Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
Eur J Endocrinol. 2012 Dec;167(6):825-8. doi: 10.1530/EJE-12-0579. Epub 2012 Sep 25.
Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case-control study to determine whether these rare variants are associated with a rarer condition, AAD.
We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products.
A heterozygous rare allele at codon 312 (312M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44-97.45, two-tailed P value 0.212, NS).
We demonstrated the presence of 89V homozygotes and the 312M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.
自身免疫性艾迪生病（AAD）是一种罕见的疾病，具有复杂的遗传基础。唾液酸乙酰酯酶（SIAE）基因中的一组罕见的、功能缺陷的遗传变异体最近与几种常见的自身免疫性疾病有关。我们进行了一项病例对照研究，以确定这些罕见的变异体是否与一种更罕见的疾病 AAD 有关。
我们分析了英国队列中的 378 名 AAD 患者和 387 名健康对照者的 9 个 SIAE 基因变异体（W48X、M89V、C196F、C226G、R230W、T312M、Y349C、F404S 和 R479C）。所有样本均采用Sequenom iPlex 化学法进行基因分型，以对引物延伸产物进行特征描述。
在一名 AAD 患者（0.13%）中发现了 312 密码子的杂合罕见等位基因（312M），但在健康对照者中未检测到。在 AAD 患者中发现 89 密码子的常见、功能隐性变异体（89V）为纯合子，但在对照组中仅为杂合子。考虑到所有 9 个检测到的等位基因，378 名 AAD 患者中有 4 名（1.06%）和 387 名健康对照者中有 1 名（0.25%）携带缺陷 SIAE 等位基因，计算得出的优势比为 4.13（95%CI 0.44-97.45，双侧 P 值 0.212，无统计学意义）。
我们在 AAD 队列中发现了 89V 纯合子和 312M 罕见等位基因，但总的来说，我们的分析并不支持 SIAE 中的罕见变异在 AAD 发病机制中的作用。然而，AAD 患者的集合相对较小，限制了排除小效应的能力。
