human IL6 locus

Journal article

Open access

Peer reviewed

Computational identification of gene–social environment interaction at the human IL6 locus

Steven W Cole, Jesusa M. G Arevalo, Rie Takahashi, Erica K Sloan, Susan K Lutgendorf, Anil K Sood, John F Sheridan and Teresa E Seeman

Proceedings of the National Academy of Sciences - PNAS, Vol.107(12), pp.5681-5686

03/23/2010

DOI: 10.1073/pnas.0911515107

PMCID: PMC2851818

PMID: 20176930

Files and links (1)

url

https://doi.org/10.1073/pnas.0911515107View

Published (Version of record) Open Access

Abstract

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.

Biological Sciences

Stress

Transcription

Inflammation

social epidemiology

gene–environment interaction

Details

Title: Subtitle: Computational identification of gene–social environment interaction at the human IL6 locus
Creators: Steven W Cole - Department of Medicine and
Jesusa M. G Arevalo - Department of Medicine and
Rie Takahashi - Department of Medicine and
Erica K Sloan - Norman Cousins Center
Susan K Lutgendorf - Department of Psychology
Anil K Sood - Departments of Gynecologic Oncology and Cancer Biology
John F Sheridan - Institute for Behavioral Medicine Research
Teresa E Seeman - Department of Medicine and
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.107(12), pp.5681-5686
DOI: 10.1073/pnas.0911515107
PMID: 20176930
PMCID: PMC2851818
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 03/23/2010
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984065887502771

Metrics

14 Record Views

209 Times Cited - Web of Science