Pazderska Agnieszka, Oftedal Bergithe E, Napier Catherine M, Ainsworth Holly F, Husebye Eystein S, Cordell Heather J, Pearce Simon H S, Mitchell Anna L
Institute of Genetic Medicine (A.P., C.M.N., H.F.A., H.J.C., S.H.S.P., A.L.M.), Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; Department of Clinical Science (B.E.O., E.S.H.), University of Bergen, 5021 Bergen, Norway; and Department of Medicine (E.S.H.), Haukeland University Hospital, 5021 Bergen, Norway.
J Clin Endocrinol Metab. 2016 Nov;101(11):3865-3869. doi: 10.1210/jc.2016-2368. Epub 2016 Sep 28.
Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions.
We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD.
DESIGN, SETTING, AND PATIENTS: This case-control association study was performed in two phases using Taqman chemistry. In the first phase, the rs3757247 SNP was genotyped in 358 UK AAD subjects and 166 local control subjects. Genotype data were also available from 5154 healthy UK controls from the Wellcome Trust (WTCCC2) for comparison. In the second phase, the SNP was genotyped in a validation cohort comprising 317 Norwegian AAD subjects and 365 controls.
The frequency of the minor T allele was significantly higher in subjects with AAD from the United Kingdom compared to both the local and WTCCC2 control cohorts (58% vs 45 and 48%, respectively) (local controls, P = 1.1 × 10; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.29-2.18; WTCCC2 controls, P = 1.4 × 10; OR, 1.44; 95% CI, 1.23-1.69). This finding was replicated in the Norwegian validation cohort (P = .0015; OR, 1.41; 95% CI, 1.14-1.75). Subgroup analysis showed that this association is present in subjects with both isolated AAD (OR, 1.53; 95% CI, 1.22-1.92) and autoimmune polyglandular syndrome type 2 (OR, 1.37; 95% CI, 1.12-1.69) in the UK cohort, and with autoimmune polyglandular syndrome type 2 in the Norwegian cohort (OR, 1.58; 95% CI, 1.22-2.06).
We have demonstrated, for the first time, that allelic variability at the BACH2 locus is associated with susceptibility to AAD. Given its association with multiple autoimmune conditions, BACH2 can be considered a "universal" autoimmune susceptibility locus.
自身免疫性Addison病（AAD）是一种罕见但遗传性很强的疾病。BACH2蛋白在T淋巴细胞成熟过程中起关键作用，其基因的等位基因变异与多种自身免疫性疾病有关。
我们旨在确定BACH2基因中rs3757247单核苷酸多态性（SNP）的等位基因是否与AAD相关。
设计、地点和患者：本病例对照关联研究分两个阶段使用Taqman化学方法进行。在第一阶段，对358名英国AAD患者和166名当地对照者进行rs3757247 SNP基因分型。还可从威康信托基金（WTCCC2）的5154名英国健康对照者获得基因型数据用于比较。在第二阶段，对一个验证队列中的317名挪威AAD患者和365名对照者进行该SNP基因分型。
与当地和WTCCC2对照队列相比，来自英国的AAD患者中次要T等位基因的频率显著更高（分别为58%对45%和48%）（当地对照者，P = 1.1×10；优势比[OR]，1.68；95%置信区间[CI]，1.29 - 2.18；WTCCC2对照者，P = 1.4×10；OR，1.44；95% CI，1.23 - 1.69）。这一发现在挪威验证队列中得到重复（P = 0.0015；OR，1.41；95% CI，1.14 - 1.75）。亚组分析表明，在英国队列中，这种关联在孤立性AAD患者（OR，1.53；95% CI，1.22 - 1.92）和2型自身免疫性多腺体综合征患者（OR，1.37；95% CI，1.12 - 1.69）中均存在，在挪威队列中则在2型自身免疫性多腺体综合征患者中存在（OR，1.58；95% CI，1.22 - 2.06）。
我们首次证明，BACH2基因座的等位基因变异与AAD易感性相关。鉴于其与多种自身免疫性疾病的关联，BACH2可被视为一个“通用”的自身免疫易感基因座。
