Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease
Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease
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DOI：
10.1007/s004390100463
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发表时间：
2001-03-01
期刊：
影响因子：
5.3
通讯作者：
De Benedictis, G
中科院分区：
文献类型：
--
作者：
Carrieri, G;Bonafè, M;De Benedictis, G
核APOE基因的等位基因epsilon4是散发性阿尔茨海默病（AD）的主要遗传危险因素。此外，APOE同种异构体对神经元细胞氧化死亡的等位基因特异性作用是已知的。由于线粒体基因组（mtDNA）在氧化磷酸化和氧化应激中的作用，APOE多态性和mtDNA遗传变异性在散发性AD遗传易感性中的相互作用可以被假设。我们通过分析AD患者样本（213名受试者）的mtDNA种系变异（mtDNA单倍群）来探索这一假设，这些患者为APOE基因分型，并将其分为APOE epsilon4携带者和非携带者。我们发现mtDNA单倍群的频率分布在epsilon4携带者和非携带者之间存在差异（P=0.018），表明APOE与mtDNA多态性之间存在非随机关联。同样的分析在两个健康受试者样本（179名年龄匹配的个体和210名年龄超过100岁的个体）中进行，显示了epsilon4等位基因和mtDNA单倍群之间的独立性。因此，APOE/mtDNA相互作用仅限于AD，并可能影响对该疾病的易感性。特别是，一些mtDNA单倍群（K和U）似乎可以中和APOE epsilon4等位基因的有害影响，将epsilon4的比值比从统计显著值降低到不显著值。
Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carrier. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018, thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.