Genome-wide imputation identifies novel associations and localises signals in idiopathic inflammatory myopathies.

OBJECTIVES The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types. This article is protected by copyright. All rights reserved

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

OBJECTIVES: The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS: The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS: We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types

Survey on worldwide trauma team activation requirement

PURPOSE : trauma team activation (TTA) is thought to be essential for advanced and specialized care of very severely injured patients. However, non-specific TTA criteria may result in overtriage that consumes valuable resources or endanger patients in need of TTA secondary to undertriage. Consequently, criterion standard definitions to calculate the accuracy of the various TTA protocols are required for research and quality assurance purposes. Recently, several groups suggested a list of conditions when a trauma team is considered to be essential in the initial care in the emergency room. The objective of the survey was to post hoc identify trauma-related conditions that are thought to require a specialized trauma team that may be widely accepted, independent from the country’s income level. METHODS : A set of questions was developed, centered around the level of agreement with the proposed post hoc criteria to define adequate trauma team activation. The participants gave feedback before they answered the survey to improve the quality of the questions. The finalized survey was conducted using an online tool and a word form. The income per capita of a country was rated according to the World Bank Country and Lending groups. RESULTS : The return rate was 76% with a total of 37 countries participating. The agreement with the proposed criteria to define post hoc correct requirements for trauma team activation was more than 75% for 12 of the 20 criteria. The rate of disagreement was low and varied between zero and 13%. The level of agreement was independent from the country’s level of income. CONCLUSIONS : The agreement on criteria to post hoc define correct requirements for trauma team activation appears high and it may be concluded that the proposed criteria could be useful for most countries, independent from their level of income. Nevertheless, more discussions on an international level appear to be warranted to achieve a full consensus to define a universal set of criteria that will allow for quality assessment of over- and undertriage of trauma team activation as well as for the validation of field triage criteria for the most severely injured patients worldwide.http://link.springer.com/journal/68am2022Surger