OBJECTIVE Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD. DESIGN Case-control study on patients with AAD and healthy controls. METHODS Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls. RESULTS With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10-44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 × 10-63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD. CONCLUSIONS We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.

中文翻译：

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瑞典自身免疫性艾迪生病患者队列中 HLA 与类固醇 21-羟化酶拷贝数变异之间的关系。

目的 针对肾上腺酶 21-羟化酶的自身抗体是自身免疫性阿狄森氏病 (AAD) 的标志性表现。类固醇21-羟化酶由CYP21A2编码，CYP21A2与高度相似的假基因CYP21A1P一起位于人类白细胞抗原(HLA)区域。这 2 个基因存在高水平的拷贝数变异，因此，我们询问 CYP21 基因的遗传变异是否与 AAD 相关。设计针对 AAD 患者和健康对照的病例对照研究。方法 使用下一代 DNA 测序，我们估计了 479 名瑞典 AAD 患者和 21-羟化酶自身抗体以及 1393 名健康对照者的 CYP21A2 和 CYP21A1P 以及 HLA 等位基因的拷贝数。结果 95% 的个体携带 2 个功能性 21-羟化酶基因，在比较患者和对照时未发现 CYP21A2 拷贝数存在差异。相比之下，我们发现 AAD 患者中假基因 CYP21A1P 的拷贝数较低 (P = 5 × 10-44)，并且 CYP21 区域中存在其他核苷酸变异的关联。然而，HLA-DQB1*02:01 的关联性最强 (P = 9 × 10-63)，它与 ​​DRB1*04:04-DQB1*03:02 单倍型结合使用，造成 AAD 的风险最大。结论 我们发现 CYP21 区域的拷贝数变异与 AAD 风险之间存在很强的关联，尽管这些关联很可能是由于与疾病相关的 HLA II 类等位基因的连锁不平衡所致。