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  • Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis.

    3 July 2018

    OBJECTIVE: To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). METHODS: We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: A comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10(-8)). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10(-6)). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. CONCLUSION: These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

  • Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

    3 July 2018

    Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

  • ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations.

    3 July 2018

    We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher's exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes ("VRNQE," "MKDRQ," "MRDRE," and "MKDRE") in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination ("*001/*005") previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10-24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

  • The Inspired Sinewave Technique: A Comparison Study With Body Plethysmography in Healthy Volunteers.

    3 July 2018

    The inspired sinewave technique is a noninvasive method to measure airway dead space, functional residual capacity, pulmonary blood flow, and lung inhomogeneity simultaneously. The purpose of this paper was to assess the repeatability and accuracy of the current device prototype in measuring functional residual capacity, and also participant comfort when using such a device. To assess within-session repeatability, six sinewave measurements were taken over two-hour period in 17 healthy volunteers. To assess day-to-day repeatability, measurements were taken over 16 days in 3 volunteers. To assess accuracy, sinewave measurements were compared to body plethysmography in 44 healthy volunteers. Finally, 18 volunteers who experienced the inspired sinewave device, body plethysmography and spirometry were asked to rate the comfort of each technique on a scale of 1-10. The repeatability coefficients for dead space, functional residual capacity, and blood flow were 48.7 ml, 0.48L, and 2.4L/min respectively. Bland-Altman analyses showed a mean BIAS(SD) of -0.68(0.42)L for functional residual capacity when compared with body plethysmography. 14 out of 18 volunteers rated the inspired sinewave device as their preferred technique. The repeatability and accuracy of functional residual capacity measurements were found to be as good as other techniques in the literature. The high level of comfort and the non-requirement of patient effort meant that, if further refined, the inspired sinewave technique could be an attractive solution for difficult patient groups such as very young children, elderly, and ventilated patients.

  • The Neuromuscular Junction and Wide Heterogeneity of Congenital Myasthenic Syndromes.

    13 August 2018

    Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. This review provides an overview on CMS and highlights recent advances in the field, including novel CMS causative genes and improved therapeutic strategies. CMS due to mutations in SLC5A7 and SLC18A3, impairing the synthesis and recycling of acetylcholine, have recently been described. In addition, a novel group of CMS due to mutations in SNAP25B, SYT2, VAMP1, and UNC13A1 encoding molecules implicated in synaptic vesicles exocytosis has been characterised. The increasing number of presynaptic CMS exhibiting CNS manifestations along with neuromuscular weakness demonstrate that the myasthenia can be only a small part of a much more extensive disease phenotype. Moreover, the spectrum of glycosylation abnormalities has been increased with the report that GMPPB mutations can cause CMS, thus bridging myasthenic disorders with dystroglycanopathies. Finally, the discovery of COL13A1 mutations and laminin α5 deficiency has helped to draw attention to the role of extracellular matrix proteins for the formation and maintenance of muscle endplates. The benefit of β2-adrenergic agonists alone or combined with pyridostigmine or 3,4-Dyaminopiridine is increasingly being reported for different subtypes of CMS including AChR-deficiency and glycosylation abnormalities, thus expanding the therapeutic repertoire available.

  • IN-SYNC. VII. Evidence for a Decreasing Spectroscopic Binary Fraction (from 1 to 100 Myr) within the IN-SYNC Sample

    13 August 2018

    © 2017. The American Astronomical Society. All rights reserved. We study the occurrence of spectroscopic binaries in young star-forming regions using the INfrared Spectroscopy of Young Nebulous Clusters (IN-SYNC) survey, carried out in SDSS-III with the APOGEE spectrograph. Multi-epoch observations of thousands of low-mass stars in Orion A, NGC 2264, NGC 1333, IC 348, and the Pleiades have been carried out, yielding H-band spectra with a nominal resolution of R = 22,500 for sources with H < 12 mag. Radial velocity precisions of ∼0.3 were achieved, which we use to identify radial velocity variations indicative of undetected companions. We use Monte Carlo simulations to assess the types of spectroscopic binaries to which we are sensitive, finding sensitivity to binaries with orbital periods ≲ 103.5days, for stars with 2500 K ≤ Teff≤ 6000 K and v sin i <100 km s-1. Using Bayesian inference, we find evidence for a decline in the spectroscopic binary fraction, by a factor of 3-4, from the age of our pre-main-sequence (PMS) sample to the Pleiades age . The significance of this decline is weakened if spot-induced radial-velocity jitter is strong in the sample, and is only marginally significant when comparing any one of the PMS clusters against the Pleiades. However, the same decline in both sense and magnitude is found for each of the five PMS clusters, and the decline reaches a statistical significance of greater than 95% confidence when considering the PMS clusters jointly. Our results suggest that dynamical processes disrupt the widest spectroscopic binaries (Porb≈ 103- 104days) as clusters age, indicating that this occurs early in the stars' evolution, while they still reside within their nascent clusters.

  • In Reply.

    13 August 2018