Genetic Polymorphisms in Estrogen Metabolic Pathway Associated with Risks of Alzheimer's Disease: Evidence from a Southern Chinese Population
Genetic Polymorphisms in Estrogen Metabolic Pathway Associated with Risks of Alzheimer's Disease: Evidence from a Southern Chinese Population
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DOI：
10.1111/jgs.14537
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发表时间：
2017-02-01
影响因子：
6.3
通讯作者：
Song, You-Qiang
中科院分区：
文献类型：
--
作者：
Chen, Lu Hua;Fan, Yan Hui;Song, You-Qiang
目的：探讨雌激素代谢途径的遗传变异是否与阿尔茨海默病（AD）的风险相关。设计：横断面研究。设置：在香港皇后玛丽医院记忆诊所招募个体。参与者：患有AD的中国人（n = 426）和没有AD的中国人（n = 350）。测量：所有受试者都接受了标准化的认知评估和雌激素代谢途径上四个候选基因的基因分型（雌激素受体a基因（ESR1）、雌激素受体B基因（ESR2）、细胞色素P450 19 A1基因（CYP19 A1）、细胞色素P450 11 A1基因（CYP11 A1））。除了显示载脂蛋白（APO）E和AD之间存在关联的一致结果外，基于整个数据集，还发现了ESR2和CYP11A1多态性与疾病相关的强有力证据。对于ESR2，发现rs4986938（置换P =.02）和rs867443（置换P =.02）的A等位基因具有显著的保护作用。对于CYP11A1，发现rs11638442（置换P =.03）和rs11632698（置换P =.03）的G等位基因具有显著的风险效应。根据APOE e4状态对受试者进行分层，其遗传效应在APOE e4阴性亚组中仍然显著。在女性中检测到CYP11A1多态性（rs2279357，rs2073475）与AD风险之间的关联，但在男性中未检测到。进一步的基因水平分析证实了ESR2和CYP11A1之间的上述关联，和路径水平分析强调了雌激素代谢途径对疾病易感性的遗传效应（置换路径水平P = 0.03）。结论：与先前的生物学研究结果一致，在中枢神经系统中的性类固醇激素，雌激素代谢途径的遗传改变被揭示在中国人群中。在一个独立的人群中证实这些研究结果是必要的，以阐明疾病的发病机制，并探讨激素治疗AD的潜力。
OBJECTIVES: To investigate whether genetic variations on the estrogen metabolic pathway would be associated with risk of Alzheimer's disease (AD).DESIGN: Cross-sectional study.SETTING: Individuals were recruited at the Memory Clinic, Queen Mary Hospital, Hong Kong.PARTICIPANTS: Chinese individuals with (n = 426) and without (n = 350) AD.MEASUREMENTS: All subjects underwent a standardized cognitive assessment and genotyping of four candidate genes on the estrogen metabolic pathway (estrogen receptor a gene (ESR1), estrogen receptor b gene (ESR2), cytochrome P450 19A1 gene (CYP19A1), cytochrome P450 11A1 gene (CYP11A1)).RESULTS: Apart from consistent results showing an association between apolipoprotein (APO) E and AD, strong evidence of disease associations were found for polymorphisms in ESR2 and CYP11A1 based on the entire data set. For ESR2, significant protective effects were found for A alleles of rs4986938 (permuted P =.02) and rs867443 (permuted P =.02). For CYP11A1, significant risk effects were found for G alleles of rs11638442 (permuted P =.03) and rs11632698 (permuted P =.03). Stratifying subjects according to APOE e4 status, their genetic effects continued to be significant in the APOE e4-negative subgroup. Associations between CYP11A1 polymorphisms (rs2279357, rs2073475) and risk of AD were detected in women but not men. Further gene-level analysis confirmed the above association between ESR2 and CYP11A1, and pathway-level analysis highlighted the genetic effect of the estrogen metabolic pathway on disease susceptibility (permuted pathway-level P =.03).CONCLUSION: Consistent with previous biological findings for sex steroid hormones in the central nervous system, genetic alterations on the estrogen metabolic pathway were revealed in the Chinese population. Confirmation of these present findings in an independent population is warranted to elucidate disease pathogenesis and to explore the potential of hormone therapy in the treatment of AD.