The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA

Objective: To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. Methods: We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. Results: GWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10−11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10−8, and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10−7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. Conclusions: Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels

Benchmarking the power of amateur observatories for TTV exoplanets detection

This document is the Accepted Manuscript version of the following article: Roman v. Baluev, et al, ‘Benchmarking the power of amateur observatories for TTV exoplanets detection’, Monthly Notices of the Royal Astronomical Society, Vol. 450(3): 3101-3113, first published online 9 May 2015. The version of record is available at doi: https://doi.org/10.1093/mnras/stv788 © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.We perform an analysis of ~80000 photometric measurements for the following 10 stars hosting transiting planets: WASP-2, -4, -5, -52, Kelt-1, CoRoT-2, XO-2, TrES-1, HD 189733, GJ 436. Our analysis includes mainly transit lightcurves from the Exoplanet Transit Database, public photometry from the literature, and some proprietary photometry privately supplied by other authors. Half of these lightcurves were obtained by amateurs. From this photometry we derive 306 transit timing measurements, as well as improved planetary transit parameters. Additionally, for 6 of these 10 stars we present a set of radial velocity measurements obtained from the spectra stored in the HARPS, HARPS-N, and SOPHIE archives using the HARPS-TERRA pipeline. Our analysis of these TTV and RV data did not reveal significant hints of additional orbiting bodies in almost all of the cases. In the WASP-4 case, we found hints of marginally significant TTV signals having amplitude 10-20 sec, although their parameters are model-dependent and uncertain, while radial velocities did not reveal statistically significant Doppler signals.Peer reviewe

Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases

Background Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants. Methods Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases. Results In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS. Conclusions Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers

Benchmarking the power of amateur observatories for TTV exoplanets detection

We perform an analysis of ~80 000 photometric measurements for the following 10 stars hosting transiting planets:WASP-2, -4, -5, -52, Kelt-1, CoRoT-2, XO-2, TrES-1, HD 189733, GJ 436. Our analysis includes mainly transit light curves from the Exoplanet Transit Database, public photometry from the literature, and some proprietary photometry privately supplied by other authors. Half of these light curves were obtained by amateurs. From this photometry we derive 306 transit timing measurements, as well as improved planetary transit parameters. Additionally, for 6 of these 10 stars we present a set of radial velocity measurements obtained from the spectra stored in the HARPS, HARPS-N and SOPHIE archives using the HARPS- TERRA pipeline. Our analysis of these transit timing and radial velocity data did not reveal significant hints of additional orbiting bodies in almost all of the cases. In the WASP-4 case, we found hints of marginally significant TTV signals having amplitude 10-20 s, although their parameters are model dependent and uncertain, while radial velocities did not reveal statistically significant Doppler signals.Facultad de Ciencias Astronómicas y GeofísicasInstituto de Astrofísica de La Plat

Immunoblot analysis of the seroreactivity to recombinant Borrelia burgdorferi sensu lato antigens, including VlsE, in the long-term course of treated patients with Erythema migrans

Objective: We evaluated whether immunoblotting is capable of substantiating the posttreatment clinical assessment of patients with erythema migrans ( EM), the hallmark of early Lyme borreliosis. Methods: In 50 patients, seroreactivity to different antigens of Borrelia burgdorferi sensu lato was analyzed by a recombinant immunoblot test (IB) in consecutive serum samples from a minimum follow-up period of 1 year. Antigens in the IgG test were decorin- binding protein A, internal fragment of p41 (p41i), outer surface protein C (OspC), p39, variable major protein-like sequence expressed (VlsE), p58 and p100; those in the IgM test were p41i, OspC and p39. Immune responses were correlated with clinical and treatment-related parameters. Results: Positive IB results were found in 50% before, in 57% directly after therapy and in 44% by the end of the follow-up for the IgG class, and in 36, 43 and 12% for the IgM class. In acute and convalescence phase sera, VlsE was most immunogenic on IgG testing 60 and 70%), and p41i (46 and 57%) and OspC (40 and 57%) for the IgM class. By the end of the follow-up, only the anti-p41i lgM response was significantly decreased to 24%. Conclusions: No correlation was found between IB results and treatment-related parameters. Thus, immunoblotting does not add to the clinical assessment of EM patients after treatment. Copyright (c) 2008 S. Karger AG, Basel

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Severe course of Lyme neuroborreliosis in an HIV-1 positive patient; case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Lyme Neuroborreliosis (LNB) in a human immunodeficiency virus (HIV) positive patient is a rare co-infection and has only been reported four times in literature. No case of an HIV patient with a meningoencephalitis due to LNB in combination with HIV has been described to date.</p> <p>Case presentation</p> <p>A 51 year old woman previously diagnosed with HIV presented with an atypical and severe LNB. Diagnosis was made evident by several microbiological techniques. Biochemical and microbiological recovery during treatment was rapid, however after treatment the patient suffered from severe and persistent sequelae.</p> <p>Conclusions</p> <p>A clinician should consider LNB when being confronted with an HIV patient with focal encephalitis, without any history of Lyme disease or tick bites, in an endemic area. Rapid diagnosis and treatment is necessary in order to minimize severe sequelae.</p

PTPN22.6, a Dominant Negative Isoform of PTPN22 and Potential Biomarker of Rheumatoid Arthritis

PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis