Alzheimer's disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the transferrin (TF) gene and rs1800562 in the homeostatic iron regulator (HFE) gene, commonly known as hemochromatosis, is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger data set from the Alzheimer's Disease Genetics Consortium, we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p = 0.38 and HFE rs1800562 p = 0.40). In addition, logistic regression with an interaction term and a synergy factor analysis both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF = 0.94; p = 0.48) in AD cases. Each of these analyses had sufficient statistical power (power > 0.99), suggesting that previously reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or false-positive associations because of limited sample sizes.

中文翻译：

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未能在大型队列中检测转铁蛋白变异与血色病和阿尔茨海默病之间的协同作用

阿尔茨海默病 (AD) 是痴呆症的最常见原因，尽管经过了数十年的努力，但仍没有有效的治疗方法。在过去十年中，许多关联研究已经确定了与 AD 状态相关的遗传标记。其中两项研究表明，转铁蛋白 (TF) 基因中的变体 rs1049296 和稳态铁调节器 (HFE) 基因中的 rs1800562（通常称为血色素沉着症）之间的上位相互作用与 AD 有遗传关联。TF 和 HFE 参与大脑中铁的转运和调节，破坏这些过程会通过增加神经变性和氧化应激加剧 AD 病理。然而，通过使用来自阿尔茨海默氏病遗传学联盟的更大的数据集，我们未能检测到 TF rs1049296 或 HFE rs1800562 与 AD 风险之间的关联（TF rs1049296 p = 0.38 和 HFE rs1800562 p = 0.40）。此外，具有交互项和协同因子分析的逻辑回归均未能检测到 AD 病例中 TF rs1049296 和 HFE rs1800562（SF = 0.94；p = 0.48）之间的上位性。这些分析中的每一个都具有足够的统计功效（功效 > 0.99），表明先前报告的关联可能是更复杂的上位相互作用、遗传异质性或由于样本量有限的假阳性关联的结果。