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[大学生论坛]:Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study欧洲由中度至重度哮喘:全基因组关联研究

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Liuhaoyu 发表于 2019-1-3 21:37:18 | 显示全部楼层 |阅读模式
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
欧洲由中度至重度哮喘:全基因组关联研究
To our knowledge, we present the largest genetic-association study of moderate-to-severe asthma to date, with 10 549 cases and 47 146 controls, identifying 24 signals that reach genome-wide significance in the meta-analysis of stages 1 and 2. 21 (88%) of 24 signals have previously been reported in studies that predominantly assessed samples from patients with mild asthma, suggesting a substantial shared genetic architecture between mild and moderate-to-severe asthma. Our findings suggest that additional factors might drive the development of more severe forms of asthma—eg, environmental exposures or epigenetics, and the presence of comorbidities. We also provide increased insight into the identification of candidate casual genes in many of these loci, including several genes associated with type 2 inflammation. Three signals we identify here have not previously been reported for asthma in genome-wide association studies: rs11603634 in the MUC5AC region (coded allele G, frequency 50·4%, risk), rs1090584 in GATA3 (coded allele A, frequency 57·06%, protective), and rs560026225 (coded allele GATT, frequency 23·60%, risk) in a locus covering KIAA1109. The rs11603634 signal is specific to moderate-to-severe asthma and we identified that MUC5AC is increased in bronchial epithelial cells of carriers of the risk allele, with MUC5B being decreased in carriers of the risk allele, albeit not reaching our significance threshold. This genotype specific expression might be caused by alterations in FOXA transcription activity. For the GATA3 and KIAA1109 signals we saw an association with all asthma, while GATA3 has been previously reported to be associated with increased concentrations of blood eosinophil and KIAA1109 has been reported as being associated with self-reported allergy.
据我们所知,我们目前对中度至重度哮喘进行了迄今为止最大规模的基因关联研究,共有10549例病例和47 146例对照,在1期和2期的荟萃分析中鉴定了24种具有全基因组意义的信号。21(88%)先前的研究报告中,24种信号中有21种(88%)来自主要评估轻度哮喘患者样本的研究,这表明轻度和中度到重度哮喘之间存在大量共同的基因结构。我们的研究结果表明,其他因素可能会推动哮喘(如哮喘)更严重形式的发展,环境暴露或表观遗传学,以及并存疾病的存在。我们还提供了更多关于在许多这些基因位点(包括与2型炎症相关的几个基因)中候选临时基因的鉴定。我们在此识别的三种信号以前从未在全基因组关联研究中报道过哮喘:覆盖KIAA1109位点的MUC5AC区域的rs11603634(编码等位基因G,频率50·4%,风险)、GATA3区域的rs1090584(编码等位基因A,频率57·06%,保护性)和rs560026225(编码等位基因GATT,频率23·60%,风险)。rs11603634信号特异于中重度哮喘,我们发现危险等位基因携带者支气管上皮细胞MUC5AC升高,危险等位基因携带者MUC5B降低,但未达到我们的显著阈值。这种基因型特异性表达可能是由FOXA转录活性的改变引起的。对于GATA3和KIAA1109信号,我们发现它们与所有哮喘都有关联,而GATA3之前已经被报道与血液嗜酸性粒细胞浓度增加有关,KIAA1109也被报道与自我报告的过敏有关。
  Therefore, we provide additional insight into the genetic architecture of moderate-to-severe asthma and we report the first evidence that genetic variants associated with the risk of developing moderate-to-severe asthma regulate mucin production.
因此,我们对中重度哮喘的遗传结构提供了更多的见解,并首次报告了与中重度哮喘发病风险相关的遗传变异调节粘蛋白产生的证据。
In this study, we identified 21 previously reported signals as being associated with asthma, including some previously associated with asthma that is severe or difficult to treat: RAD50and HLA-DR/HLA-DQ, and 17q21(ORMDL3/GSDMB/ZPB2).
