Genetic Variants Associated with FDNY WTC-Related Sarcoidosis
Genetic Variants Associated with FDNY WTC-Related Sarcoidosis
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DOI：
10.3390/ijerph16101830
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发表时间：
2019-05-02
影响因子：
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通讯作者：
Prezant, David J.
中科院分区：
文献类型：
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作者：
Cleven, Krystal L.;Ye, Kenny;Prezant, David J.
结节病是一种病因不明的全身性肉芽肿性疾病。它可能是在遗传引发的异常免疫反应的背景下对暴露或炎症触发反应而发生的。因此，遗传学研究对于我们了解结节病的发病机制可能很重要。我们开展了一项病例对照研究，探讨了纽约市消防局 (FDNY) 患有与世贸中心 (WTC) 相关的结节病的消防员与接触过世贸中心但未患结节病的消防员之间的遗传变异。对与肉芽肿形成、炎症、免疫反应和/或结节病相关的 51 个候选基因的基因座在增强子/启动子、外显子和 5' 非翻译区域进行了高密度测序。人类白细胞抗原 (HLA) 和非 HLA 基因的 17 种等位基因变异被发现与结节病相关，并且全部位于 1 号和 6 号染色体内。我们的结果还表明，胸腔外受累与 HLA 和非 HLA 基因的等位基因变异之间存在关联，不仅在 1 号和 6 号染色体上发现，而且在 16 号和 17 号染色体上也发现。我们发现 WTC 相关结节病的遗传变异与之前报道的遗传变异之间存在相似性。一般人群中散发的结节病病例。此外，我们还发现了一些以前从未报道过的与结节病相关的等位基因变异。如果在已知环境暴露的大型研究中得到证实，这些新发现可能会深入了解结节病发展的关键基因与环境的相互作用。
Sarcoidosis is a systemic granulomatous disease of unknown etiology. It may develop in response to an exposure or inflammatory trigger in the background of a genetically primed abnormal immune response. Thus, genetic studies are potentially important to our understanding of the pathogenesis of sarcoidosis. We developed a case-control study which explored the genetic variations between firefighters in the Fire Department of the City of New York (FDNY) with World Trade Center (WTC)-related sarcoidosis and those with WTC exposure, but without sarcoidosis. The loci of fifty-one candidate genes related to granuloma formation, inflammation, immune response, and/or sarcoidosis were sequenced at high density in enhancer/promoter, exonic, and 5' untranslated regions. Seventeen allele variants of human leukocyte antigen (HLA) and non-HLA genes were found to be associated with sarcoidosis, and all were within chromosomes 1 and 6. Our results also suggest an association between extrathoracic involvement and allele variants of HLA and non-HLA genes found not only on chromosomes 1 and 6, but also on chromosomes 16 and 17. We found similarities between genetic variants with WTC-related sarcoidosis and those reported previously in sporadic sarcoidosis cases within the general population. In addition, we identified several allele variants never previously reported in association with sarcoidosis. If confirmed in larger studies with known environmental exposures, these novel findings may provide insight into the gene-environment interactions key to the development of sarcoidosis.