Summary
In this detailed presentation, Professor Jonathan Barker provides an overview of the evolving genetic understanding of psoriasis, tracing progress from early foundational epidemiological studies to state-of-the-art genomic discoveries and clinical applications. The talk begins by acknowledging the seminal work of Gunner Lomholt, whose 60-year-old epidemiological research in the Faroe Islands firmly established psoriasis as a heritable condition, setting the stage for genetic inquiry. The mapping of the human genome in 2000 marked a revolutionary step, enabling large-scale genetic analyses that revealed the complex polygenic nature of psoriasis.
Current genetic research has identified 109 genomic loci significantly associated with psoriasis, with the latest data adding 49 novel loci since 2017. These loci are primarily involved in immune pathways, specifically five key biological pathways critical in psoriasis pathophysiology: the skin barrier, type 1 interferon signaling, NF-kappa B signaling, antigen processing and presentation, and T cell deviation along the IL-23/IL-17 axis. This genetic evidence aligns closely with the mechanisms targeted by contemporary drug development, particularly biologics aimed at IL-23, IL-17, and TNF-alpha pathways, enhancing their likelihood of success.
Two recent clinical examples demonstrate how genetics translate into therapy: the development of a selective tyrosine kinase II inhibitor targeting a major psoriasis susceptibility gene and the successful targeting of the IL-36 pathway in generalized pustular psoriasis (GPP), leading to FDA approval of spezolimab for this severe subtype. Genetics also shed light on psoriasis comorbidities, notably the causal role of obesity in psoriasis onset established through Mendelian randomization analyses, emphasizing the importance of addressing obesity in clinical management.
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The Genetic Basis of Psoriasis
The core question regarding psoriasis is: What causes it? The crucial epidemiological study that definitively established an inheritable component to psoriasis was conducted by a Danish dermatologist, Gunner Lomholt, in the Faroe Islands. Interestingly, next year marks the 60th anniversary of his seminal work, and the IPC will be sponsoring a meeting in the Faroe Islands to celebrate his contributions and the advancements made since then. We now know there’s a significant heritable component to psoriasis; in fact, it’s likely the most important factor in its causation.
Another significant advancement, unrelated to psoriasis itself, was in genetic methodology, particularly the initial mapping of the human genome in draft form in the year 2000. This breakthrough made it possible to rapidly genotype large numbers of people, allowing us to answer questions about the genetic makeup of individuals with common, complex, polygenic diseases.
Utilizing Genetic Information in Psoriasis
Reflecting on how we can use this information in a complex disease like psoriasis, genetics can help us:
- Identify the causal biology: In the vast immunological complexity of psoriasis, genetics helps us determine what’s primary and what’s secondary.
- Identify susceptible individuals: We can pinpoint who is predisposed to developing the disease.
- Understand disease natural history: This includes predicting who might develop psoriatic arthritis, who will have severe disease, and so on.
- Unravel comorbidity associations: Genetics helps clarify the relationship between psoriasis and its various comorbidities.
- Stratify the disease: Is psoriasis one disease or many different ones, not just in terms of phenotype but also in response to treatment? Genetics can assist with all these questions.
Current Understanding of Psoriasis Genetics
To summarize our understanding of psoriasis genetics in 2022, as presented at the SID, we now know of 109 loci throughout the human genome that significantly associate with psoriasis. Forty-nine of these were new in 2022 compared to 2017. This translates to 143 independent signals outside of the MHC region. As you can see from the illustration on the right, which shows the top 30 genetic hits, nearly all are involved in innate and adaptive immune responses. Indeed, figures like JT Elder and Alex Tsoi have suggested that the psoriasis genome is an immunome.
However, the genetic findings are not random. The genetics point to five specific pathways important in psoriasis pathophysiology:
- Skin Barrier
- Type 1 Interferon Signaling
- NF-κB Signaling
- Antigen Processing and Presentation
- T-cell Deviation down the IL-23/IL-17 axis
It’s no surprise, therefore, that genetics strongly supports current drug development in the disease, particularly with respect to IL-23, IL-17, and to some extent, TNF-alpha. This genetic support for drug development is crucial because many studies now demonstrate that if you have a genetic association for your drug target alongside biological support, the chances of that drug reaching the market from Phase 1 are doubled. Consequently, many large companies have adjusted their drug pipelines to incorporate genetic considerations.
