Accutane Genetic Risk Factors

Genetic Risk Factors for Post Accutane Syndrome

Whilst there’s an increasing awareness of some of the risks posed by isotretinoin treatment, from changes to vision, hair loss and even neurological changes – many dermatologists will still readily write prescriptions. Many who’ve subsequently experienced side effects often claim they weren’t adequately warned of the possible consequences, especially where more enduring symptoms are concerned.

Claims of lasting changes to cognitive function appear justified especially in the light of more recent research. The most striking study to evidence profound neurological changes was a 2005 brain imaging study which found that patients treated with Isotretinoin experienced a dramatic 21% reduction in brain activity in the orbitofrontal cortex. [1] This is a vital region of the frontal lobe dedicated to higher cognitive faculties, and so disturbances in this area should be cause for concern.

However, recent advances in the field of genetics and the ubiquitous use of home DNA testing kits means that patients can perhaps gain a better insight into their own personal risk of developing side effects from medications like Accutane. Medication response can be radically altered based simple “letter” changes in the DNA code. These simple swaps can feasibly mean the difference between developing debilitating side effects or only experiencing the desired therapeutic effects.

Fig. 1 Rendering of a Single Nucleotide Polymorphism. [2]

These individual variations in the genetic code are referred to as Single Nucleotide Polymorphism (SNPs). At a particular position in the DNA sequence, one person might have an “A” while another has a “G” (or C or T). Whilst most SNPs have no direct effect on health or development, but some lie within or near genes and can influence how those genes function (for example, by altering an amino acid in a protein or affecting how strongly a gene is expressed).

Genetic Risk Factors for Accutane

Of all the possible side effects of Accutane, the one with greatest cause of concern is the sudden onset of depression. The latest research on the science of depression has indicated that the most mechanism is to do with ‘neurogenesis’ (the growth of new neurons). There’s already strong evidence to suggest that elevated retinoic acid signalling, as in during Isotretinoin treatment, can significantly hamper the development of new neurons – and even directly trigger programmed cell death (‘apoptosis’). [2][3] This is because the primary function of retinoic acid is in regulating the cell cycle, and triggering differentiation of progenitor cells.

A 2024 meta-analysis sought to establish the possible genetic risk factors of developing depression during Isotretinoin treatment. Fifteen studies involving 8,000 isotretinoin users and 10,000 non-users were included; all were deemed moderate to high quality based on Cochrane and Newcastle-Ottawa assessments. Follow-up periods ranged from 6 months to 5 years. After pooling the data, it was found that isotretinoin users collectively had 30% higher odds of developing depression (pooled OR 1.3, 95% CI 1.1-1.5).

Depression Risk Genes

In the meta-analysis two genes emerged as candidates in influencing isotretinoin-induced mood changes: RAR-alpha (Retinoic Acid Receptor Alpha) and LEP (Leptin Gene). Isotretinoin binds to retinoic acid receptors (including RAR-alpha) in the brain to exert neurological effects – so this finding stands to reason.

Certain single-nucleotide polymorphisms (SNPs) in the RARA gene alter the receptor’s sensitivity or expression levels. In people carrying those variants, isotretinoin may have caused exaggerated changes in neurotransmitter pathways (such as 5-HT1A) as well as dysregulation of neural progenitor cells (the precursor cells needed to develop new neurons).

This conclusion is supported by other evidence that the overexpression of Retinoic Acid Receptor-alpha results in retinoic acid more strongly triggering cell death (apoptosis) in skin cell cultures. [4] Given how potently isotretinoin is already able to cause early cell cycle arrest (G0/G1), individuals with higher RAR-alpha expression likely experience stronger neurological effects.

The other risk gene, more surprisingly, was Leptin. Leptin is produced primarily by fat cells, also modulates brain circuits involved in mood and stress response. LEP polymorphisms can influence leptin levels or receptor interactions in the hypothalamus. Hypothalamic cells are one of the cell types known to vulnerable to cell death when exposed to high concentrations of retinoic acid. [5]

Metabolic Risk Genes

The link to leptin highlights the potentially very significant role of metabolic health in the development of depression during Isotretinoin treatment. In fact, other studies have highlighted the association between polymorphisms for genes controlling metabolic health and the severity of isotretinoin adverse effects. In a study of 230 acne patients treated with Isotretinoin it was found that the treatment gave rise to significant increases in total cholesterol, triglycerides and liver enzymes – with two SNPs moderately contributing to this metabolic change (rs1501299 and rs2241766). [6]

One of the primary mechanisms through which Accutane is believed to work is by suppressing the activity of IGF-1. Despite its name, Growth Hormone isn’t primarily responsible for growth. Instead, GH acts more like an initiator for the real driver of growth and development: Insulin-like Growth Factor-1 (IGF-1). When GH is released from the pituitary gland, it travels through the bloodstream to the liver, where it stimulates IGF-1 production. IGF-1 then moves on to peripheral tissues to promote cell division and tissue growth. [7]

Studies have found that isotretinoin (Accutane) significantly reduces both IGF-1 and its binding proteins (IGFBPs) after three months of treatment. [8] Nearly all circulating IGF-1 is bound to one of six IGFBPs, which transport it through the bloodstream to peripheral tissues (such as bone and muscle) and protect it from rapid degradation. The most abundant of these is IGFBP-3, and this isoform is specifically suppressed by Accutane. Interestingly, while IGF-1 levels drop, growth hormone appears to be unchanged. In a separate study of 105 patients treated with Accutane for three months, both IGF-1 and IGFBP-3 levels decreased, with the greatest reductions occurring at the highest dose (0.2-0.5 mg/kg/day). [9] At that dose, mean IGF-1 fell from 415.8 ± 93.3 to 337.2 ± 100.7.

Intriguingly, genotyping acne patients treated with Isotretinoin have found that polymorphisms for Leptin also appear to contribute to degree of IGF-1 suppression. [10] The patients that carry the Leptin polymorphism that resulted in the smallest changes in liver enzymes also experienced a greater reduction in serum IGF-1 levels. Unsurprisingly, these patients had the greatest reduction in acne following the treatment.

Conclusion

In conclusion, individual genetic polymorphisms can profoundly influence both Accutane’s effectiveness and its risk of side effects. Despite substantial variability in these polymorphisms among patients, genetic testing before initiating therapy remains relatively uncommon. Two genes in particular-leptin and RAR-alpha-appear critical for predicting a patient’s outcome. Leptin polymorphisms not only help determine side-effect risk but also influence how effectively the medication clears acne.

If you are interested in how your genes may have impacted your treatment with Isotretinoin and have access to your genome through a DNA provider like 23andMe, MyHeritage or Ancestry then consider purchasing the Custom Genetic Report. Within minutes of uploading your raw file you will receive a comprehensive report on your risk gene variants and how they may have impacted your treatment.