Summary To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

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

Accumulating evidence indicates that body weight, alcohol and smoking are associated with psoriasis. However, these factors have scarcely been investigated in relation to onset and disease activity at onset of psoriasis. A population-based case-control study was performed including 373 cases with onset of first-time plaque psoriasis within 12 months and matched healthy controls. Psoriasis activity was measured using the Psoriasis Area and Severity Index (PASI). Analyses were performed using conditional logistic regression. In multivariable analyses for each unit increment in body mass index, there was statistically significant 9% increased risk for psoriasis onset and 7% higher risk for increased PASI. Obesity (body mass index > or =30) compared with normal body weight was associated with a two-fold increased risk for psoriasis onset. Smoking was associated with a 70% increased risk for onset, but was not related to PASI. A positive association with alcohol drinking was observed among men, but not among women. No associations were observed for weight gain and use of smokeless tobacco. Our results indicate that excessive body weight and smoking are risk factors for onset of psoriasis and that higher body mass index increases the PASI of plaque psoriasis at onset.

In this population of healthy well-nourished men, greater dietary intakes of protein, zinc, red meat, and fish and seafood were associated with higher IGF-I concentrations.

Psoriasis is a multifactorial disease with a strong genetic background. It associates strongly to HLA-Cw*0602. HLA-C interacts with killer immunoglobulin-like receptors (KIR) on natural killer (NK) and some natural killer-T (NKT) cells. KIR's function is triggered by specific binding to HLA ligands, which depends on the amino acid 80 of the MHC class I alpha-chain. This permits classifying all HLA-C alleles into two functional groups: asparagine (N80) or lysine (K80) carrying alleles. Psoriasis patients recruited at disease onset were categorized as guttate, vulgaris without arthropathy and vulgaris with arthropathy plus skin lesions. Patients and carefully matched controls were genotyped for position 80 of HLA-C and for KIR. Based on possible HLA/KIR combinations, individuals were classified according to expected NK/NKT cell responses: balanced (B), excess inhibition (EI), excess activation (EA), or undetermined (U). HLA-Cw6 and position 80 genotyping associated strongly to disease, whereas KIR2DS1 associated weakly. Individuals of the U and EI classes were more common among guttate psoriasis patients, which related to HLA-Cw*0602 status. These results suggest that different levels for NK/NKT cell activation thresholds, not only reduction, contribute to immune deregulation in psoriasis. In the guttate phenotype, balanced HLA-C/KIR interactions might be altered by the presence of concomitant streptococcal infections.

Circulating IGF binding protein (IGFBP)-1 levels have been associated with insulin sensitivity, the metabolic syndrome, several cardiovascular risk factors, and possibly with cancer. We examined long-term nutrient intake and metabolic and anthropometric factors in relation to IGFBP-1 levels in 226 men, 42-76 yr old, who completed 14 24-h diet recall interviews. Spearman rank correlation coefficients were calculated. Serum IGFBP-1 levels were significantly inversely correlated with insulin, homeostasis model assessment-insulin resistance, and IGF-I and positively correlated with age. Furthermore, IGFBP-1 was inversely correlated with anthropometric measures reflecting obesity, somewhat stronger in middle-aged (<65 yr) than in older men. Serum IGFBP-1 increased with higher energy and carbohydrate intake but only in the younger age group. The difference in mean IGFBP-1 levels comparing men in the top quartile of carbohydrate intake with those in the bottom quartile was 45% in men of age 42-54 yr (P = 0.01). Insulin, body mass index, and carbohydrate intake together explained 39% of the variability in IGFBP-1 levels in men 42-54 yr of age, 27% in men 55-64 yr, and 6% in men 65 or more years old. Our data suggest that metabolic, anthropometric, and nutritional factors are important determinants of IGFBP-1 levels in healthy men.

