Association of CHAT Gene Polymorphism rs3793790 and rs2177370 with Donepezil Response and the Risk of Alzheimer’s Disease Continuum

Abstract

Background

Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer’s disease continuum (ADC).

Objective

This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.

Material and Methods

According to 2018 National Institute on Aging and Alzheimer’s Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ– patients using a logistic regression analysis.

Results

The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64–28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28–4.95).

Conclusion

The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.

Keywords:

• Alzheimer’s disease
• pharmacogenomics
• variant
• gene
• donepezil

Acknowledgments

An unauthorized version of the Chinese MMSE was used by the study team without permission, this issue was rectified between the authors and PAR. The MMSE is a copyrighted instrument and may not be used or reproduced in whole or in part, in any form or language, or by any means without written permission of PAR. This work was supported by the Chinese PLA General Hospital, Beijing, China (XYZ-202108). We sincerely appreciate all participants for their contributions to this study.

Disclosure

All authors declare no conflicts of interest in this work.

Additional information

Funding

This study received grants from the National Clinical Research Center for Geriatric Diseases (NCRCG-PLAGH-2022002), the program of the Health Bureau of Military Commission Logistics Security Department (21BJZ20), and National Key Research and Development Program of China (2023YFC3605403).