GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Multippel erythema migrans, borrelialymfocytom og nevroborreliose hos eit barn.

BACKGROUND: Lyme disease after a tick bite often presents as erythema migrans, yet less frequent variants of this disease, such as Borrelia lymphocytoma, multiple erythema migrans and neuroborreliosis, are also seen occasionally. CASE PRESENTATION: We report a case of a tick-bitten child who first presented with an indistinct macular erythema around the left eye and a more distinct macular erythema on and around the left ear. The next day, she developed a facial palsy. INTERPRETATION: The case was interpreted as facial multiple erythema migrans and Borrelia lymphocytoma on the ear, followed by neuroborreliosis. The diagnosis of lymphocytoma was made from clinical findings and PCR of skin biopsy. She recovered quickly after intravenous ceftriaxone and is now healthy.

Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study.

BACKGROUND: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. METHODS AND FINDINGS: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied. CONCLUSIONS: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.

Obesity, Waist Circumference, Weight Change, and Risk of Incident Psoriasis: Prospective Data from the HUNT Study.

Although psoriasis has been associated with obesity, there are few prospective studies with objective measures. We prospectively examined the effect of body mass index, waist circumference, waist-hip ratio, and 10-year weight change on the risk of developing psoriasis among 33,734 people in the population-based Nord-Trøndelag Health Study (i.e., HUNT), Norway. During follow-up, 369 incident psoriasis cases occurred. Relative risk (RR) of psoriasis was estimated by Cox regression. One standard deviation higher body mass index, waist circumference, and waist-hip ratio gave RRs of 1.22 (95% confidence interval [CI] = 1.11-1.34), 1.26 (95% CI = 1.15-1.39), and 1.18 (95% CI = 1.07-1.31), respectively. Compared with normal weight participants, obese people had an RR of 1.87 (95% CI = 1.38-2.52), whereas comparing the fourth with the first quartile of waist circumference gave an RR of 1.95 (95% CI = 1.46-2.61). One standard deviation higher weight change gave an RR of 1.20 (95% CI = 1.07-1.35), and people who increased their body weight by 10 kg or more had an RR of 1.72 (95% CI = 1.15-2.58) compared with being weight stable. In conclusion, obesity and high abdominal fat mass doubles the risk of psoriasis, and long-term weight gain substantially increases psoriasis risk. Preventing weight gain and promoting maintenance of a normal body weight could reduce incidence of psoriasis.