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Did you know DNA affects your risk of psoriasis?

Psoriasis, immunity and genes - Heritable DNA changes that increase your risk of psoriasis

Picture medieval knights in armour. Iron plates, shaped, tempered and hardened for maximum protection. They were virtually invincible, at least until an enemy managed to penetrate one of the weak points between the plates.

Our skin is the equivalent of a knight’s armour. It’s a barrier that protects us from ‘germs’ – things that might pose a threat to our health. Luckily, if a cut or scrape breaches this shield, we have evolved a second line of defence – our immune system. This system can usually quickly and efficiently eliminate invaders and initiate the healing process. But it it a different story if you happen to be one of approximately 7.4 million Americans who suffer from psoriasis. These people know firsthand that the immune system can sometimes malfunction, and lose its ability to distinguish a foreign invader from a normal, healthy cell. This is known as autoimmunity, and psoriasis is an autoimmune disease that affects the skin. Not surprisingly, it is genetic variations in several immune system genes that are the strongest predictors for the risk of this frustrating skin problem.

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Psoriasis is characterized by dry, red skin lesions with silvery scales. It is one of the most baffling and persistent conditions to affect the skin. Even after several decades of research, the actual cause of psoriasis remains elusive. What is known is that the skin cells of affected individuals multiply much faster than normal and this is coupled to an overactive immune response.

Central to this immune response are dendritic cells, which are immune cells that are embedded in the layers of our skin. Normally, as these cells consume foreign invaders, they present parts of the pathogen (called ‘antigens’) on their surface using a large protein complex called the human leukocyte antigen (HLA) complex. The dendritic cells carry these antigens to the lymph nodes where they trigger T cells to attack the invader.

T cells, a type of white blood cell, are supposed to target foreign invaders, and are not supposed to attack our own tissues. However, two genetic variants (rs1265181 and rs12191877) in the HLA-C gene can disrupt the normal functioning of the T cells, increasing the risk that they will attack healthy skin cells and cause psoriasis. Inheriting the rs1265181 variant enhances the risk of psoriasis by 10-fold, and is associated with an earlier onset of disease, as well as much severe symptoms.

The second component of the immunity link to psoriasis involves molecules called cytokines. These messenger molecules are used by cells to communicate with one another. For example, dendritic cells use the IL-12 cytokine to activate T cells. And T cells have the IL23R protein on their surface to relay this activation signal. The IL12B gene encodes one component of IL-12. The rs2082412 variant of IL12B enhances IL-12 activity, increasing the risk of psoriasis by 44% due to T cell over-activation. Similarly, a variant of the IL23R gene (rs2201841) makes T cells more sensitive to the activation signal, enhancing the risk of psoriasis by 13%. IL-13 is another cytokine involved in T cell production. The rs20541 variant of the IL13 gene is likely responsible for the large number of T cells found in psoriatic lesions.

The role of cytokines in psoriasis doesn’t end there. Two cytokines that reduce inflammation, TNFAIP3 and its interacting protein TNIP, are also linked to this devastating skin disease. Mice that lack a functional TNFAIP3 gene develop faster growing keratinocytes, or skin cells, which mimic psoriasis. In people, the rs610604 variant of TNFAIP3 leads to more severe psoriasis symptoms, likely due to reduced TNFAIP3 protein function and poorer control of the inflammatory response.

TNIP functions downstream of TNFAIP3 to also reduce inflammation. Inheritance of the rs17728338 variant of TNIP elevates the risk of psoriasis by 59%. Interestingly, the impact of these genetic variants depends heavily on ethnicity, which explains the differences in the prevalence of psoriasis between different ethnic groups.

Like many of the other conditions that affect the skin, psoriasis can have a huge negative impact on the quality of life. Studies show that patients with psoriasis are more likely to have lower levels of employment and income. When you combine this with the cost associated with long-term therapy required to manage the symptoms, you can imagine the burden faced by someone with psoriasis. Although knowing your genetic susceptibility to psoriasis can’t help you to avoid this disease, there is hope that future studies will improve the management of this common skin health condition.

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