Abstract
Early adverse life events (EALs) have been associated with regional thinning of the subgenual cingulate cortex (sgACC), a brain region implicated in the development of disorders of mood and affect, and often comorbid functional pain disorders, such as irritable bowel syndrome (IBS). Regional neuroinflammation related to chronic stress system activation has been suggested as a possible mechanism underlying these neuroplastic changes. However, the interaction of genetic and environmental factors in these changes is poorly understood. The current study aimed to evaluate the interactions of EALs and candidate gene polymorphisms in influencing thickness of the sgACC. 210 female subjects (137 healthy controls; 73 IBS) were genotyped for stress and inflammation-related gene polymorphisms. Genetic variation with EALs, and diagnosis on sgACC thickness was examined, while controlling for race, age, and total brain volume. Compared to HCs, IBS had significantly reduced sgACC thickness (p = 0.03). Regardless of disease group (IBS vs. HC), thinning of the left sgACC was associated with a significant gene–gene environment interaction between the IL-1β genotype, the NR3C1 haplotype, and a history of EALs (p = 0.05). Reduced sgACC thickness in women with the minor IL-1β allele, was associated with EAL total scores regardless of NR3C1 haplotype status (p = 0.02). In subjects homozygous for the major IL-1β allele, reduced sgACC with increasing levels of EALs was seen only with the less common NR3C1 haplotype (p = 0.02). These findings support an interaction between polymorphisms related to stress and inflammation and early adverse life events in modulating a key region of the emotion arousal circuit.
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Abbreviations
- SgACC:
-
Subgenual anterior cingulate cortex
- VmPFC:
-
Ventromedial prefrontal cortex
- IBS:
-
Irritable bowel syndrome
- HC:
-
Healthy control
- EALs:
-
Early adverse life events
- SNPs:
-
Single nucleotide polymorphisms
- GCR NR3C1:
-
Glucocorticoid receptor
- IL-1β:
-
Proinflammatory cytokines interleuken-1β
- HPA:
-
Hypothalamus–pituitary–adrenal axis
- fMRI:
-
Functional brain imaging
- CT:
-
Cortical thickness
- GM:
-
Gray matter
- GI:
-
Gastroenterological
- ETI:
-
Early traumatic inventory
- HAD:
-
Hospital and Anxiety Depression Scale
- MP-RAGE:
-
Magnetization-prepared rapid acquisition gradient echo
- TR:
-
Repetition time
- TE:
-
Echo time
- NF-κB:
-
Nuclear factor-κB
- TGMV:
-
Total grey matter volume
- LD:
-
Linkage disequilibrium
- GLM:
-
General linear model
- CNS:
-
Central nervous system
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Acknowledgments
This research was supported in part by grants from the National Institute of Health: R01 DK048351 (EAM), P50 DK064539 (EAM), P30 DK041301 (UCLA Cure Center), K01 DK085133 (LAK); Pilot scans were provided by Ahamsom-Lovelace Brain Mapping Center. The authors acknowledge the valuable editorial contributions made to the manuscript by Cathy Liu.
Conflict of interest
The authors declare no conflict of interest. Drs. Mayer, Labus, Bradesi, Chang, and Kilpatrick’s work has been funded by the NIH.
Ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of California Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Gupta, A., Labus, J., Kilpatrick, L.A. et al. Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females. Brain Struct Funct 221, 1667–1679 (2016). https://doi.org/10.1007/s00429-015-0996-9
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DOI: https://doi.org/10.1007/s00429-015-0996-9