PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■I型干扰素是参与针对病毒的先天免疫的细胞因子。I型干扰素调节的遗传性疾病与一系列自身免疫和脑血管表型有关。涉及I型干扰素遗传疾病的致病变异的携带者通常被认为是无症状的。初步数据显示,然而,基因决定的I型干扰素反应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。我们的目标是确定参与I型干扰素调节和信号传导的基因中的功能变异是否与自身免疫的风险相关。中风,人群队列中的痴呆症。
■我们将使用UKBiobank（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。我们将从文献综述和基因本体论中手动管理I型干扰素调节和信号基因，其次是临床和功能过滤。将基于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%)。将通过罕见的变异遗传风险评分和基因水平测试来评估变异与15种临床和三种神经放射学表型的关联。使用Bonferroni校正的p值阈值从测试的遗传单位和表型的数量。我们将探索重要的遗传单位与196个其他健康相关结果的关联，以帮助解释它们的相关性并探索I型干扰素遗传扰动的临床谱。
■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都提供了书面知情同意书.这项研究将使用UKB资源进行，申请号为93160。我们希望在同行评审的期刊和国际心血管会议上传播我们的结果。
■我们将使用UKBiobank（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。我们将从文献综述和基因本体论中手动管理I型干扰素调节和信号基因，其次是临床和功能过滤。将基于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%)。将通过罕见的变异遗传风险评分和基因水平测试来评估变异与15种临床和三种神经放射学表型的关联。使用Bonferroni校正的p值阈值从测试的遗传单位和表型的数量。我们将探索重要的遗传单位与196个其他健康相关结果的关联，以帮助解释它们的相关性并探索I型干扰素遗传扰动的临床谱。
■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都提供了书面知情同意书.这项研究将使用UKB资源进行，申请号为93160。我们希望在同行评审的期刊和国际心血管会议上传播我们的结果。
