Rotraut Mössner

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility 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.

Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaque-type psoriasis

Background  Because psoriatic arthritis (PsA) usually develops years after the first manifestation of skin symptoms, in many cases the initial diagnosis of PsA depends on the dermatologist.

Genetic Variants of the IL-23R Pathway: Association with Psoriatic Arthritis and Psoriasis Vulgaris, but No Specific Risk Factor for Arthritis

Variants in two genes of the IL-23 receptor (R) pathway have recently been shown to be associated with psoriasis vulgaris (PV). We were interested whether the risk conferred by these variants differs between psoriatic skin and joint disease. Four variants of the IL12B and IL23R genes were analyzed in 1,114 PV patients, 748 patients with psoriatic arthritis (PA) and 937 healthy controls before and after stratification for the major psoriasis risk allele at psoriasis susceptibility locus 1 (PSORS1). For both PA and PV, we detected the strongest association with two IL12B single-nucleotide polymorphisms and the corresponding haplotype as reflected by minimal P-values of 10(-7) and highest odds ratios of 1.50 (1.28-1.75) for rs6887695 in PA patients and 1.50 (1.27-1.76) for rs3212227 in the PV cohort, respectively. For IL23R, only rs11209026 showed an association. The results remained significant after correction for multiple testing. No difference was observed after stratification for the PSORS1 risk allele. While confirming recent reports on variants of the IL-23R pathway as susceptibility factors for PV, our study is the first to extend analysis of both genes to PA. However, our results indicate that these variants are not specific risk factors for arthritis, but relevant for susceptibility to psoriasis in general.

Replication of LCE3C–LCE3B CNV as a Risk Factor for Psoriasis and Analysis of Interaction with Other Genetic Risk Factors

Recently, a deletion of two late cornified envelope (LCE) genes within the epidermal differentiation complex on chromosome 1 was shown to be overrepresented in 1,426 psoriasis vulgaris (PsV) patients of European ancestry. In this study, we report a confirmation of this finding in 1,354 PsV patients and 937 control individuals of German origin. We found an allele frequency of the deletion of 70.9% in PsV patients and of 64.9% in control individuals (chi(2)=17.44, P=2.97 x 10(-5), odds ratio (95% confidence interval)=1.31 (1.15-1.48)). The overall copy number of the two LCE genes had no influence on the age of onset, but we observed a dosage effect at the genotype level. There was no evidence of statistically significant interaction with copy number of the beta-defensin cluster on 8p23.1 or with an IL-23R pathway variant in a combined data set of German and Dutch individuals, whereas evidence for interaction with the PSORS1 risk allele in German individuals was marginal and did not remain significant after correction for multiple testing. Our study confirms the recently published finding that the deletion of the two LCE genes is a susceptibility factor for PsV with dosage effect, while, because of power limitation, no final conclusion regarding interaction with other PsV risk factors can be made at this stage.

Genetic factors in contact allergy--review and future goals.

The genetics of contact allergy are still only partly understood, despite decades of research; this might be a consequence of inadequately defined phenotypes used in the past. A recommendation is to study an extreme phenotype, namely, polysensitization (sensitization to three or more unrelated allergens). Another approach to unravel the genetics of contact allergy is the study of candidate genes. In this review, we summarize studies on the associations between genetic variation (e.g. single‐nucleotide polymorphisms) in certain candidate genes and contact allergy. Polymorphisms and mutations affecting the following proteins were studied: (i) filaggrin; (ii) N‐acetyltransferase (NAT) 1 and 2; (iii) glutathione‐S‐transferase (GST) M and T; (iv) manganese superoxide dismutase; (v) angiotensin‐converting enzyme (ACE); (vi) tumour necrosis factor (TNF); and (vii) interleukin‐16 (IL‐16). The polymorphisms of NAT1, NAT2, GSTM, GSTT, ACE, TNF and IL‐16 were shown to be associated with an increased risk of contact allergy. In one of our studies, the increased risk conferred by the TNF and IL‐16 polymorphisms was confined to polysensitized individuals. Other relevant candidate genes may be identified by studying diseases related to contact allergy in terms of clinical symptoms, a more general pathology (inflammation), and possibly an overlapping genetic background, such as irritant contact dermatitis.

Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations.

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Tumor necrosis factor antagonists in the therapy of psoriasis

The identification of new pathophysiological mechanisms in chronic inflammatory diseases and the development of techniques that allow production of antibodies and fusion proteins that antagonize target molecules with high specificity has not only revolutionized the treatment of rheumatoid arthritis and chronic inflammatory bowel disease, but it also has revolutionized the treatment of psoriasis in recent years. Two different classes of so-called biological therapies (biologics) have become available to treat psoriasis: tumor necrosis factor (TNF) antagonists and T-cell modulators. TNF antagonists that have been studied with psoriasis include the antibodies infliximab and adalimumab and the fusion protein etanercept. These treatments differ in their capacity to reduce the skin symptoms of psoriasis and other important characteristics of the drug profile. This article summarizes the important aspects of efficacy, safety, and practicability of TNF antagonists in the treatment of psoriasis. This article may be helpful for the daily routine when selecting the right therapy for a patient and managing the TNF antagonist during maintenance therapy.

Mutations in IL36RN in patients with generalized pustular psoriasis.

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Cytokine gene polymorphisms in atopic dermatitis

Summary Background Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T‐helper 2‐type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms.

Association analysis of IL19, IL20 and IL24 genes in palmoplantar pustulosis.

Background  Interleukin (IL) 19, IL‐20 and IL‐24 belong to the IL‐10 cytokine family and have been identified to play a role in the regulation of epidermal functions and in inflammation. The genes encoding IL‐19, IL‐20 and IL‐24 are located within a gene cluster on chromosome 1q31–32 and carry frequent genetic variations.