Genetic Insights in Clinical Practice
Let me give you two interesting examples that apply to psoriasis:
- Tyrosine Kinase 2 (TYK2) / Janus Kinase (JAK): Interestingly, TYK2 is the third biggest genetic hit in psoriasis after the MHC (HLA-C*06:02) and the IL-23 pathway. There is now a selective TYK2 inhibitor in advanced clinical trials showing efficacy very similar to what we’re seeing with some of the biologics, but as an oral drug. I find this incredibly exciting.
- Generalized Pustular Psoriasis (GPP): A story you might be more familiar with is the clear evidence that generalized pustular psoriasis has a different genetic basis from plaque forms of the disease. Specifically, there are mutations within the interleukin-36 receptor antagonist (IL-36RN). Even in individuals with GPP who don’t have these specific genetic mutations, it’s clear that the IL-36 pathway is disturbed. At least two biologics are being trialed in GPP targeting the IL-36 pathway. A single injection can clear the disease in a significant number of individuals, and they remain clear for some time. Excitingly, not just for the companies but for us clinical dermatologists who will be treating these patients, one of these drugs, spesolimab, has now been FDA-approved and, as of two days ago, approved in Japan as well. We eagerly await quick approval from the EMA and the separate UK MHRA. This truly exemplifies the journey “from gene to clinic in 11 years.”
Psoriasis and Comorbidities: The Role of Genetics
Genetics can also help us with other important clinical questions, such as the issue of psoriasis and comorbidities. A strong association between two morbidities doesn’t necessarily describe cause and effect; the question is, what is the direction of causation? One of the major associations with psoriasis is obesity.
You can use a genetic methodology called Mendelian randomization to investigate this. (Please don’t ask me to explain how Mendelian randomization works; it’s quite challenging, but there’s a fantastic YouTube video by the Professor of Genetic Epidemiology in Bristol, whose information is in the bottom right of the slide, which explains the methodology.) This methodology has been applied to the question of the association between obesity and psoriasis, and it’s completely clear that obesity causes psoriasis, and psoriasis does not cause obesity. Indeed, other studies—and I believe you’ll hear more about this in the Renauterring lecture tomorrow—show that obesity is the second most important known determinant of disease after genetic heritability. So, genes and obesity are major factors in psoriasis causation.
HLA-C*06:02 and Future Directions
In the few minutes I have left, I’d like to address the “elephant in the room” when we talk about genetics: HLA-C*06:02. We’ve known about this for many years; it’s by far the main genetic risk factor for psoriasis. If you have a copy of HLA-C*06:02, your odds of developing psoriasis can be as much as 12 times higher. It’s a big deal and has a greater genetic effect in terms of susceptibility than all other loci combined. However, it’s neither necessary nor sufficient to cause the disease. The reason people might not think about it too much at the moment is because it’s not a therapeutic target, so other biological pathways receive more attention.
Nevertheless, HLA-C*06:02 could potentially help us in the clinic going forward. There’s now good evidence that responses to IL-23 inhibition compared with TNF inhibition can be predicted, at least to some extent, by genotyping individuals for HLA-C*06:02. Indeed, in studies we were involved in using the British registry, if you compare adalimumab (TNF inhibition) with ustekinumab (IL-12/23 inhibition), an HLA-C*06:02-negative patient has a three times higher chance of achieving PASI 90 with adalimumab than with ustekinumab. So, this raises the question: can we use this in some biomarker algorithm to assess outcomes?
It’s also important to note that while HLA-C*06:02 is the main genetic susceptibility factor for psoriasis, it’s clearly not the main susceptibility factor for psoriatic arthritis. There’s no evidence of an association between C*06:02 and psoriatic arthritis. So, when people talk about “psoriatic disease,” bear in mind that the genetics of the two conditions are completely different; personally, I think “psoriatic disease” can be a bit of a misnomer.
Finally, to conclude my talk, one of the big things geneticists are now trying to do in common complex diseases is to use all the genetic associations to see if, when combined, they can provide various predictions about the disease’s natural history and susceptibility, and even influence treatment. This methodology is called a polygenic risk score. Polygenic risk scores have already shown benefits in studying susceptibility to cardiovascular disease and inflammatory bowel disease (which in many ways is a hop, skip, and a jump away from psoriasis). We know there’s data showing that polygenic risk scores in psoriasis can associate with age of onset, with or without the inclusion of HLA-C*06:02. More work needs to be done to refine this and apply it to other important clinical questions such as risk prediction, supporting diagnosis, guiding treatment decision-making, and identifying prognosis.