CHRNA7基因多型性與乙醯膽鹼酶抑制劑於阿茲海默症認知療效之關聯性研究

Abstract

背景.乙醯膽鹼酶抑制劑(acetylcholinesterase inhibitor)為目前阿茲海默症之主要治療藥物，但其價錢昂貴，且只有部份療效。CHRNA7基因負責轉譯神經細胞上的α7尼古丁乙醯膽鹼接受器(α7nAChR)，在此類藥物作用相關的膽鹼性神經傳導以及神經保護機制，扮演重要的角色。其中，galantamine (一種乙醯膽鹼酶抑制劑)具有正向異位調控α7尼古丁乙醯膽鹼接受器的功能。因此，本研究旨在探討CHRNA7基因多型性與乙醯膽鹼酶抑制劑認知療效之關聯，及探討此影響是否會因不同種類之乙醯膽鹼酶抑制劑而有所差異。因尼古丁也會作用在α7尼古丁乙醯膽鹼接受器，本研究進一步探討上述基因的影響和吸菸/二手菸暴露是否有交互作用。 方法.自2007到2010年間，共233位使用乙醯膽鹼酶抑制劑的阿茲海默症患者，從三間教學醫院的神經科門診收案。本研究總共挑選9個常見的(頻率>5%) haplotype-tagging單一核苷酸多型性(htSNP)。對乙醯膽鹼酶抑制劑治療的認知反應者 (cognitive responder)定義為用藥六個月後比用藥前的簡易智能狀態測驗(MMSE)分數上升(含)兩分以上。本研究為觀察性的世代追蹤研究，藉由病歷回顧記錄用藥史及簡易智能狀態測驗分數。統計分析使用羅吉斯迴歸。 結果. 研究結果顯示：女性阿茲海默症患者若帶有變異的CHRNA7 rs8024987對偶基因，較可能會是乙醯膽鹼酶抑制劑的反應者[1 or 2 vs. 0 copies: adjusted odds ratio (AOR), 2.92; 95% CI, 1.24-6.88, 性別pinteraction=0.03]，經多重檢定校正後仍然顯著。該模式於ROC curve 下的c-statistic為0.73 (95% CI, 0.64-0.82)。帶有第一個單倍體區塊中GG單倍體(haplotype)的女性患者，也較可能為反應者[AOR, 2.59; 95% CI, 1.10-6.07]。帶有rs8024987對偶基因變異的女性，有14倍的機率會是galantamine的反應者。rs8024987對偶基因變異和尼古丁暴露病史對於乙醯膽鹼酶抑制劑的療效無顯著交互作用(p interaction=0.73)，但rs8024987對偶基因變異對於認知反應的影響在有尼古丁暴露的女性更為顯著[1 or 2 v.s. 0 copies:AOR, 7.42]，相較之下此基因變異對無尼古丁暴露史女性的療效影響較小[AOR, 3.71] 。 結論.此研究首度發現女性阿茲海默症患者，其CHRNA7 rs8024987多型性與乙醯膽鹼酶抑制劑六個月的認知反應有關，尤其對 galantamine使用者。此關係與性別有顯著交互作用，亦會受到尼古丁暴露之影響。本研究可提供未來進行個人化治療的基礎。

Background. Acetylcholinesterase inhibitors (AChEI) are the mainstay treatment for Alzheimer’s disease (AD) but with high cost and moderate efficacy. CHRNA7 gene encodes the α7 subunit of nicotinic acetylcholine receptor (nAChR), which is important in the cholinergic neurotransmission and neuroprotection pathway by AChEI. Among different types of AChEI, galantamine is also a positive allosteric modulator of nAChR. This study aimed to investigate the effect of CHRNA7 polymorphisms on AChEI cognitive response, and whether the effect differs among AChEI types. Since nicotine is known to act on α7nAChR, we also explored how smoking or second-hand-smoke modifies this association. Methods. A total of 233 mild to moderate AD patients, who received AChEI, were recruited from the neurology clinics of three hospitals from 2007 to 2010. Nine common (frequency > 5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in CHRNA7 were genotyped. Cognitive responders to AChEI were defined as the improvement of Mini-Mental State Examination (MMSE) score greater or equal to two points between baseline and 6 months. This is an observational study, and data on AChEI use and MMSE scores was collected longitudinally through chart review. The statistical analysis was conducted by using logistic regression. Results. Among AD women, variant carriers of CHRNA7 rs8024987 were associated with better response to AChEI as compared to non-carriers [1 or 2 v.s. 0 copies: adjusted odds ratio (AOR)=2.92, 95% confidence interval (CI)=1.24-6.88; p interaction for sex=0.03]. The c-statistic of the multivariate receiver operating characteristic (ROC) curve was 0.73 (95% CI=0.64-0.82). GG haplotype in block one was also associated with better response (AOR=2.59, 95% CI=1.10-6.07). Women carrying rs8024987 variant were 14 times more likely to be responders to galantamine. No significant interaction was observed between nicotine exposure and rs8024987 (p interaction=0.73).The association became more evident for women carrying rs8024987 variant and had nicotine exposure(1 vs. 0 copies: AOR= 7.42; 2 vs. 0 copies: AOR=3.71] as compared to women with the same genotype but without nicotine exposure. Conclusion. This study, for the first time, found a significant association between CHRNA7 variant and better cognitive response to AChEI in AD women. The association was especially evident for galantamine. However, this finding should be interpreted carefully because of small sample size. Our findings lend credence to the future of personalized treatment.