GPR44: Can This Gene Predict Hair Regrowth From PGD2 Inhibitors?

Article Summary

Can your genes predict the effectiveness of PGD2 inhibitors for hair loss? The GPR44 gene, encoding the prostaglandin D2 receptor (DP2), is a potential target in hair loss treatment. Elevated levels of prostaglandin D2 (PGD2) have been linked to hair growth inhibition, making GPR44 a key player. However, while early studies showed promise, follow-up research yielded mixed results, and a clinical trial of a GPR44 blocker did not show significant efficacy. This article explores the role of GPR44 in hair loss, the current state of research, and whether genetic variations in GPR44 can influence treatment response.

Full Article

GPR44 is a gene that encodes the G-protein-coupled receptor 44, also known as the prostaglandin D2 receptor (DP2). This receptor plays a pivotal role in various physiological processes, including inflammation and immune responses.

GPR44 is considered significant in the context of hair loss because some believe it is involved in hair growth inhibition. 

Early studies evaluating prostaglandin activity in the hair follicle found that elevated levels of prostaglandin D2 (PGD2) have been found in the scalps of individuals with androgenic alopecia. PGD2 exerts its effects through the GPR44 receptor. 

This article will delve into the importance of the GPR44 gene in hair loss, its potential as a therapeutic target, and the significant role that understanding your genetic makeup can play in making informed treatment decisions.

What is GPR44?

The GPR44 gene (also called CRTh2) codes for the expression of a type of receptor for prostaglandins, specifically PGD2.^[1]National Library of Medicine. (2024). PTGDR2 Prostaglandin D2 Receptor 2 [Homo sapiens (human)]. NIH. Available at: https://www.ncbi.nlm.nih.gov/gene/11251 (Accessed: 12 July 2024.) Prostaglandin D2 is a bioactive lipid compound that belongs to the family of prostaglandins, which are derived from arachidonic acid. Prostaglandins are involved in various physiological processes, including inflammation, allergic reactions, and regulation of sleep-wake cycles. PGD2 is produced by several types of cells, including mast cells, dendritic cells, and other types of immune cells.

Studies suggest that PGD2 has been found to inhibit hair growth in isolated human hair follicles and mice. Furthermore, PGD2 has been found to be elevated in the scalps of balding men diagnosed with androgenetic alopecia.^[2]Nieves, A., Garza, L.A. (2014). Does Prostaglandin D2 Hold the Cure to Male Pattern Baldness? Experimental Dermatology. 23(4). 224-227. Available at: https://doi.org/10.1111/exd.12348^[3]Garza, L.A., Liu, Y., Alagesan, B., Lawson, J.A., Norberg, S.M., Loy, D.R., Zhao, T., Blatt, H.B., Stanton, D.C., Carrasco, L., Ahluwalia, G., Fischer, S.M., Fitzgerald, G.A., Cotsarelis, G. (2012). … Continue reading

What is the Evidence for Targeting GPR44 for Hair Loss?

As mentioned above, PGD2 binds to its receptor, GPR44, to exert its effects. Studies on human scalp samples from the bald and haired areas of balding men found that the level of PGD2 was significantly higher in the scalps of the balding areas (Figure 1). Furthermore, PGE2, which has been linked to human hair growth, was found to be significantly lower in the bald scalp (Figure 1).^[4]Garza, L.A., Liu, Y., Alagesan, B., Lawson, J.A., Norberg, S.M., Loy, D.R., Zhao, T., Blatt, H.B., Stanton, D.C., Carrasco, L., Ahluwalia, G., Fischer, S.M., Fitzgerald, G.A., Cotsarelis, G. (2012). … Continue reading

The same study evaluated the effect of high levels of PGD2 in mouse skin, hypothesizing that it might lead to the initiation of features of androgenic alopecia. The researchers used K14-Ptgs2 transgenic mice that are genetically modified to overexpress the Ptgs2 gene (also known as COX-2) specifically in the skin. These mice are often used in prostaglandin signaling studies as these specific genetic modifications increase levels of PGD2, PGE2, and 15-dPGJ2.

The mice overexpressing this gene were found to have hair follicles that entered premature catagen with subsequent development of alopecia.^[6]Garza, L.A., Liu, Y., Alagesan, B., Lawson, J.A., Norberg, S.M., Loy, D.R., Zhao, T., Blatt, H.B., Stanton, D.C., Carrasco, L., Ahluwalia, G., Fischer, S.M., Fitzgerald, G.A., Cotsarelis, G. (2012). … Continue reading

In a series of experiments, researchers investigated the effects of prostaglandin D2 (PGD2) on hair growth using C57Bl/6 mice, a common laboratory strain. They topically applied PGD2 to the shaved backs of these mice and measured hair length 20 days after depilation.