在本研究中,我们识别出21个先前报道的与哮喘相关的信号,包括一些先前报道的与严重或难以治疗的哮喘相关的信号:rad50和HLA-DR/HLA-DQ,以及17q21(ORMDL3/GSDMB/ZPB2)。
  Using eQTL analyses, we identified candidate causal genes for moderate-to-severe asthma; however, the level of evidence for each potential candidate gene based on linkage disequilibrium with sentinel SNP, relevant tissue and cell type, and statistical significance varied from highly supportive to suggestive. Overall, these signals highlight the role of innate and adaptive immunity and type 2 inflammation in moderate-to-severe asthma including: CD247, which encodes T-cell receptor ζ; trans-acting T-cell specific transcription factor GATA-3 (GATA3), an important transcription factor in T cells; interleukin-18 receptor 1 (IL18R1) and interleukin-1 receptor-like 1 (IL1RL1), receptors for key cytokines interleukin-18 and interlukin-33, respectively; thymic stromal lymphopoietin (TSLP), which drives type 2 inflammation; human leukocyte antigen genes that encode the major histocompatibility complex; transcription regulator protein BACH2 (BACH2), a transcriptional regulator in type 2 inflammation; interleukin-33 (IL33), an innate cytokine; and signal transducer and activator of transcription 6 (STAT6), a signalling molecule downstream of interleukin 4 and 13, which are drivers of type 2 inflammation. The other genes identified highlight roles in homoeostasis of airway cells, including D-2-hydroxyglutarate dehydrogenase (D2HGDH), which regulates α-ketoglutarate concentrations, influencing histone and DNA methylation; sodium/hydrogen exchanger 2 (SLC9A2), a sodium-hydrogen exchanger involved in the regulation of cell pH and volume;  inhibitor of growth protein 5 (ING5), a transcription factor involved in epithelial to mesenchymal transition; DNA repair protein RAD50 (RAD50), which is involved in DNA double-strand break repair; solute carrier family 22 member 5 (SLC22A5), an organic cation transporter with a role in epithelial cells; protein CLEC16A (CLEC16A), a regulator of autophagy; gasdermin-B (GSDMB), which is linked with airway smooth-muscle contraction; and ORM1-like protein 3 (ORMDL3), which is linked with airway remodelling.
利用eQTL分析,我们确定了中重度哮喘的候选致病基因;然而,基于与前哨位点SNP的连锁失衡、相关组织和细胞类型以及统计显著性的证据水平从高度支持到具有暗示意义。总的来说,这些信号突出的作用和2型天然免疫与适应性免疫炎症严重哮喘的包括:CD247, t细胞受体ζ进行编码;反式作用的T细胞特异性转录因子GATA-3 (GATA3)是T细胞中一种重要的转录因子;白细胞介素-18受体1 (IL18R1)和白细胞介素-1受体样1 (IL1RL1)分别是白细胞介素-18和白细胞介素-33的关键细胞因子受体;胸腺基质淋巴细胞生成素(TSLP),驱动2型炎症;编码主要组织相容性复合体的人类白细胞抗原基因;转录调节蛋白BACH2 (BACH2), 2型炎症中的转录调节蛋白;白细胞介素-33 (IL33),一种天生的细胞因子;信号转换器和转录6 (STAT6)的激活剂,转录6是白细胞介素4和13下游的信号分子,是2型炎症的驱动因素。确定的其他基因在气道细胞的体内平衡,突出角色包括D-2-hydroxyglutarate脱氢酶(D2HGDH),负责监管α-ketoglutarate浓度,影响组蛋白与DNA甲基化;钠/氢交换器2 (SLC9A2),参与调节细胞pH和体积的钠-氢交换器;生长蛋白5 (ING5)的抑制剂,一种参与上皮细胞向间充质转化的转录因子;DNA修复蛋白RAD50参与DNA双链断裂修复;溶质载体家族22号成员5 (SLC22A5),一种具有上皮细胞作用的有机阳离子转运体;自噬调节蛋白CLEC16A (CLEC16A);与气道平滑肌收缩相关的gasdermin-B (GSDMB);与orm1相似的蛋白3 (ORMDL3)与气道重构有关。

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