Robson K J H, Lehmann D J, Wimhurst V L C, Livesey K J, Combrinck M, Merryweather-Clarke A T, Warden D R, Smith A D
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
J Med Genet. 2004 Apr;41(4):261-5. doi: 10.1136/jmg.2003.015552.
There is evidence that iron may play a role in the pathology of Alzheimer's disease (AD). There may be genetic factors that contribute to iron deposition resulting in tissue damage thus exacerbating AD.
We have genotyped 269 healthy elderly controls, 191 cases with definite or probable AD, and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort.
We have examined the interaction between the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene as risk factors for developing AD. Our results showed that each of the two variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. The interaction was significant by logistic regression (p = 0.014) and by synergy factor analysis (p = 0.015, synergy factor = 5.1). Further, carriers of these two alleles plus apolipoprotein E epsilon4 (APOE4) were at still higher risk of AD: of the 14 tri-carriers of the three variants, identified in this study, 12 had AD and two MCI.
We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redox-active iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4. Since 4% of Northern Europeans carry the two iron-related variants and since iron overload is a treatable condition, these results merit replication.
有证据表明铁可能在阿尔茨海默病（AD）的病理过程中起作用。可能存在导致铁沉积从而造成组织损伤进而加重AD的遗传因素。
我们对来自OPTIMA队列的269名健康老年对照、191例确诊或可能患有AD的病例以及69例轻度认知障碍（MCI）患者进行了基因分型。
我们研究了转铁蛋白（TF）基因的C2变体与血色素沉着症（HFE）基因的C282Y等位基因之间的相互作用，将其作为发生AD的风险因素。我们的结果表明，仅在另一种变体存在的情况下，这两种变体中的每一种都与AD风险增加相关。单独的任何一个等位基因都没有任何影响。与所有其他人群相比，两种变体的携带者患AD的风险高5倍。通过逻辑回归分析（p = 0.014）和协同因子分析（p = 0.015，协同因子 = 5.1），这种相互作用具有显著性。此外，这两个等位基因的携带者加上载脂蛋白E ε4（APOE4）患AD的风险更高：在本研究中确定的14名三种变体的三联携带者中，12人患有AD，2人患有MCI。
我们认为TF C2和HFE C282Y的组合可能导致氧化还原活性铁过量并在神经元中诱导氧化应激，而在APOE4携带者中这种情况会加剧。由于4%的北欧人携带这两种与铁相关的变体，并且由于铁过载是一种可治疗的病症，这些结果值得重复验证。
