Variants in RUNX3 contribute to susceptibility to psoriatic arthritis, exhibiting further common ground with ankylosing spondylitis.

OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. METHODS: Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. RESULTS: Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 × 10(-8) by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.15-1.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 × 10(-2) ; OR 1.13 [95% CI 1.00-1.28]), indicating a role in the skin manifestations of psoriasis. CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cell-mediated diseases.

Disease Activity and Increased Risk of Cardiovascular Death among Patients with Psoriatic Arthritis.

OBJECTIVE: Recent studies indicate increased cardiovascular (CV) morbidity and mortality in patients with psoriatic arthritis (PsA), but results are inconsistent. This prompted our investigation of the mortality rate, cause of death, and incidence of acute CV events in patients from northern Sweden with PsA. METHODS: Patients with established PsA (464) were included. To calculate standardized mortality ratio (SMR) and standardized incidence ratio (SIR) for CV events, data were extracted from the National Causes of Death Register and the National Inpatient Care Register in Sweden, and compared with the general population. The study period was 1995-2011. To study the effect of inflammatory activity, a composite disease activity index (DAI) was used. RESULTS: The SMR (95% CI) for overall mortality and diseases of the circulatory system (International Classification of Diseases, 10th edition; I00-I99) was 1.22 (0.89-1.63) and 1.64 (1.02-2.52), respectively. In regression analysis, DAI was significantly associated with death (OR 1.99, 95% CI 1.41-2.80) when adjusted for age and sex (p < 0.001), and remained significant after stratifying patients into the 2 major causes of death: diseases of the circulatory system and malignant neoplasms. Peripheral and axial disease was associated with death (OR 4.02, 95% CI 1.84-8.84, p < 0.001) compared with peripheral disease only. The SIR (95% CI) for a CV event (myocardial infarction or stroke) was 0.597 (0.40-0.86); this association was only significant in men. CONCLUSION: Patients with PsA had a small but significant increase in SMR for death due to diseases of the circulatory system compared with the general population. Among patients, death was associated with DAI, as well as axial involvement in combination with peripheral disease, indicating more aggressive disease phenotypes.

Intron-mediated expression of the human neuropeptide Y Y1 receptor.

The Neuropeptide Y (NPY) family of neuropeptides exert their function through a family of heptahelical G-protein coupled receptors regulating essential physiological processes. A 97 base pair intron (intron IV) intervenes the coding sequence of the human NPY Y1 receptor (hY1) gene and was found frequently retained at variable levels in poly A+ mRNA isolated from multiple human tissues. When included in hY1 expression vectors, either in its natural position or 5' of the hY1 cDNA, intron IV mediated a significant increase of both hY1 mRNA and corresponding functional receptor protein in transfected mammalian cells, implying an in vivo regulatory function of the endogenous intron. Our results further indicate that the nuclear history of the hY1 pre-mRNA influence ectopic hY1 production through post-transcriptional mechanisms and argues against intron IV acting as a transcriptional enhancer as well as the possibility that a putative hY1 related 5TM accessory protein encoded by the non-spliced hY1 mRNA would facilitate hY1 production on a post-translational level.

Outcome of exercise electrocardiography in familial amyloidotic polyneuropathy patients, Portuguese type, under evaluation for liver transplantation.

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited systemic amyloidosis caused by mutated transthyretin (TTR). Liver transplantation is currently the only available treatment that halts the progress of the disease. Cardiovascular complications are common in FAP, and cardiac arrhythmias are typical complications in FAP Val30Met. For patients with late onset FAP, as the Swedish patients, coronary heart disease has been found in several patients, and a QS complex is not an uncommon finding in FAP-patients ECG raising the suspicion of coronary heart disease. The aim of this study was to evaluate exercise ECG in FAP patients before transplantation with regard to mortality and morbidity. Thirty-eight FAP patients who underwent examination by exercise ECG, as part of the evaluation for liver transplantation were included in the study. Of these, 30 patients were transplanted, and the surviving patients were followed for at least 2 years. Exercise ECG was performed on bicycles with standard 12 leads. Non-parametric statistical analyses were used in all calculations. Six patients died 0-5.5 years after transplantation. They were older than the survivors (p < 0.01), but their duration of disease did not deviate from that of survivors (p = 0.8). They were also less able to increase their heart rates during exercise than the survivors (p < 0.05). For all transplanted patients, a significant relationship was found between patients' increase of heart rate, blood pressure and maximal workload, and the duration of disease and also for the PND-score, signifying that the outcome of exercise ECG predominantly was related to the patients autonomic and motor function, and not to their heart function.

Association between the PTPN22 +1858 C/T polymorphism and psoriatic arthritis.

INTRODUCTION: The purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls. METHODS: A total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls. RESULTS: Carriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (χ2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005). CONCLUSIONS: In this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹7). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²°, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.