JAKs may predict psoriasis risk

Variants in Janus kinase (JAK)1 rs310241 and JAK3 rs3008 may increase susceptibility to psoriasis, according to a recent study.¹

JAKs have attracted significant interest in dermatology, says corresponding author Aya M. AlOrbani, MD, lecturer in dermatology at Cairo University Hospital, Cairo, Egypt. “But the focus has mainly been on JAKs as a therapeutic target.”

Clinical studies have shown that JAK inhibition improves diseases such as psoriasis, vitiligo and alopecia areata. “But not many studies have assessed how genetic changes or polymorphisms in the JAK genes could affect psoriasis,” she says.

To further explore the genetic architecture of psoriasis, investigators in the Kasr Al-Ainy Psoriasis Unit (KAPU), Cairo University Hospital, compared blood samples from 150 Egyptian patients with psoriasis and samples from 120 age- and sex-matched healthy volunteers.

Using the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique, investigators screened samples for nucleotide polymorphisms in JAK1 rs310241 and JAK3 rs3008. They chose these variants partly because the JAK1 rs310241 polymorphism has been associated with other immune-mediated illnesses such as Crohn’s disease and Behçet’s disease.

Investigators noted that the GG (homozygous) genotypes of JAK1 rs310241 and JAK3 rs3008 conferred approximately 7.7-fold and 3.3-fold increased risk for psoriasis, respectively.¹ P values were 0.000 and 0.003, respectively; 95% confidence intervals (CIs) were 2.8-21.5 and 1.5-6.9, respectively.

“Polymorphisms are like genetic markers," says AlOrbani. "The discovery that these polymorphisms exist may help us predict which patients are at high risk of developing psoriasis in the future.” Further down the road, she adds, this knowledge may help physicians tailor treatments to patients’ individual clinical situations. “The next step might be to study the effect of these polymorphisms on response to treatments.”

JAKs are basically secondary messengers that mediate biological signaling, she says. “Inflammatory cytokines bind to receptors, and JAK molecules are recruited.” JAK activation triggers a cascade of further signaling events involving phosphorylation of selected receptor chain tyrosines, binding of signal transcription and activator of transcription (STAT) proteins and phosphorylation of these STATs.

For both JAK polymorphisms studied, frequency of the G allele was significantly higher in patients with psoriasis versus controls and significantly increased the risk of psoriasis. “Patients who had the G allele in the JAK1 gene had twice the risk of developing psoriasis, and those with the JAK3 allele had a 1.7-fold increased risk,” says AlOrbani.

Regarding gender, researchers noted no relationship with the JAK1 variant. However, the JAK3 rs3008 mutant variant occurred more commonly in male patients. “This was quite interesting, because the distinction in gender with genetic polymorphisms hasn’t been studied extensively before.” One paper noted gender differences in expression of certain major histocompatibility complex (MHC) genes in psoriatic arthritis. Another study showed that the association between rs887466 and psoriasis may differ in men and women, and that the influence of rs1062470 on disease severity is also gender-dependent.

The only other study that has assessed JAK polymorphisms in patients with psoriasis was conducted in Korea, says AlOrbani. “Unlike us, these researchers did not find a difference in polymorphisms in psoriasis patients versus healthy controls in the JAK1 and JAK3 genes.”² How- ever, the Korean study detected both protective and susceptibility loci in JAK2.

“Ethnicities differ," she says. "The JAK polymorphisms might make a difference in studies repeated in different populations.”

Disclosures: Aya M. AlOrbani, MD, reports no relevant financial interests.

References:

1. Sayed KS, El-Komy MHM, Shehata H, et al. JAK1 rs310241 and JAK3 rs3008 genotypes may increase susceptibility to psoriasis: a case control study [published online before print September 2, 2020]. Skin Pharmacol Physiol. 2020;33:207-212.

2. Kim SY, Hur MS, Choi BG, et al. A preliminary study of new single polymorphisms in the T helper type 17 pathway for psoriasis in the Korean population. Clin Exp Immunol. 2017;187:251-258.