From the Guidelines
Several genes are associated with hyperadrenergic autonomic dysfunction or HPA axis dysregulation, including COMT, MTHFR, CRHR1, FKBP5, and NR3C1, which can affect the regulation of stress hormones, neurotransmitters, and the body's stress response system. The most commonly implicated genes in hyperadrenergic autonomic dysfunction or HPA axis dysregulation are:
- COMT (Catechol-O-methyltransferase)
- MTHFR (Methylenetetrahydrofolate reductase)
- CRHR1 (Corticotropin-releasing hormone receptor 1)
- FKBP5 (FK506 binding protein 5)
- NR3C1 (Nuclear receptor subfamily 3 group C member 1, also known as the glucocorticoid receptor gene) These genes play a crucial role in regulating stress hormones, neurotransmitters, and the body's stress response system, and mutations or variations in these genes can lead to autonomic dysfunction or HPA axis dysregulation 1. For example, COMT influences dopamine and norepinephrine metabolism, while MTHFR affects folate metabolism, which is important for neurotransmitter production. CRHR1, FKBP5, and NR3C1 are directly involved in the regulation of the HPA axis and cortisol signaling. Understanding these genetic factors can help in developing personalized treatment approaches for individuals with autonomic dysfunction or HPA axis dysregulation. However, it's essential to note that genetic testing alone is not sufficient for diagnosis, and a comprehensive clinical evaluation is necessary for proper management of these conditions. Additionally, other genes such as SDHB, SDHD, SDHC, and SDHAF2 have been implicated in hereditary pheochromocytoma/paraganglioma syndromes, which can also lead to autonomic dysfunction or HPA axis dysregulation 1. In the context of SIDS, genes related to the serotonin transporter, cardiac channelopathies, and the development of the autonomic nervous system have been examined for altered genetic makeup, and polymorphisms in the promoter region of the serotonin transporter have been reported to be more prevalent in infants who die of SIDS compared with controls 1. However, the relationship between these genes and hyperadrenergic autonomic dysfunction or HPA axis dysregulation is complex and requires further research to fully understand the underlying mechanisms. In clinical practice, a comprehensive evaluation of the patient's medical history, physical examination, and laboratory results is necessary to diagnose and manage autonomic dysfunction or HPA axis dysregulation, and genetic testing should be considered as part of a broader diagnostic approach.
From the Research
Genes Associated with Hyperadrenergic Autonomic Dysfunction or HPA Axis Dysregulation
- The following genes have been associated with hyperadrenergic autonomic dysfunction or HPA axis dysregulation:
- Glucocorticoid receptor gene (GR) 2
- Mineralocorticoid receptor gene (MR) 2, 3
- Serotonin transporter gene (5-HTT) 2
- Brain-derived neurotrophic factor (BDNF) 2, 4
- Tyrosine hydroxylase (TH) 4
- NR3C1 gene 5, 3, 6
- NR3C2 gene 3
- FKBP5 gene 3, 6
- Corticotrophin Releasing Hormone (CRH) 6
- Corticotrophin Releasing Hormone Receptor 1 (CRHR1) 6
- Corticotrophin Releasing Hormone Receptor 2 (CRHR2) 6
- Arginine Vasopressin (AVP) 6
- Angiotensin Converting Enzyme (ACE) 6
- CYP11A1 3
- CYP17A1 3
- POU1F1 3
- AKR1D1 3
- HSD3B2 3
- PROP1 3
- AVPRA1 3
- SRD5A1 3
- POMC 3
Gene-Environment Interactions
- Gene-environment interactions between HPA-axis genes and stressful life events have been reported for several genes, including:
HPA Axis Regulation
- Genes involved in HPA-axis regulation, such as those listed above, may contribute to the relation between relevant neurobiological substrates and stress-related disorders 3
- Epigenetic changes in HPA axis-associated genes, such as NR3C1, may be influenced by early life stress and contribute to HPA axis dysregulation 5