①过敏和自身免疫性疾病之间的关系是复杂的，了解很少。②我们试图研究过敏和自身免疫性疾病在基因位点和途径上的共性，以阐明共同的疾病机制。③我们荟萃分析了两项全基因组范围内关于自我报告的过敏和致敏的相关性研究，共包括62,330名受试者。这些结果被用来计算与自身免疫性疾病相关的单核苷酸多态性(SNPs)的富集。此外，我们还探索了遗传途径和转录因子结合位点的富集，并利用编码路线图DNA -超敏感位点数据计算了不同细胞中基因调控区域的敏感SNP富集，从而表征了组织特异性调控位点上不同负担的共性。最后，我们将过敏数据与所有已知疾病的数据进行了比较。④在先前与16种自身免疫性疾病相关的290个基因座中，我们发现与过敏相关的29个基因座(P = 1.4e-17)显著富集，伪发现率小于0.05。这种富集似乎是自身免疫性疾病的一个普遍特征。在常见基因座中，48%对过敏和自身免疫性疾病有相同的作用方向。此外，我们还观察到免疫细胞中染色质通路和区域内的敏感SNP富集，这在自身免疫性疾病患者中也有体现，但在其他疾病患者中没有。⑤我们确定了过敏和自身免疫性疾病之间的易感性位点和通路的共性，提示了共同的疾病机制。对这些共同遗传机制的进一步研究可能有助于理解这些疾病之间的复杂关系，包括疾病流行率的平行增加。
Shared genetic variants suggest common pathways in allergy and autoimmune diseases
September 2017Volume 140, Issue 3, Pages 771–781
The relationship between allergy and autoimmune disorders is complex and poorly understood.
We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.
We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.
Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.
We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
Eskil Kreiner, MD, PhD∗, Johannes Waage, PhD∗, Marie Standl, PhD, Susanne Brix, PhD, Tune H. Pers, PhD, Alexessander Couto Alves, PhD, Nicole M. Warrington, PhD, Carla M.T. Tiesler, MSc, Elaine Fuertes, PhD, Lude Franke, PhD, Joel N. Hirschhorn, MD, PhD, Alan James, MD, Angela Simpson, MD, PhD, Joyce Y. Tung, PhD, Gerard H. Koppelman, MD, PhD, Dirkje S. Postma, MD, PhD, Craig E. Pennell, MD, PhD, Marjo-Riitta Jarvelin, MD, Adnan Custovic, MD, PhD, Nicholas Timpson, PhD, Manuel A. Ferreira, PhD, David P. Strachan, MD, John Henderson, MD, David Hinds, PhD, Hans Bisgaard, MD, DMSc'Correspondence information about the author MD, DMSc Hans Bisgaard Email the author MD, DMSc Hans Bisgaard, Klaus Bønnelykke, MD, PhD