The results showed a significant inhibition of hair growth in the treated areas. To further explore the mechanism, the team used a separate mouse model with the GPR44 gene (which encodes a PGD2 receptor) knocked out. Interestingly, these GPR44-deficient mice demonstrated resistance to hair loss when PGD2 was applied topically, indicating that PGD2’s effect on hair loss was through the GPR44 receptor.^[7]Garza, L.A., Liu, Y., Alagesan, B., Lawson, J.A., Norberg, S.M., Loy, D.R., Zhao, T., Blatt, H.B., Stanton, D.C., Carrasco, L., Ahluwalia, G., Fischer, S.M., Fitzgerald, G.A., Cotsarelis, G. (2012). … Continue reading

Clinical studies have found an association between the rs533116 and rs545659 polymorphisms of the GPR44 gene that enhances the expression of GPR44 in the lungs, resulting in an increase in asthma severity.^[9]Campos Alberto, E., Maclean, E., Davidson, C., Palikhe, N.S., Storie, J., Tse, C., Brenner, D., Mayers, I., Vliagoftis, H., El-Sohemy, A., Cameron, L. (2012). The Single Nucleotide Polymorphism CRTh2 … Continue reading^[10]Huang, J.L., Gao, P.S., Mathias, R.A., Yao, T.C., Chen, L.C., Kuo, M.L., Hsu, S.C., Plunkett, B., Togias, A., Barnes, K.C., Stellato, C., Beaty, T.H., Huang, S.K. Sequence Variants of the Gene … Continue reading 

This increase in the expression of receptors like GPR44 may increase responsiveness to PGD2, so it’s possible that these findings may also apply to people with androgenic alopecia.

What is the Evidence Against Targeting GPR44 for Hair Loss?

In 2012, a study from the University of Pennsylvania and Johns Hopkins University generated a lot of excitement about a potential new treatment avenue for hair loss. The researchers found that PGD2 was elevated in the balding scalp but not in non-balding areas of the scalp of men with hair loss. Furthermore, they found that PGD2 inhibits hair growth.^[11]Garza, L.A., Liu, Y., Alagesan, B., Lawson, J.A., Norberg, S.M., Loy, D.R., Zhao, T., Blatt, H.B., Stanton, D.C., Carrasco, L., Ahluwalia, G., Fischer, S.M., Fitzgerald, G.A., Cotsarelis, G. (2012). … Continue reading. This sparked an interest in prostaglandins as hair growth inhibitors.

Unfortunately, follow-up studies showed conflicting results – thanks to poorly controlled variables – and it is still unclear whether there is a causal relationship between prostaglandins and androgenetic alopecia.^[12]English, R., Ruiz, S. (2021). Conflicting Reports Regarding the Histopathological Features of Androgenic Alopecia: Are Biopsy Location, Hair Diameter Diversity, and Relative Hair Follicle … Continue reading

A randomized, double-blind, placebo-controlled Phase 2a trial on setipiprant, a drug designed to bind to GPR44 and block PGD2 from exerting its effect, was conducted on males aged 18-49 with androgenic alopecia. The study found that setipiprant at 1000 mg twice daily for 24 weeks did not demonstrate efficacy compared to a placebo in improving hair growth, as measured by target area hair count and participant self-assessment. While setipiprant was safe and well-tolerated, it failed to show significant improvements indicating that targeting PGD2 alone is not sufficient to treat male pattern hair loss.^[13]DuBois, J., Bruce, S., Stewart, D., Kempers, S., Harutunian, C., Boodhoo, T., Weitzenfeld, A, Chang-Lin, J.E. (2021). Setipiprant for Androgenetic Alopecia in Males: Results from a Randomized, … Continue reading

What Do Your Genetic Results Mean?

Your Result	GPR44-1 Variant 1	GPR44-2 Variant 2
	Rs545659 TT	Rs545659 AA
What it means	May be at a lower risk of having elevated levels of PGD2 in the lungs/scalp.	May be at an increased risk of having higher levels of GPR44 in the lungs/scalp.
The Implication	You might not be a good candidate for PGD2 inhibitors as a treatment for hair loss	You might be a better candidate for PGD2 inhibitors as a treatment for hair loss
Your Result	GPR44-1 Variant 1	GPR44-2 Variant 2	GPR44-2 Variant 3
	Rs533116 AA	Rs533116 GG	Rs533116 GA
What it means	May be at a lower risk of having elevated levels of PGD2 In the lungs/scalp.	May be at moderate risk of having higher levels of GPR44 in the lungs/scalp.	May be at an increased risk of having higher levels of GPR44 in the lungs/scalp.
The Implication	You might not be a good candidate for PGD2 inhibitors as a treatment for hair loss	You might be an average candidate for PGD2 inhibitors as a treatment for hair loss	You might be a better candidate for PGD2 inhibitors as a treatment for hair loss

What Relevance Does GPR44 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.

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

Yes, initial studies have shown that PGD2 levels are increased in the scalps of balding men. Experiments in mice suggest that PGD2 may inhibit hair growth. (score = 1)

• Does the totality of evidence implicate GPR44 as a causal agent for hair loss? (1 point)

There is not enough consistency of evidence to support the relationship between prostaglandin activity and androgenetic alopecia, due to further results conflicting with initial results. (score = 0)

• Does the totality of evidence implicate GPR44 as a predictive factor for hair loss treatment responsiveness? (2 points)

Although earlier studies showed that PGD2 is elevated in balding scalps, targeting this has not shown to be effective at treating hair loss. (score = 0)

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

No score on number (3). (score = 0)

Total Score = 1

Final Thoughts

While early research has highlighted the potential involvement of the GPR44 gene in hair loss through its interaction with prostaglandin D2 (PGD2), the current evidence is not robust enough to make definitive treatment recommendations based solely on the GPR44 genotype. Therefore, more comprehensive and consistent research is needed to validate the role of GPR44 in hair loss and its potential as a predictive factor for treatment responsiveness.