Rioux Bastien, Chong Michael, Walker Rosie, McGlasson Sarah, Rannikmäe Kristiina, McCartney Daniel, McCabe John, Brown Robin, Crow Yanick J, Hunt David, Whiteley William
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK.
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Wellcome Open Res. 2023 Nov 23;8:550. doi: 10.12688/wellcomeopenres.20385.1. eCollection 2023.
Type I interferons are cytokines involved in innate immunity against viruses. Genetic disorders of type I interferon regulation are associated with a range of autoimmune and cerebrovascular phenotypes. Carriers of pathogenic variants involved in genetic disorders of type I interferons are generally considered asymptomatic. Preliminary data suggests, however, that genetically determined dysregulation of type I interferon responses is associated with autoimmunity, and may also be relevant to sporadic cerebrovascular disease and dementia. We aim to determine whether functional variants in genes involved in type I interferon regulation and signalling are associated with the risk of autoimmunity, stroke, and dementia in a population cohort.
We will perform a hypothesis-driven candidate pathway association study of type I interferon-related genes using rare variants in the UK Biobank (UKB). We will manually curate type I interferon regulation and signalling genes from a literature review and Gene Ontology, followed by clinical and functional filtering. Variants of interest will be included based on pre-defined clinical relevance and functional annotations (using LOFTEE, M-CAP and a minor allele frequency <0.1%). The association of variants with 15 clinical and three neuroradiological phenotypes will be assessed with a rare variant genetic risk score and gene-level tests, using a Bonferroni-corrected p-value threshold from the number of genetic units and phenotypes tested. We will explore the association of significant genetic units with 196 additional health-related outcomes to help interpret their relevance and explore the clinical spectrum of genetic perturbations of type I interferon.
The UKB has received ethical approval from the North West Multicentre Research Ethics Committee, and all participants provided written informed consent at recruitment. This research will be conducted using the UKB Resource under application number 93160. We expect to disseminate our results in a peer-reviewed journal and at an international cardiovascular conference.
I型干扰素是参与针对病毒的固有免疫的细胞因子。I型干扰素调节的遗传紊乱与一系列自身免疫和脑血管表型相关。参与I型干扰素遗传紊乱的致病变体携带者通常被认为无症状。然而，初步数据表明，I型干扰素反应的基因决定的失调与自身免疫有关，也可能与散发性脑血管疾病和痴呆有关。我们旨在确定参与I型干扰素调节和信号传导的基因中的功能变体是否与人群队列中的自身免疫、中风和痴呆风险相关。
我们将使用英国生物银行（UKB）中的罕见变体对I型干扰素相关基因进行假设驱动的候选途径关联研究。我们将通过文献综述和基因本体手动筛选I型干扰素调节和信号传导基因，然后进行临床和功能筛选。将根据预定义的临床相关性和功能注释（使用LOFTEE、M-CAP和次要等位基因频率<0.1%）纳入感兴趣的变体。将使用罕见变体遗传风险评分和基因水平测试评估变体与15种临床和3种神经放射学表型的关联，使用根据测试的遗传单位和表型数量进行Bonferroni校正的p值阈值。我们将探索显著遗传单位与另外196种与健康相关的结果之间的关联，以帮助解释它们的相关性，并探索I型干扰素基因扰动的临床谱。
UKB已获得西北多中心研究伦理委员会的伦理批准，所有参与者在招募时均提供了书面知情同意书。本研究将使用申请编号为93160的UKB资源进行。我们期望在同行评审期刊和国际心血管会议上发表我们的结果。
