A Genetic Risk Score Combining Ten Psoriasis Risk Loci Improves Disease Prediction

Psoriasis is a chronic, immune-mediated skin disease affecting 2–3% of Caucasians. Recent genetic association studies have identified multiple psoriasis risk loci; however, most of these loci contribute only modestly to disease risk. In this study, we investigated whether a genetic risk score (GRS) combining multiple loci could improve psoriasis prediction. Two approaches were used: a simple risk alleles count (cGRS) and a weighted (wGRS) approach. Ten psoriasis risk SNPs were genotyped in 2815 case-control samples and 858 family samples. We found that the total number of risk alleles in the cases was significantly higher than in controls, mean 13.16 (SD 1.7) versus 12.09 (SD 1.8), p = 4.577×10−40. The wGRS captured considerably more risk than any SNP considered alone, with a psoriasis OR for high-low wGRS quartiles of 10.55 (95% CI 7.63–14.57), p = 2.010×10−65. To compare the discriminatory ability of the GRS models, receiver operating characteristic curves were used to calculate the area under the curve (AUC). The AUC for wGRS was significantly greater than for cGRS (72.0% versus 66.5%, p = 2.13×10−8). Additionally, the AUC for HLA-C alone (rs10484554) was equivalent to the AUC for all nine other risk loci combined (66.2% versus 63.8%, p = 0.18), highlighting the dominance of HLA-C as a risk locus. Logistic regression revealed that the wGRS was significantly associated with two subphenotypes of psoriasis, age of onset (p = 4.91×10−6) and family history (p = 0.020). Using a liability threshold model, we estimated that the 10 risk loci account for only11.6% of the genetic variance in psoriasis. In summary, we found that a GRS combining 10 psoriasis risk loci captured significantly more risk than any individual SNP and was associated with early onset of disease and a positive family history. Notably, only a small fraction of psoriasis heritability is captured by the common risk variants identified to date

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Corrigendum: Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis (Nature Communications (2015) 6 (6046) DOI:10.1038/ncomms7046

Methotrexate in psoriasis and psoriatic arthritis

Methotrexate (MTX) is the most commonly prescribed first-line therapy in psoriatic arthritis (PsA) internationally and is also commonly used in the treatment of psoriasis. However, data supporting its use in PsA are limited and significant toxicities can occur. This article summarises a debate at the 2019 GRAPPA annual meeting that focused on the use of MTX in psoriasis and PsA. Four clinicians and one patient research partner presented clinical study data and the patient experience summarising the efficacy, tolerability and toxicity of MTX for both skin and musculoskeletal manifestations. A live survey of attending GRAPPA members collected data on current and planned future use of MTX across the world

The GRAPPA-OMERACT Working Group: 4 prioritized domains for completing the core outcome measurement set for psoriatic arthritis 2019 updates

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis (PsA) working group provided updates at the 2019 GRAPPA annual meeting on its work toward developing a Core Outcome Set for PsA. The working group prioritized 4 domains, including musculoskeletal disease activity (enthesitis and dactylitis), fatigue, physical function, and structural damage. In this report, the working group summarizes its progress in standardizing the Core Outcome Set for these 4 domains

What Have Genome-Wide Studies Told Us About Psoriatic Arthritis?

There is convincing evidence to suggest a strong genetic component to psoriatic arthritis (PsA), with studies reporting a 40-fold risk to first-degree relatives of patients with disease. However, compared with rheumatoid arthritis, our understanding of the genetic etiology of PsA is less well-developed. Only three modestly sized genome-wide association studies of PsA have been undertaken to date, but they have identified the HLA-C region, IL12B, TRAF3IP2, and FBXL19 genes as being associated with PsA susceptibility. Results of genome-wide association studies of psoriasis and rheumatoid arthritis have been used to identify candidate genes for subsequent testing in PsA and have led to the identification of additional susceptibility factors for PsA. Most show overlap with psoriasis, whereas the overlap with rheumatoid arthritis is less pronounced. However, two loci show strong evidence for association with PsA but not psoriasis: HLA-B27 and the IL-13 gene locus. © Springer Science+Business Media, LLC 2012