Genetics of psoriasis: Clinical practice pearls

In this issue of Healio Psoriatic Disease, we focus on the genetics of psoriasis, a daunting topic for sure! Psoriasis is one of the most heritable of complex genetic trait diseases. Over 65 susceptibility loci have been identified, but 75% of psoriasis heritability is not explained by currently known variants, suggesting there is much more to learn.

So, what does a clinician need to know about the genetics of psoriasis? Plenty! I will summarize some key findings that I find very helpful in my clinical practice.

First, as I am sure you will agree, a common question that patients with psoriasis have is whether their child will develop psoriasis. I always explain that 40% of people with psoriasis have a family history of the disease. This statistic is often helpful for patients with no family history, as they are reassured to know that the majority of those affected do not have a family history given that psoriasis occurs due to a complex interplay of multiple genes and environmental exposures. In the accompanying table, I summarize genetic risk of developing psoriasis for counseling patients. It is important to understand that inheritance of severity of psoriasis is poorly understood, and just because a patient has severe psoriasis does not mean that their offspring will develop a severe case.

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A second common question is whether genetic testing can be useful in the management of psoriasis. In general, the answer is no. HLA-C*06:02 negative psoriasis patients with psoriatic arthritis are six times more likely to respond to adalimumab compared with ustekinumab, but in the United States we do not currently use genetic testing to inform treatment decisions. This genetic finding is useful, however, as it provides a biologic basis for trying tumor necrosis factor alpha inhibitors in psoriasis patients who fail interleukin (IL)-23 pathway drugs. I will occasionally check an HLA-B27 in my psoriasis patients with atypical joint symptoms as this locus is associated with a higher risk of psoriatic arthritis in patients with psoriasis. For my patients with generalized pustular psoriasis, I will sometimes request a genetics consultation if their disease is atypical or difficult to manage, as this condition can be caused by mutations in IL36RN, AP1S3 and CARD14.

Finally, an important topic is how genetics relate to comorbidity. Recent approaches — called Mendelian randomization studies — demonstrate a causal relationship between the genetics of obesity and the development of psoriasis as well as a bidirectional relationship between the genetics of psoriasis and the genetics of cardiovascular disease. In other words, the genetics of psoriasis can cause cardiovascular disease and the genetics of cardiovascular disease can cause psoriasis. These findings emphasize the importance of identifying and managing traditional cardiovascular risk factors in people with psoriasis as well as recognizing that our patients may require additional support to promote weight given these genetic underpinnings.

• References:
• Dand N, et al. Acta Derm Venereol. 2020;doi:10.2340/00015555-3384.
• Rahman P, et al. Ann Rheum Dis. 2005;doi:10.1136/ard.2004.030775.
• Budu-Aggrey A, et al. PLoS Med. 2019;doi:10.1371/journal.pmed.1002739.
• Gao N, et al. Front Immunol. 2022;doi:10.3389/fimmu.2022.918224.
• Patrick MT, et al. Nat Commun. 2022;doi:10.1038/s41467-022-34323-4.
• Barbieri JS, et al. JAMA Dermatol. 2022;doi:10.1001/jamadermatol.2021.4467.