CRABP2: Can This Gene Predict Regrowth From Retinoids?

Article Summary

The CRABP2 gene, which plays a role in retinoic acid metabolism, has been linked to hair health. Retinoic acid, a derivative of vitamin A, is known to influence hair growth, and some studies suggest CRABP2 may also be involved. However, the evidence connecting CRABP2 variants to hair loss and treatment effectiveness is still emerging. While certain CRABP2 variants may impact retinoic acid levels in the body, the data is not yet strong enough to make definitive treatment recommendations based on these genetic differences. Further research is needed to clarify how CRABP2 might affect hair loss treatments.

Full Article

CRABP2 is one of two genes found within the CRABP family alongside CRABP1. CRABP2 is a key regulator of retinoic acid, a vitamin A derivative, transporting it around the cell and helping its metabolism. Both CRABP2 and retinoic acid have been suggested in the literature to have roles in the maintenance of hair health. This is particularly evident for retinoic acid, which has been suggested to regulate hair health in a dose-dependent manner. A few studies have also investigated genetic variation in CRABP2, suggesting that some variants may be linked to hair loss. This article will explore how relevant CRABP2 is to hair loss treatment effectiveness and how to interpret your genetic results to make the correct treatment choice.

What is CRABP2?

The cellular retinoic acid binding protein (CRABP) gene family is very small, consisting of just two members – cellular retinoic acid binding protein 1 (CRABP1) and cellular retinoic acid binding protein 2 (CRABP2). CRABP1 is expressed throughout the body, whereas CRABP2 expression is restricted to certain tissues, such as the skin. Both CRABP genes are high-affinity binding proteins of retinoic acid, which is a derivative of vitamin A. Although research has yet to fully elucidate their exact functions, it is understood that CRABP1 and CRABP2 both play a role in the transport and metabolism of retinoic acid.^[1]Wei, L. N. (2016). Cellular retinoic acid binding proteins: Genomic and non-genomic functions and their regulation. The Biochemistry of Retinoid Signaling II: The Physiology of Vitamin A-Uptake, … Continue reading

In sheep, it has been shown that CRABP2 is highly expressed in dermal papilla cells (DPCs), which play a key role in the growth and development of hair follicles. Moreover, they showed that CRABP2 regulates the proliferation of DPCs and that the overexpression of CRABP2 promoted increased DPC proliferation. Although this research was conducted in cells taken from sheep, it does suggest that CRABP2 may play a role in the maintenance of hair.^[2]He, M., Lv, X., Cao, X., Yuan, Z., Quan, K., Getachew, T., Mwacharo, J.M., Haile, A., Li, Y., Wang, S. and Sun, W. (2023). CRABP2 Promotes the Proliferation of Dermal Papilla Cells via the … Continue reading

These results suggest that increased expression of CRABP2 could be beneficial for hair loss. However, the association between CRABP2 and hair maintenance is slightly more complex than it first appears. In tissue taken from a mouse model of alopecia areata (AA), the expression of CRABP2 (both the gene and protein) was increased compared to control mice. Similarly, CRABP2 protein expression was higher in tissue taken from humans with AA. Ultimately, the findings of the paper suggest that increased retinoic acid synthesis may contribute to the pathogenesis of AA.^[3]Duncan, F.J., Silva, K.A., Johnson, C.J., King, B.L., Szatkiewicz, J.P., Kamdar, S.P., Ong, D.E., Napoli, J.L., Wang, J., King Jr, L.E. and Whiting, D.A. (2013). Endogenous retinoids in the … Continue reading

Conversely, it has also been shown that a reduction in retinoic acid signaling may be associated with hair loss. Mice lacking a key retinoic acid receptor exhibited impaired anagen initiation within their hair follicles (the growing phase), which was likely a contributory factor in the progressive alopecia that these mice developed.^[4]Li, M., Chiba, H., Warot, X., Messaddeq, N., Gérard, C., Chambon, P., & Metzger, D. (2001). RXRα ablation in skin keratinocytes results in alopecia and epidermal alterations. Development, … Continue reading

Further evidence has been added to support these findings, suggesting that retinoic acid signaling may contribute to AGA similarly to androgens. It is widely accepted that androgens drive the pathogenesis of AGA and lead to the miniaturization of hair follicles. However, a study conducted in 30 male patients with AGA revealed that genes involved in retinoic acid signaling are upregulated, suggesting that retinoic acid signaling may promote follicle miniaturization.^[5]Ho, B.S.Y., Vaz, C., Ramasamy, S., Chew, E.G.Y., Mohamed, J.S., Jaffar, H., Hillmer, A., Tanavde, V., Bigliardi-Qi, M. and Bigliardi, P.L. (2019). Progressive expression of PPARGC1α is associated … Continue reading

Despite appearing contradictory, it is possible that all of these studies are accurate and that both a deficiency and excess of retinoic acid can contribute to hair loss. Indeed, the literature suggests that retinoic acid may regulate hair health in a dose-dependent manner, whereby the optimal and ‘healthy’ level of retinoic acid sits somewhere between low and high.^[6]VanBuren, C. A., & Everts, H. B. (2022). Vitamin A in skin and hair: an update. Nutrients, 14(14), 2952. Available at: https://doi.org/10.3390/nu14142952

