Longer First Introns Are a General Property of Eukaryotic Gene Structure

While many properties of eukaryotic gene structure are well characterized, differences in the form and function of introns that occur at different positions within a transcript are less well understood. In particular, the dynamics of intron length variation with respect to intron position has received relatively little attention. This study analyzes all available data on intron lengths in GenBank and finds a significant trend of increased length in first introns throughout a wide range of species. This trend was found to be even stronger when using high-confidence gene annotation data for three model organisms (Arabidopsis thaliana, Caenorhabditis elegans, and Drosophila melanogaster) which show that the first intron in the 5′ UTR is - on average - significantly longer than all downstream introns within a gene. A partial explanation for increased first intron length in A. thaliana is suggested by the increased frequency of certain motifs that are present in first introns. The phenomenon of longer first introns can potentially be used to improve gene prediction software and also to detect errors in existing gene annotations

Oral abstracts 1: SpondyloarthropathiesO1. Detecting axial spondyloarthritis amongst primary care back pain referrals

Background: Inflammatory back pain (IBP) is an early feature of ankylosing spondylitis (AS) and its detection offers the prospect of early diagnosis of AS. However, since back pain is very common but only a very small minority of back pain sufferers have ASpA or AS, screening of back pain sufferers for AS is problematic. In early disease radiographs are often normal so that fulfilment of diagnostic criteria for AS is impossible though a diagnosis of axial SpA can be made if MRI evidence of sacroiliitis is present. This pilot study was designed to indicate whether a cost-effective pick up rate for ASpA/early AS could be achieved by identifying adults with IBP stratified on the basis of age. Methods: Patients aged between 18 and 45 years who were referred to a hospital physiotherapy service with back pain of more than 3 months duration were assessed for IBP. All were asked to complete a questionnaire based on the Berlin IBP criteria. Those who fulfilled IBP criteria were also asked to complete a second short questionnaire enquiring about SpA comorbidities, to have a blood test for HLA-B27 and CRP level and to undergo an MRI scan of the sacroiliac joints. This was a limited scan, using STIR, diffusion-weighted, T1 and T2 sequences of the sacroiliac joints to minimize time in the scanner and cost. The study was funded by a research grant from Abbott Laboratories Ltd. Results: 50 sequential patients agreed to participate in the study and completed the IBP questionnaire. Of these 27 (54%) fulfilled criteria for IBP. Of these, 2 patients reported a history of an SpA comorbidity - 1 psoriasis; 1 ulcerative colitis - and 3 reported a family history of an SpA comorbidity - 2 psoriasis; 1 Crohn's disease. 4 were HLA-B27 positive, though results were not available for 7. Two patients had marginally raised CRP levels (6, 10 -NR ≤ 5). 19 agreed to undergo MRI scanning of the sacroiliac joints and lumbar spine; 4 scans were abnormal, showing evidence of bilateral sacroiliitis on STIR sequences. In all cases the changes met ASAS criteria but were limited. Of these 4 patients 3 were HLA-B27 positive but none gave a personal or family history of an SpA-associated comorbidity and all had normal CRP levels. Conclusions: This was a pilot study yielding only limited conclusions. However, it is clear that: Screening of patients referred for physiotherapy for IBP is straightforward, inexpensive and quick. It appears that IBP is more prevalent in young adults than overall population data suggest so that targeting this population may be efficient. IBP questionnaires could be administered routinely during a physiotherapy assessment. HLA-B27 testing in this group of patients with IBP is a suitable screening tool. The sacroiliac joint changes identified were mild and their prognostic significance is not yet clear so that the value of early screening needs further evaluation. Disclosure statement: C.H. received research funding for this study from Abbott. A.K. received research funding for this study, and speaker and consultancy fees, from Abbott. All other authors have declared no conflicts of interes

Spondylarthropathies (including psoriatic arthritis): 244. Validity of Colour Doppler and Spectral Doppler Ultrasound of Sacroilicac Joints Againts Physical Examination as Gold Standard

Background: Sacroiliac joints (SJ) involvement is a distinctive and charasteristic feature of Spondyloarthritis (SpA) and x-ray is the test routinely used to make a diagnosis. However, x-ray reveals late structural damage but cannot detect active inflammation. The objective of this study was to assess the validity of Doppler ultrasound in SJ. Methods: Prospective blinded and controlled study of SJ, in which three populations were compared. We studied 106 consecutive cases, who were divided into three groups: a) 53 patients diagnosed with SpA who had inflammatory lumbar and gluteal pain assessed by a rheumatologist; b) 26 patients diagnosed with SpA who didn't have SJ tenderness and had normal physical examination; c) control group of 27 subjects (healthy subjetcs or with mechanical lumbar pain). All patients included that were diagnosed with SpA met almost the European Spondyloarthropathy Study Group (ESSG) classification criteria. Physical examination of the SJ included: sacral sulcus tenderness, iliac gapping, iliac compression, midline sacral thrust test, Gaenslen's test, and Patrick s test were used as gold standard. Both SJ were examined with Doppler ultrasound (General Electric Logiq 9, Wauwatosa WI, USA) fitted with a 9-14 Mhz lineal probe. The ultrasonographer was blinded to clinical data. Doppler in SJ was assessed as positive when both Doppler colour and resistance index (RI) < 0.75 within the SJ area were present. Statistical analysis was performed estimating sensitivity and specificity against gold standard. The Kappa correlation coefficient was used for reliability study. Results: 106 cases (53 female, 55 male; mean age 36 10 years) were studied. There were no statistical differences between groups related to age or sex. Physical examination of SJ was positive in 38 patients (59 sacroiliac joints). US detected Doppler signal within SJ in 37 patients (58 SJ): 33 of them were symptomatic SpA (52 SJ), one of them were asymptomatic SpA (1 SJ) and one was a healthy control (1 SJ). The accuracy of US when compared to clinical data as gold standard at subject level in the overall group was: sensitivity of 68.6% and specificity of 85.7%, positive predictive value of 70.5% and negative predictive value of 84.5%. A positive likelihood ratio of 4.8, a negative likelihood ratio of 0.36 and a kappa coefficient of 0.55 were achieved. Conclusions: Doppler US of SJ seems to be a valid method to detect active SJ inflammation. Disclosure statement: The authors have declared no conflicts of interes

