NR3C1: Can This Gene Predict Responsiveness to Glucocorticoids?

Article Summary

The NR3C1 gene codes for the glucocorticoid receptor, a key player in the regulation of metabolism, immune response, and stress adaptation. Variations in the NR3C1 gene, such as the rs6198 SNP, have been linked to differences in glucocorticoid sensitivity with some variants leading to increased expression of the GRβ isoform. While some companies say that this variation can predict treatment responsiveness to glucocorticoids in alopecia areata, there is a distinct lack of evidence. This article delves into the implications of NR3C1 polymorphisms for glucocorticoid responsiveness and evaluates the current evidence on how these genetic variations might affect therapeutic outcomes.

Full Article

The NR3C1 gene encodes the glucocorticoid receptor, which is essential for mediating the effects of glucocorticoids in various physiological processes, including metabolism, immune response, and stress regulation. This receptor plays a critical role in the body’s ability to respond to glucocorticoid medications, making it a key factor in conditions treated with these drugs.

This article will delve into the role of NR3C1 in glucocorticoid responsiveness and the evidence (or lack thereof) supporting it as a target for hair loss.

What is NR3C1?

The NR3C1 gene codes for the glucocorticoid receptor (GR). This receptor is involved in various physiological processes, including metabolism regulation, immune response, and stress response.^[1]GeneCards. (no date). NR3C1 Gene – Nuclear Receptor Subfamily 3 Group C Member 1. GeneCards. Available at: … Continue reading. Glucocorticoids are a type of steroid used to treat inflammatory and autoimmune diseases as well as cancer.^[2]Strehl, C., Ehlers, L., Gaber, T., Butthereit, F. (2019). Glucocorticoids – All Rounders Tackling the Versatile Players of the Immune System. Frontiers in Immunology. 10 GR is necessary for … Continue reading 

What is the Evidence for Targeting NR3C1 for Hair Loss?

GR is essential for glucocorticoids to exert their effects. There are two isoforms of GR encoded by the NR3C1 gene: GRα and GRβ. GRα is the classic GR protein, mediating the action of glucocorticoids. 

GRβ contains a unique extra sequence that gives it several distinct properties: GRβ does not bind to activators of glucocorticoids, resides in the nucleus of the cells, and is by itself inactive. However, when expressed alongside GRα, GRβ inhibits the activity of GRα.^[3]Oakley, R.H., Cidlowski, J.A. (2013). The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease. Journal of Allergy and Clinical Immunology. 132(5). 1033-1044. … Continue reading 

Simply put, if GRꞵ binds to GRɑ, it stops it from working correctly. This can lead to reduced sensitivity or even resistance to glucocorticoids in tissues expressing GRβ at higher levels.

In one retrospective study involving 122 children with acute lymphoblastic leukemia, researchers found that a specific genetic variant, called rs6198, can affect how the body responds to glucocorticoid medications.^[4]Gasic, V., Zukic, B., Stankovic, B., Janic, D., Dokmanovic, L., Lazic, J., Krstovski, N., Dolzan, V., Jazbec, J., Pavlovic, S., Kotur, N. (2018). Pharmacogenomic Markers of Glucocorticoid Response in … Continue reading 

When a patient had the GG allele variant, it was found that it stabilized the messenger RNA (mRNA), which is the molecule that carries instructions from DNA to make proteins. This stabilization leads to more of a particular form of the glucocorticoid receptor, which doesn’t bind to the medication as well as the normal form. 

Because this receptor doesn’t bind well, the treatment may not work as effectively, which could explain why some patients developed resistance to glucocorticoid therapy. This means their bodies don’t respond as well to the treatment, making it less effective in controlling their condition.

What is the Evidence Against Targeting NR3C1 for Hair Loss?

Some companies that test your genotype to suggest treatments use this gene as a marker for glucocorticoid sensitivity. While the evidence suggests that variations of NR3C1 can negatively affect glucocorticoid receptor activity, there is no published evidence showing that there are subsequent effects on corticosteroid treatment responsiveness in hair.

What Do Your Genetic Results Mean?

Your Result	NR3C1 (rs6198)
	Variant 1 GG genotype	Variant 2 GA genotype	Variant 3 AA genotype
What it means	Increased expression of the GRβ isoform	Moderate expression of the GRβ isoform	Normal expression of GR and less expression of the GRβ isoform
The Implication	You may want to avoid glucocorticoid treatment	You may respond less well to glucocorticoid treatment	You may respond normally to glucocorticoid treatment

What Relevance Does NR3C1 Have For Hair Loss Treatment?

We have also created a rubric that helps to determine the relevance of a specific gene to hair loss based on the quality of the evidence in the above studies.

On a scale of 1-5, how important are these genetic results? (1 is the lowest, 5 is the highest)

This score is a rating based on evidence quality.

• Does this gene have any potential relevance for hair loss? (1 point)

Yes. Due to the inhibitory effect of GRβ on GR activity, this variation may affect response to glucocorticoid treatment in cases of hair loss. (score = 1)

• Does the totality of evidence implicate GRα as a causal agent for hair loss? (1 point)

No, there doesn’t appear to be any evidence implicating GRα in hair loss.

• Does the totality of evidence implicate GRα as a predictive factor for hair loss treatment responsiveness? (2 points)

While there is evidence to suggest that the activity of GRα may be affected by this variation, there is no published evidence to indicate that it can predict responsiveness to glucocorticoid treatment. (score = 0)

• Is this quality of evidence on (3) strong enough to influence treatment recommendations? (1 point)

No, the quality of evidence is not strong enough to influence treatment recommendations due to the lack of published evidence. (score = 0)

Total Score = 1

Final Thoughts

The NR3C1 gene, which encodes the glucocorticoid receptor, plays a crucial role in various physiological processes, including stress response and inflammation. While variations in the gene, particularly the rs6198 variant, have been linked to altered glucocorticoid sensitivity, the evidence for its role in hair loss remains inconclusive. Therefore, more research is needed to determine its relevance and utility in predicting or treating hair loss.