PDF(Pubmed)
Abstract：
Autoimmune Addison\'s disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.
摘要：
自身免疫性Addison病（AAD）是一种罕见但危及生命的内分泌疾病，由肾上腺皮质的自身免疫性破坏引起。先前的全基因组关联研究（GWAS）表明，免疫相关基因附近的常见变异，主要编码参与免疫反应的蛋白质，影响发展这种情况的风险。然而,关于拷贝数变异（CNV）对AAD易感性的贡献知之甚少。我们使用来自挪威和瑞典个体（1,182例和3,810例对照）的全基因组基因分型数据来研究CNV在AAD病因中的推定作用。尽管罕见CNV的频率在病例和对照之间相似，我们观察到较大的缺失(>1,000kb)在患者中更为常见(OR=4.23,95%CI1.85-9.66,p=0.0002).尽管如此,没有一个大的病例缺失是最终致病的，在有和没有大CNV的病例之间，临床表现和AAD多基因风险评分相似。在AAD患者独有的缺失中，我们强调了LRBA和BCL2L11基因中的两个超罕见缺失,我们推测这两个缺失可能导致了这些携带者的多基因风险.总之,罕见CNVs似乎不是AAD的主要原因，但需要进一步研究以确定罕见缺失对AAD易感性的多基因负荷的潜在贡献。