BackgroundThe influence of streptococcal infections in the pathogenesis of psoriasis is not yet understood. In vitro data suggest that streptococcal factors influence T-cell function in psoriasis in a HLA-dependent manner, but studies designed to measure the HLA-C/Streptococci interaction are lacking. In the present study, we hypothesized that there is a statistical interaction between the result of streptococcal throat cultures and the presence of the HLA-Cw*0602 allele in psoriasis patients.MethodsWe performed a case control study using the "Stockholm Psoriasis Cohort" consisting of patients consecutively recruited within 12 months of disease onset (Plaque psoriasis = 439, Guttate psoriasis = 143), matched to healthy controls (n = 454) randomly chosen from the Swedish Population Registry. All individuals underwent physical examination including throat swabs and DNA isolation for HLA-Cw*0602 genotyping.The prevalence of positive streptococcal throat swabs and HLA-Cw*0602 was compared between patients and controls and expressed as odds ratios with 95% confidence intervals. Associations were evaluated separately for guttate and plaque psoriasis by Fisher's exact test.ResultsRegardless of disease phenotype, the prevalence of positive streptococcal throat swabs in HLA-Cw*0602 positive patients was twice the prevalence among HLA-Cw*0602 negative patients (OR = 5.8 C.I. = 3.57–9.67, p < 0.001), while no difference was observed among Cw*0602 positive versus negative controls.The corresponding odds ratios for the guttate and plaque psoriasis phenotypes were 3.5 (CI = 1.5–8.7, p = 0.01) and 2.3 (CI = 1.0–5.1, p = 0.02) respectively.ConclusionThese findings suggest that among HLA-Cw*0602 positive psoriasis patients, streptococci may contribute to the onset or exacerbation of the inflammatory process independent of the disease phenotype. However, studies on the functional interaction between HLA-C and streptococcal factors are needed.

IMPORTANCE Psoriasis is a heterogeneous disease. Improved understanding of prognosis and long-term outcomes in new-onset psoriasis may improve care.OBJECTIVE To describe the clinical course of psoriasis and identify possible indicators of long-term outcomes. DESIGN, SETTING, AND PARTICIPANTSThe Stockholm Psoriasis Cohort was a noninterventional inception cohort study enrolling patients between 2001 and 2005. The present study was conducted from January 15, 2019, to February 5, 2021. At enrollment and 10 years, patients were examined by dermatologists and rheumatologists. Data from examinations were complemented by questionnaires, medical records, and registers. A total of 721 patients with recent-onset psoriasis (<12 months duration), 15 years or older were recruited using advertising and referrals from a broad range of health care settings.MAIN OUTCOMES AND MEASURES Disease severity and psoriatic arthritis (PsA). Recursive partitioning and regression models were implemented to identify probable indicators of long-term outcomes.RESULTS A total of 721 patients (median [interquartile range] age, 39 [27-55] years; 405 [56%] women), including 542 (75%) with plaque-onset and 174 (24%) with guttate-onset psoriasis, were enrolled. The median follow-up was 9.6 years (interquartile range, 8.8-10.4 years). The cumulative incidence of severe psoriasis at 12 years from enrollment was 21%. Among 509 patients examined clinically after 10 years, 77 of 389 patients (20%) with plaque onset and 56 of 116 (48%) with guttate onset had minimal disease activity without treatment, and 120 of 509 (24%) had PsA. Recursive partitioning identified strata with distinct risks for severe skin disease and PsA: the cumulative incidence of severe disease in patients with plaque phenotype, above-median disease activity, and scalp lesions was 52% (95% CI, 41%-64%), compared with 11% (95% CI, 8%-14%) in patients with below-median disease activity at inclusion; and 48 of 82 patients (59%) with peripheral enthesitis had PsA after 10 years compared with 37 of 304 patients (12%) without initial joint pain (P < .001). Smoking (hazard ratio, 1.70; 95% CI, 1.10-2.63) and activating genes in the interleukin-23 (IL-23) pathway (odds ratio, 1.55; 95% CI, 1.14-2.11) were also significantly associated with a severe disease course. Systemic therapy at or before enrollment was associated with a lower risk for severe disease at 10 years compared with later initiation of systemic therapy (odds ratio, 0.24; 95% CI, 0.06-0.90). CONCLUSIONS AND RELEVANCEThe findings of this cohort study suggest that combinations of clinical characteristics at onset and activating genes in the IL-23 pathway are significantly associated with the clinical course of psoriasis, whereas joint pain and peripheral enthesitis may indicate the probability of PsA. Patients within those categories merit specialist referral and closer follow-up. The possibility of modifying the disease course with early systemic intervention should be tested.