Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort
Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort
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DOI：
10.1002/art.41929
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发表时间：
2021-12-23
影响因子：
13.3
通讯作者：
Lundberg, Ingrid E.
中科院分区：
文献类型：
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作者：
Bianchi, Matteo;Kozyrev, Sergey V.;Lundberg, Ingrid E.
客观的。特发性炎症性肌病 (IIM) 是一组异质性复杂的自身免疫性疾病，其特征是骨骼肌和肌外区室炎症以及干扰素 (IFN) 系统激活。我们进行这项研究是为了检验遗传变异对疾病易感性的影响，并确定 IIM 研究的新途径。方法。使用靶向 DNA 测序从斯堪的纳维亚病例对照队列（由 454 名 IIM 患者和 1,024 名健康对照者组成）中的 1,900 个免疫相关基因中挖掘相似的编码和潜在调节单核苷酸变异。基于基因的聚合测试，以及罕见变异和基因水平的富集分析，被用来探索基因型-表型关系。结果。对所有变异体（包括罕见变异体）进行基于基因的聚合测试，确定 IFI35 是 IIM 的潜在遗传风险位点，表明 I 型 IFN 通路激活的遗传特征。 IFI35 位点的功能注释强调了与骨骼肌特异性基因 PTGES3L 相关的调控网络，该基因是 IIM 发病机制的潜在候选者。在抗合成酶综合征亚组中检测到主要组织相容性复合体基因座中 AGER 和 PSMB8 的总体遗传关联，该亚组也显示出 I 型 IFN 通路的不太明显的遗传特征。富集分析表明 IIM 患者存在同义和非编码罕见变异的负担，表明与这些类别的罕见变异相关的疾病易感性增加。结论。我们的研究表明罕见遗传变异对 IIM 和特定患者亚组的疾病易感性的贡献，并查明了与之前通过基因表达谱发现的结果一致的遗传关联。这些特征突出了与疾病发病机制潜在相关的遗传特征。
Objective. Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods. Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from similar to 1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations.Results. Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion. Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.