Department of Neurology, Focus Program Translational Neuroscience, [corrected] University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
J Med Genet. 2012 Sep;49(9):558-62. doi: 10.1136/jmedgenet-2012-101175.
Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.
We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments.
Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively).
Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
单核苷酸多态性（SNP）rs429358（ε4）和 rs7412（ε2）均会引起载脂蛋白 E（APOE）基因的氨基酸序列改变，先前已对其与多发性硬化症（MS）风险的相关性进行了测试。然而，这些研究均没有足够的效力在可接受的Ⅰ型错误率下检测到适度的效应大小。由于这两个 SNP 仅在常用的微阵列基因分型平台上不完全捕获，因此直到最近，它们在全基因组关联研究中的评估才受到阻碍。
我们对 12740 名迄今为止未研究其 APOE 状态的受试者进行了基因分型，使用最新的高分辨率参考面板对来自五个独立全基因组关联研究数据集的 8739 名受试者的原始基因型数据进行了推断，并从以前的候选基因评估中提取了 8265 名受试者的基因型数据。
尽管有足够的效力在一系列 OR 下检测到全基因组显著阈值的关联，但我们的分析并不支持 rs429358 或 rs7412 对 MS 易感性的作用。这包括对 13913 例 MS 病例和 15831 例对照的联合数据进行的荟萃分析（rs429358 和 rs7412 的 OR 分别为 0.95，p=0.259 和 OR 1.07，p=0.0569）。
鉴于我们分析的样本量很大，这里研究的两个 APOE 错义 SNP 不太可能对 MS 易感性产生任何相关影响。
