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Prédisposition génétique à la sensibilité aux rétinoïdes ?

Can our genes predict sensitivity to retinol?

Backed by a robust scientific foundation, retinol is perceived as one of the most potent active ingredients for mitigating the signs of skin aging. However, it presents a wide range of side effects, despite its regulated use in skincare formulas. Moreover, this retinol-induced irritation tends to occur repeatedly among individuals. Therefore, could genetic factors govern the irritation induced by the use of retinol?

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Retinol Sensitivity, a Matter of Genetics?

Although it is known to enhance the appearance of the skin, thetopical application of retinol can often cause irritation and some side effects. The skin may become dry, red, flaky, and tight for a few days. It has been suggested that various mechanisms are involved in retinol-induced irritation, including the release of pro-inflammatory cytokines (MCP-1 and IL-8), a disruption of the skin barrier characterized by a genetic imbalance of factors related to the stratum corneum, or its degradation into phototoxic byproducts due to its instability under the effects of UV and heat.

However, these observations were deemed insufficient to explain the onset of this skin irritation. A genetic approach was then considered to explain the mechanism governing skin irritation induced by retinol. Previously, several studies had already demonstrated that genes could be associated with the efficacy and side effects of drugs.

Thus, in a 2021 article, researchers undertook a genetic analysis on 173 individuals of Korean origin, where they studied the irritating property of retinol-based formulas. To do this, DNA sequencing was performed on these individuals through saliva sampling by DNA chips in order to obtain a quantitative profile of the gene expression of different individuals, compared to a so-called reference sequence.

The results of the analysis allowed us to identify 30 genetic variants belonging to 10 genes, known to play a role in retinoid metabolism (RARB and RXRB) and general skin sensitivity (EGFR, CD44, IL18, IL4R, BCL2, CD86, RXRB, MMP10, and COL6A2) as significantly contributing to skin irritation from retinol. We all have DNA sequence variations on the same gene, called nucleotide polymorphisms (PNS), which can then affect its expression and functioning.

The researchers then selected 14 candidate genes that had previously been highlighted as playing a role in retinoid metabolism and skin sensitivity and examined the SNPs. They then based their subsequent experiments and analyses on 3 of these genes that they deemed most important, a selection based on the intensity of the effect.

The researchers utilized a statistical model to create a polygenic risk score to stratify individuals into "low", "medium", or "high" risk of sensitivity to retinoids based on the SNPs they had identified. The symptoms they evaluated were correlated with the risk score.

What are the limitations of the study?

While this study is relevant, certain aspects appear to be subjective. The candidate genes analyzed were based on a transcriptomic study of a reconstituted skin model. Why not adopt a bioinformatics approach using the data generated during their genetic analysis and their experiments to select their candidate genes? Later, they based their experiments on 3 of these genes which they deemed important, a selection based on the intensity of the effect. Why exclude the RARB gene, the retinoid receptor, when it showed a "strong effect" unlike the IL4R gene.

In a broader sense, this approach to understanding how we react to substances can form a new concept to limit skin reactions with more detailed and personalized formulations.

Sources

  • KANG K.-S. & al. The mechanism of retinol-induced irritation and its application to anti-irritant development. Toxicology Letters (2003).

  • GENG S. & al. All‐trans retinoic acid alters the expression of the tight junction proteins Claudin‐1 and ‐4 and epidermal barrier function‐associated genes in the epidermis. International Journal of Molecular Medecin (2019).

  • KANG N.-G. & al. Anti-irritant strategy against retinol based on the genetic analysis of Korean population/ A genetically guided top–down approach. Pharmaceutics (2021).

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