Can our genes predict sensitivity to retinol?

Although it is known for enhancing 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 characterised by a genetic imbalance of factors related to the stratum corneum, or its degradation into phototoxic by-products 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, known as nucleotide polymorphisms (PNS), which can 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 which they deemed most important, a selection based on the intensity of the effect.

The researchers employed a statistical model to establish a polygenic risk score, with the aim of stratifying individuals into "low", "medium", or "high" risk categories of sensitivity to retinoids, based on the SNPs they had identified. The symptoms they evaluated were found to correlate with the risk score.

What are the limitations of the study?

Whilst this study is relevant, certain aspects appear to be subjective. The candidate genes analysed 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 demonstrated a "strong effect" unlike the IL4R gene.

In a broader sense, this approach to understanding how we react to substances could form a new concept aimed at limiting skin reactions through more detailed and personalised formulations.