MedWire News: Researchers have found new psoriasis susceptibility loci that could aid diagnosis of the condition and the development of new treatments.
In the first of five studies published advance online by Nature Genetics, a team of researchers led by Richard Trembath (King's College London, UK) carried out a genome-wide association study involving 2622 individuals with psoriasis and 5667 individuals without the skin condition.
They identified eight new genomic loci that showed a strong association with psoriasis, seven of which harboured genes with recognized immune functions.
In replication studies involving more than 9000 individuals, the odds ratio estimates for the eight loci ranged from 1.12 to 1.40.
Moreover, the team reports an interaction between one of the loci, ERAP1, which regulates the MHC class I peptide endoplasmic reticulum aminopeptidase 1, and the established HLA-C risk allele, with variation at the ERAP1 locus only associated with psoriasis in individuals carrying the HLA-C risk allele.
"Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis," concludes the team.
Meanwhile, two other genome-wide association studies in the journal involving German participants identified a psoriasis susceptibility locus at TRAF3IP2, which encodes a protein involved in interleukin (IL)-17 signaling.
"We thus speculate that a dysregulation of TRAF3IP2 might have a major impact on IL-17 signaling and, hence, on the activation of nuclear factor (NF)-κB-pathways, leading to the upregulation of pro-inflammatory factors," Andre Franke, from Christian-Albrechts-University in Kiel, Germany, and colleagues write.
Variation in the TRAF3IP2 gene was found to be associated with both psoriasis and psoriatic arthritis, suggesting shared susceptibility.
André Reis, from the University of Erlangen-Nuremberg in Germany, and colleagues found that the coding variant p.Asp10Asn at rs33980500 was the single nucleotide polymorphism most significantly associated with psoriatic arthritis.
Binding of this TRAF3IP2 variant to TRAF6 was reduced in functional assays, note Reis et al. This suggests that "p.ASP10Asn may modulate downstream signals of different crucial immunoreceptors through altered TRAF interactions," they say.
"This may ultimately lead to a shift in balance between B- and T-cell responses and innate immunity into an arthritogenic disequilibrium," the team suggests, providing a possible new and shared pathway for psoriatic arthritis and psoriasis vulgaris.
For the fourth study, researchers led by James Elder, from the University of Michigan Medical School in Ann Arbor, USA, carried out a meta-analysis of two recent psoriasis genome-wide association studies involving 1831 affected individuals and 2546 controls, as well as a replication group of over 8000 individuals.
They identified three new susceptibility loci, including one at NOS2 (rs4795067), one at FBXL19 (rs10782001), and one near PSMA6-NFKBIA (rs12586317).
NOS2 encodes inducible nitric oxide synthase, which is expressed by a subset of CD11c-positive, CD1c-negative, tumor necrosis factor-α-producing inflammatory dendritic cells, which are markedly expanded in psoriatic lesions, while FBXL19, an F-box family member inhibits NF-κB activity by lysine demethylation.
NFKBIA and PSMA6 are also both attractive candidate genes for psoriasis susceptibility, as NFKBIA encodes IκB-α, an inhibitor of NF-κB signaling, and PSMA6 encodes a proteosomal subunit involved in MHC class I antigen processing.
All three loci were also associated with psoriatic arthritis and purely cutaneous psoriasis.
The final study involved Chinese patients and identified six new psoriasis susceptibility loci - ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, and ZNF816A.
The researchers note that two of these loci, ZNF816A and GJB2, also showed evidence of association with psoriasis in a replication group of European patients, and they also replicated an association between the TNIP1-ANXA6 locus, which had been identified in the European population, in their Chinese population.
This finding suggests genetic heterogeneity of psoriasis within Chinese and European populations, say Xue-Jun Zhang, from Anhui Medical University in Hefei, China, and colleagues.
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