In clinic, acne is often framed as a straightforward sequence: puberty increases sebum, bacteria proliferate, inflammation follows. It’s a practical story, but it leaves gaps. Why do retinoids remain so consistently effective if the core problem is “just bacteria”? And why do sebaceous glands within comedonal areas sometimes look less robust rather than simply overactive?

A 2025 review, The genetics of acne, proposes that genetic evidence points to an earlier “starting point.” The author leans on findings from rare inherited syndromes and from genome-wide association studies (GWAS) — large-scale studies that scan the entire genome to identify variants statistically linked to disease risk. Across these lines of evidence, the recurring theme is not an inborn tendency toward stronger inflammation, but rather the biology of sebaceous-gland precursor (stem/progenitor) cells and how they behave at a critical junction within the follicle [1].

A useful way to think about this is the “wrong choice” metaphor. At the site where the sebaceous gland empties into the hair canal, a pool of precursor cells supports ongoing renewal. Under normal conditions, these cells differentiate along appropriate pathways: toward sebaceous-gland cells or toward the lining of the follicular canal. When that program is disrupted, cells can adopt the “wrong” identity. This concept is commonly described as the comedone switch hypothesis [2]. The end result is a comedone: not merely a plug of oil, but the visible consequence of altered differentiation and tissue organization. In genetic terms, the most consistent signals map to processes that govern how cells divide, decide their fate, adhere, and migrate — essentially, how the follicle maintains its architecture.

Why does this matter clinically? Because it offers a coherent explanation for variability. Two patients may share similar age, similar routines, and comparable oiliness, yet follow very different trajectories. Genetics appears to weigh heavily in disease expression and especially in severity; more severe forms are often the ones that cluster in families.

Rare inherited syndromes act like a magnifying glass for mechanism. The review highlights conditions in which severe acne begins around puberty and responds well to conventional therapy — an important clue that the downstream biology likely overlaps with common acne. In syndromes linked to altered signaling pathways (such as FGFR2 in Apert syndrome), the acne phenotype is clinically recognizable and treatable, reinforcing that these genetic “experiments of nature” may illuminate broadly relevant pathways. Other examples point toward the importance of movement and positioning: if the descendants of precursor cells fail to relocate appropriately, they may not receive the right local cues and can end up in an in-between state — consistent with the abnormal lining and structure seen in comedones.

The most practice-oriented part of the review is its synthesis of GWAS findings in severe acne. These studies do not imply that we are ready to treat acne based on a genetic panel. But they do identify biological “pressure points.” Across large datasets, risk loci have repeatedly implicated pathways involved in follicle development and cell-fate control, aligning with the idea that the follicle’s early structural program matters [3, 4]. Notably, variants that directly and consistently point to heightened inflammatory drive appear less prominent. This does not deny inflammation — acne is often clinically dominated by it — but it suggests that inflammation may frequently be secondary, a layer built on top of a follicular bottleneck that has already formed.

Lifestyle and environment enter the conversation through epigenetics: the ways diet, stress, and pollution can influence gene activity without changing DNA sequence. The review notes that evidence is still limited, but the direction is compelling. Epigenetic changes could help explain why flares recur in the same areas — perhaps local immune responses have been “trained,” making certain sites more reactive to subsequent triggers.

What should clinicians take from this model right now?

1. Comedogenesis is foundational. Controlling comedones is not a cosmetic extra; it is a core strategy. If the follicular program remains disrupted, inflammation can keep cycling back.
2. Retinoids fit the biology. Their role becomes easier to explain: they are not simply “drying agents,” but tools that help normalize keratinization and differentiation within the follicle.
3. Expectations can be set more accurately. Genetics offers a credible rationale for why the same regimen can produce different outcomes, and why patients with a strong family history may need longer-term, structured support.

Overall, acne genetics shifts the emphasis: the earliest decisive steps may occur before inflammation becomes clinically obvious, at the level of sebaceous-gland precursor cell behavior and follicular organization. Inflammation remains a crucial target for symptom relief, but durable control may depend on whether we can keep the “comedone switch” from flipping in the first place [1].

Practice checklist

• Explain to patients that a comedone can reflect a disrupted follicular “program,” not simply a “dirty pore.”
• Ask about family history of severe acne and scarring to inform risk framing and long-term planning.
• Prioritize sustained comedone control strategies, not only short-term anti-inflammatory measures.
• Discuss Cutibacterium acnes with nuance: it can contribute, but it is unlikely to be the sole driver.
• Use antibiotics conservatively and for clear indications, mindful of resistance and microbiome disruption.
• When prescribing retinoids, frame the mechanism as normalization of follicular differentiation/keratinization and counsel on safety per guidelines [5].
• For highly inflammatory phenotypes, clarify that inflammation may be layered on top of pre-existing comedonal change and may require parallel management.

Conclusion

Genetic evidence encourages a reframing of acne: the pivotal biology may unfold inside the follicle before inflammation dominates the picture. Inflammation is still the key target for rapid improvement, but longer-term success may depend on controlling the processes that generate comedones in the first place. This perspective also supports clearer, more empathetic patient communication about why acne behaves differently from person to person [1].

References

1. van Steensel M.A.M. The genetics of acne. Ann Hum Genet 2025; 89(5): 333–341. https://doi.org/10.1111/ahg.70014
2. Saurat J.-H. Strategic targets in acne: the comedone switch in question. Dermatology 2015; 231(2): 105–111.
3. Petridis C., Navarini A.A., Dand N., et al. Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne. Nat Commun 2018; 9(1): 5075.
4. Mitchell B.L., Saklatvala J.R., Dand N., et al. Genome-wide association meta-analysis identifies 29 new acne susceptibility loci. Nat Commun 2022; 13(1): 702.
5. Zaenglein A.L., Pathy A.L., Schlosser B.J., et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016; 74(5): 945–973.e33.