Ortiz-Fernández Lourdes, Sawalha Amr H
Division of Rheumatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Med (Lausanne). 2021 Feb 12;8:625710. doi: 10.3389/fmed.2021.625710. eCollection 2021.
Behçet's disease is a chronic multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers. Although its etiology remains unclear, it is thought that both genetic and environmental factors contribute to the onset and progression of Behçet's disease. Here, we provide an updated view of the genetic landscape and architecture of Behçet's disease. Large-scale genetic studies performed to date revealed 21 genetic susceptibility loci associated with the disease at a GWAS level of significance (-value = 5 × 10). We performed epigenetic pattern enrichment analysis in Behçet's disease associated loci, providing new insights into the molecular mechanisms underlying its pathophysiology. Our data suggest the crucial involvement of several immune cell types, including natural killer cells, monocytes, and B cells in the pathogenesis of the disease. Pathway enrichment analysis identified important biological processes involved. Using large-scale genetic data available from ~200 immune-related loci (Immunochip), we estimate Behçet's disease heritability to be at least 16%. We further used the same approach to estimate the heritability explained by the known Behçet's disease-associated loci, suggesting that they explain ~ 60% of the genetic component underlying Behçet's disease. These results indicate a significant role of non-genetic factors in causing Behçet's disease and that additional genetic variation influencing the risk of Behçet's disease remains to be identified. Finally, we calculated a cumulative genetic risk score across populations reinforcing the link between geographic variations in disease prevalence with its genetic component.
白塞病是一种慢性多系统炎症性疾病，其特征为复发性口腔和生殖器溃疡。尽管其病因尚不清楚，但人们认为遗传和环境因素均对白塞病的发病和进展有影响。在此，我们对白塞病的遗传格局和结构提供了最新观点。迄今为止进行的大规模基因研究在全基因组关联研究（GWAS）显著水平（P值 = 5 × 10⁻⁸）下揭示了21个与该病相关的遗传易感性位点。我们对白塞病相关位点进行了表观遗传模式富集分析，为其病理生理学的潜在分子机制提供了新见解。我们的数据表明，包括自然杀伤细胞、单核细胞和B细胞在内的几种免疫细胞类型在该病的发病机制中起关键作用。通路富集分析确定了所涉及的重要生物学过程。利用来自约200个免疫相关位点（免疫芯片）的大规模基因数据，我们估计白塞病的遗传度至少为16%。我们进一步采用相同方法估计已知白塞病相关位点所解释的遗传度，表明它们解释了白塞病潜在遗传成分的约60%。这些结果表明非遗传因素在白塞病发病中起重要作用，且仍有待确定影响白塞病风险的其他遗传变异。最后，我们计算了不同人群的累积遗传风险评分，加强了疾病患病率的地理差异与其遗传成分之间的联系。