This leads to a somewhat paradoxical situation, as retinoic acid is necessary for hair growth, but it can also cause hair loss when present in high concentrations. Thus, the therapeutic use of retinoic acid in treating hair loss is a challenging prospect.^[7]Sadgrove, N. J., & Simmonds, M. S. (2021). Topical and nutricosmetic products for healthy hair and dermal antiaging using “dual‐acting”(2 for 1) plant‐based peptides, hormones, and … Continue reading

That said, several studies have shown that the application of tretinoin, a type of retinoic acid, has beneficial effects in treating hair loss. One study was conducted on 56 patients with AGA, who were treated with either a placebo, 0.5% minoxidil, 0.025% tretinoin, or a combination of minoxidil and tretinoin.^[8]Bazzano, G. S., Terezakis, N., & Galen, W. (1986). Topical tretinoin for hair growth promotion. Journal of the American Academy of Dermatology, 15(4), 880-893. Available at: … Continue reading Tretinoin treatment alone was shown to stimulate some hair regrowth in more than half of the patients who received the treatment. Further positive results were observed with combination treatment.

This was also shown in a study conducted on 31 male patients with AGA. The study showed that once-daily application of tretinoin and minoxidil, in combination, was as effective at treating hair loss as twice-daily minoxidil on its own (Figure 1).^[10]Shin, H. S., Won, C. H., Lee, S. H., Kwon, O. S., Kim, K. H., & Eun, H. C. (2007). Efficacy of 5% minoxidil versus combined 5% minoxidil and 0.01% tretinoin for male pattern hair loss: a … Continue reading

What is the Evidence for Targeting CRABP2 for Hair Loss?

Collectively, the evidence does suggest that CRABP2 and retinoic acid are key factors in hair loss. Owing to this, it is feasible that genetic variation in CRABP2 could influence the efficacy of hair loss treatments.

In a study conducted on newborn babies, it was found that the rs12724719 polymorphism was linked to retinoic acid levels. Specifically, those with the AA genotype had a greater concentration of retinoic acid in the blood of their umbilical cord than those with the GA or GG genotypes. It is believed that such an increase in retinoic acid may have been caused by reduced CRABP2 expression, impairing its ability to transport retinoic acid into the nucleus of the cell.^[12]Manolescu, D. C., El-Kares, R., Lakhal-Chaieb, L., Montpetit, A., Bhat, P. V., & Goodyer, P. (2010). Newborn serum retinoic acid level is associated with variants of genes in the retinol … Continue reading

Although this study was conducted in newborn umbilical cord blood, and so is probably not representative of how the genetic variant affects adults or hair, the results are still interesting. If adults with the AA genotype also exhibit increased levels of retinoic acid, then therapeutic supplementation with retinoic acid to treat hair loss may be less effective in those individuals. Moreover, given that retinoic acid levels are already high, increasing levels further may increase the risk of those individuals experiencing retinoic acid-induced hair loss, as discussed earlier.

A separate study was conducted on over 25,000 patients with AGA, a mix of both males and females. Interestingly, their analysis revealed an association between the rs12724719 polymorphism and AGA. Unfortunately, the authors did not specifically state which of the genotypes were linked to AGA and which were not. However, this is yet another indication that genetic variation in CRABP2 and the rs12724719 polymorphism may influence hair health and treatments.^[13]Francès, M. P., Vila-Vecilla, L., Russo, V., Caetano Polonini, H., & de Souza, G. T. (2024). Utilising SNP Association Analysis as a Prospective Approach for Personalising Androgenetic Alopecia … Continue reading

What Do Your Genetic Results Mean?

Your Result	CRABP2 (rs12724719)
	Variant 1 – GG genotype	Variant 2 – GA genotype	Variant 3 – AA genotype
What it Means	Associated with normal levels of retinoic acid in the blood	Associated with normal levels of retinoic acid in the blood	Associated with elevated levels of retinoic acid in the blood
The Implication	May benefit from retinoic acid supplementation	May benefit from retinoic acid supplementation	May not benefit from retinoic acid treatment (i.e, vitamin A supplementation or retinoid topicals)

What Relevance Does CRABP2 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. CRABP2 has been found to be upregulated in patients with alopecia areata (score = 1)

• Does the totality of evidence implicate CRABP2 as a causal agent for hair loss? (1 point)

No. There is very little published literature that indicates CRABP2 causes hair loss. (score = 0)

• Does the totality of evidence implicate CRABP2 as a predictive factor for hair loss treatment responsiveness? (2 points)

No. There is no published literature that shows that CRABP2 polymorphisms affect hair loss treatments (score = 0)

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

Since CRABP2 fails question #3, it cannot be awarded points for question #4 (score = 0)

Total Score = 1

Final Thoughts

While there is evidence that genetic variation in CRABP2 is associated with AGA and may affect retinoic acid levels, the evidence is not yet sufficient to make definitive treatment recommendations based solely on genotype. Importantly, no studies have yet explored how genetic variation in CRABP2 affects treatment with retinoic acid or any other therapeutic. Additional studies that seek to answer this question must be conducted to confirm the true predictive value of testing CRABP2 variants to personalize hair treatments.