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Homozygous MHC genotypes and longevity

To investigate the relevance of the major histocompatibility complex (MHC) in longevity, we carried out a molecular analysis of the MHC in 432 unrelated healthy individuals. The comparison of individuals 25 years showed that the 5.8-kb DQA1 allele, which corresponds to HLA-DR53, was negatively associated with longevity (p = 0.0035) resulting mainly from decreased homozygosity with age for that allele (p = 0.008), and restricted to males (p = 0.008). The difference was more striking for the 5.8 kb DQA1: 9.0 kb HSP70 haplotype again only in males (26.3 vs. 6.2%; p = 0.017, OR = 5.4, 95% CI = 1.5 - 19.5). The oldest male subject homozygous for this DQA1: HSP70 haplotype was 54 years (p = 0.005). Comparing leukemic patients and healthy individuals with the same ethnic and geographical origin, homozygosity for these genotypes was more frequent in the young leukemic group. The results suggested the existence of recessive deleterious genes in a segment of HLA-DR53 haplotypes

Prevalence and associated factors for falls in women with established inflammatory polyarthritis

OBJECTIVE: To determine the one-year period prevalence and factors associated with falls in a community based cohort of women with established inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register is a primary-care based inception cohort of subjects with IP aged 16 years and over. At the 10-year visit, subjects completed the Health Assessment Questionnaire (HAQ) and were examined for both active and inactive joint involvement. A subset of subjects was invited to complete a questionnaire about falls in the previous 12 months and questions about putative risk factors for falls. Logistic regression was used to determine whether there was any association between falls in the previous year and both putative disease and non-disease related risk factors. RESULTS: Of the 316 women (mean age 59 yrs) who completed the falls questionnaire, 34% reported a fall in the previous year. Falls were more frequent in those over age 75 years, although there was no significant linear increase in risk with age. Swollen joint count [per 10 joints, odds ratio (OR) 1.7; 95% confidence interval (CI) 1.0, 2.8] and increasing visual analog scale pain score (per 10 mm, OR 1.1; 95% CI 1.0, 1.2) were associated with an increased risk of falls. Those who fell had higher overall HAQ scores (OR 1.7; 95% CI 1.3, 2.3) as well as higher scores for all of the individual domains of the HAQ (OR 1.7 to 2.2). Similarly, low levels of outdoor physical activity (OR 3.3; 95% CI 1.7, 6.5), impaired vision (OR 2.7; 95% CI 1.2, 6.3), and impaired general health (OR 2.9; 95% CI 1.7, 4.8) were associated with an increased risk of falls. In a multivariate model, HAQ score, low levels of physical activity, impaired vision, and impaired general health were independently linked with falls. Sixty-one percent of subjects with 3 of these risk factors had reported a fall in the previous year. CONCLUSION: In this inception cohort of women with longstanding IP, one in 3 reported falling in the previous year. Using a simple measure, a group that had particularly high risk can be identified

Human major histocompatibility complex contains several leukemia susceptibility genes

In mice, homozygosity for the Mhc haplotype H-2k is associated with increased susceptibility to spontaneous and virus-induced leukemia, lymphoma and other neoplasms in the predisposed host. The influence of the Mhc on malignant development in these models is to shorten the latency after virus inoculation. Here, we present evidence that a similar phenomenon results in early-onset of human leukemia. A molecular analysis of the MHC in 112 CML patients showed that those who developed the disease when aged less than 35 years (early-onset group) had higher homozygosity rates for the DOA1, HSP70 and C4 alleles of the DR53 group of ancestral haplotypes, for a subtype of HLA-A3, and a higher allele frequency of BfFb compared to the late-onset group. The oldest patient (n = 13) homozygous for DR53 was 52-years-old (p = 0.004), and all HLA-A3 homozygous patients (n = 4) were in the early-onset group (p = 0.01). The relative risk for early-onset CML yielded by HLA-A3 homozygosity was 17.6. The well-known serological HLA-Cw4 association was not confirmed at the DNA level and thought to be due to linkage disequilibrium with BfFb. The factor B association was sex-limited. The DR52 group haplotypes appeared to be protective. The HLA-identical sibling frequency was increased only in the early-onset group (p < 0.01). Our findings agree with the concept of an MHC influence on the development of malignancies. The similarity in the location of the susceptibility loci and the serological cross-reaction between H-2Ek and DR53 raise the possibility that the mouse and human MHC share the same leukemia susceptibility genes