Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
J Alzheimers Dis. 2019;68(4):1535-1547. doi: 10.3233/JAD-181116.
Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.
脑源性神经营养因子（BDNF）从去甲肾上腺素能神经元的前突触分泌可能保护阿尔茨海默病（AD）大脑免受淀粉样蛋白病理学的影响。虽然 BDNF 多态性（rs6265）与认知能力下降加快和海马体萎缩增加有关，但 BDNF 与 AD 风险的可复制遗传关联尚未得到证实。这可能是由于 BDNF 与其他编码参与调节 BDNF 分泌的蛋白质的基因座之间潜在的上位相互作用所致（DBH 和 Sortilin）。我们对包含来自北欧（87%的样本）和西班牙（13%）的 5682 名对照和 2454 名 AD 患者的 BDNF、DBH 和 SORT1 基因座进行了多队列病例对照关联研究。BDNF 基因座与 AD 风险增加相关（比值比；OR=1.1-1.2，p=0.005-0.3），这一效应大小在北欧（OR=1.1-1.2，p=0.002-0.8）中是一致的，但在较小的西班牙（OR=0.8-1.6，p=0.4-1.0）亚组中不一致。BDNF 与性别之间的协同相互作用（协同因子；SF=1.3-1.5，p=0.002-0.02）转化为与女性（OR=1.2-1.3，p=0.007-0.00008）相比，BDNF 与 AD 相关的风险更高（OR=0.9-1.0，p=0.3-0.6）。虽然 DBH 多态性（rs1611115）也与 AD 风险增加相关（OR=1.1，p=0.04），但 BDNF（rs6265）和 DBH（rs1611115）之间的协同相互作用（SF=2.2，p=0.007）比任何一个基因单独贡献更大的 AD 风险，这种影响在女性（SF=2.4，p=0.04）中比男性（SF=2.0，p=0.2）更大。这些数据支持在编码参与 DBH-BDNF 炎症途径的蛋白质的基因座上存在复杂的遗传相互作用，该途径可改变 AD 风险，尤其是在女性中。
