Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.
Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.
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DOI：
10.1016/j.ajhg.2016.05.014
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发表时间：
2016-06-02
影响因子：
9.8
通讯作者：
Forsberg LA
中科院分区：
文献类型：
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作者：
Dumanski JP;Lambert JC;Rasi C;Giedraitis V;Davies H;Grenier-Boley B;Lindgren CM;Campion D;Dufouil C;European Alzheimer’s Disease Initiative Investigators;Pasquier F;Amouyel P;Lannfelt L;Ingelsson M;Kilander L;Lind L;Forsberg LA
与女性相比，男性的预期寿命较短，但潜在因素尚不清楚。晚发性散发性阿尔茨海默病 (AD) 是一种常见且致命的神经退行性疾病，许多种系遗传变异已被发现会影响患 AD 的风险。我们之前的研究结果表明，一种根本不同的遗传变异，即血细胞中终生获得性 Y 染色体丢失 (LOY)，与全因死亡率和非血液肿瘤风险增加相关，并且 LOY 可能是由吸烟引起的。我们在这里测试了一个假设，即具有 LOY 的男性更容易患 AD，并在三项不同类型的独立研究中表明 LOY 与 AD 相关。在一项病例对照研究中，患有 AD 诊断的男性具有较高程度的 LOY 嵌合（调整后的比值比 = 2.80，p = 0.0184，AD 事件 = 606）。此外，在两项前瞻性研究中，血液采样时具有 LOY 的男性在随访期间发生 AD 诊断的风险更大（风险比 [HR] = 6.80，95% 置信区间 [95% CI] = 2.16–21.43，AD 事件 = 140，p = 0.0011）。因此，血液中的LOY与AD和癌症的风险相关，这表明血细胞中的LOY可能通过有缺陷的免疫监视在其他组织的疾病过程中发挥作用。作为男性特有的风险因素，LOY 可以解释为什么男性平均寿命比女性短。
Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16–21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.