AbstractIntroductionDespite advances, understanding the protective role of the apolipoprotein E (APOE) ε2 allele in Alzheimer's disease (AD) remains elusive.MethodsWe examined associations of variants comprised of the TOMM40 rs8106922 and APOE rs405509, rs440446, and ε2‐encoding rs7412 polymorphisms with AD in a sample of 2862 AD‐affected and 169,516 AD‐unaffected non‐carriers of the ε4 allele.ResultsAssociation of the ε2/ε3 heterozygote of men with AD is 38% (P = 1.65 × 10−2) more beneficial when it is accompanied by rs8106922 major allele homozygote and rs405509 and rs440446 heterozygotes than by rs8106922 heterozygote and rs405509 and rs440446 major allele homozygotes. No difference in the beneficial associations of these two most common ε2/ε3‐bearing variants with AD was identified in women. The role of ε2/ε3 heterozygote may be affected by different immunomodulation functions of rs8106922, rs405509, and rs440446 variants in a sex‐specific manner.DiscussionCombination of TOMM40 and APOE variants defines a more homogeneous AD‐protective ε2/ε3‐bearing profile in men.

中文翻译：

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男性中 TOMM40-APOE 变异加强了 ε2/ε3 杂合子与阿尔茨海默病的保护性关联

摘要介绍尽管取得了进展，但了解载脂蛋白 E 的保护作用（APOE) 阿尔茨海默病 (AD) 中的 ε2 等位基因仍然难以捉摸。方法我们检查了由以下组成的变体的关联托姆40rs8106922 和APOE在 2862 个受 AD 影响的样本和 169,516 个未受 AD 影响的 ε4 等位基因非携带者样本中，rs405509、rs440446 和 ε2 编码 rs7412 多态性与 AD 相关。结果男性 ε2/ε3 杂合子与 AD 的关联率为 38%（磷= 1.65 × 10−2) 当它伴随着 rs8106922 主要等位基因纯合子和 rs405509 和 rs440446 杂合子时，比 rs8106922 杂合子和 rs405509 和 rs440446 主要等位基因纯合子伴随时更有益。在女性中，这两种最常见的带有 ε2/ε3 的变异与 AD 的有益关联没有发现差异。ε2/ε3杂合子的作用可能以性别特异性方式受到rs8106922、rs405509和rs440446变体的不同免疫调节功能的影响。讨论的组合托姆40和APOE变体在男性中定义了更均匀的 AD 保护性 ε2/ε3 轴承轮廓。