First results from the Very Small Array -- I. Observational methods

The Very Small Array (VSA) is a synthesis telescope designed to image faint structures in the cosmic microwave background on degree and sub-degree angular scales. The VSA has key differences from other CMB interferometers with the result that different systematic errors are expected. We have tested the operation of the VSA with a variety of blank-field and calibrator observations and cross-checked its calibration scale against independent measurements. We find that systematic effects can be suppressed below the thermal noise level in long observations; the overall calibration accuracy of the flux density scale is 3.5 percent and is limited by the external absolute calibration scale.Comment: 9 pages, 10 figures, MNRAS in press (Minor revisions

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10<sup>−8</sup>, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10<sup>−7</sup>, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10<sup>−20</sup>, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10<sup>−22</sup>, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10<sup>−4</sup>), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific

First results from the Very Small Array -- III. The CMB power spectrum

We present the power spectrum of the fluctuations in the cosmic microwave background detected by the Very Small Array (VSA) in its first season of observations in its compact configuration. We find clear detections of first and second acoustic peaks at l~200 and l~550, plus detection of power on scales up to l=800. The VSA power spectrum is in very good agreement with the results of the Boomerang, Dasi and Maxima telescopes despite the differing potential systematic errors.Comment: 10 pages, 6 figure, MNRAS in press. (Minor revisions - accepted 17 December 2002

First results from the Very Small Array -- II. Observations of the CMB

We have observed the cosmic microwave background temperature fluctuations in eight fields covering three separated areas of sky with the Very Small Array at 34 GHz. A total area of 101 square degrees has been imaged, with sensitivity on angular scales 3.6 - 0.4 degrees (equivalent to angular multipoles l=150-900). We describe the field selection and observing strategy for these observations. In the full-resolution images (with synthesised beam of FWHM ~ 17 arcmin) the thermal noise is typically 45 microK and the CMB signal typically 55 microK. The noise levels in each field agree well with the expected thermal noise level of the telescope, and there is no evidence of any residual systematic features. The same CMB features are detected in separate, overlapping observations. Discrete radio sources have been detected using a separate 15 GHz survey and their effects removed using pointed follow-up observations at 34 GHz. We estimate that the residual confusion noise due to unsubtracted radio sources is less than 14 mJy/beam (15 microK in the full-resolution images), which added in quadrature to the thermal noise increases the noise level by 6 %. We estimate that the rms contribution to the images from diffuse Galactic emission is less than 6 microK. We also present images which are convolved to maximise the signal-to-noise of the CMB features and are co-added in overlapping areas, in which the signal-to-noise of some individual CMB features exceeds 8.Comment: 11 pages, 5 figures, accepted for publication in MNRAS. Replaces original version - more detailed abstract, corrected typo

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all nonredundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the metaanalysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPsThis work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Non-Gaussianity in the Very Small Array CMB maps with Smooth-Goodness-of-fit tests

(Abridged) We have used the Rayner & Best (1989) smooth tests of goodness-of-fit to study the Gaussianity of the Very Small Array (VSA) data. Out of the 41 published VSA individual pointings dedicated to cosmological observations, 37 are found to be consistent with Gaussianity, whereas four pointings show deviations from Gaussianity. In two of them, these deviations can be explained as residual systematic effects of a few visibility points which, when corrected, have a negligible impact on the angular power spectrum. The non-Gaussianity found in the other two (adjacent) pointings seems to be associated to a local deviation of the power spectrum of these fields with respect to the common power spectrum of the complete data set, at angular scales of the third acoustic peak (l = 700-900). No evidence of residual systematics is found in this case, and unsubstracted point sources are not a plausible explanation either. If those visibilities are removed, a cosmological analysis based on this new VSA power spectrum alone shows no differences in the parameter constraints with respect to our published results, except for the physical baryon density, which decreases by 10 percent. Finally, the method has been also used to analyse the VSA observations in the Corona Borealis supercluster region (Genova-Santos et al. 2005), which show a strong decrement which cannot be explained as primordial CMB. Our method finds a clear deviation (99.82%) with respect to Gaussianity in the second-order moment of the distribution, and which can not be explained as systematic effects. A detailed study shows that the non-Gaussianity is produced in scales of l~500, and that this deviation is intrinsic to the data (in the sense that can not be explained in terms of a Gaussian field with a different power spectrum).Comment: 14 pages, 7 figures. Accepted for publication in MNRA

The CMB power spectrum out to l=1400 measured by the VSA

We have observed the cosmic microwave background (CMB) in three regions of sky using the Very Small Array (VSA) in an extended configuration with antennas of beamwidth 2 degrees at 34 GHz. Combined with data from previous VSA observations using a more compact array with larger beamwidth, we measure the power spectrum of the primordial CMB anisotropies between angular multipoles l = 160 - 1400. Such measurements at high l are vital for breaking degeneracies in parameter estimation from the CMB power spectrum and other cosmological data. The power spectrum clearly resolves the first three acoustic peaks, shows the expected fall off in power at high l and starts to constrain the position and height of a fourth peak.Comment: 6 pages with 5 figures, MNRAS in press (minor corrections