TY - JOUR
T1 - Genetic Polymorphisms in Estrogen Metabolic Pathway Associated with Risks of Alzheimer's Disease
T2 - Evidence from a Southern Chinese Population
AU - Chen, Lu Hua
AU - Fan, Yan Hui
AU - Kao, Patrick Yu Ping
AU - Ho, Deborah Tip Yin
AU - Ha, Joyce Cheuk Tung
AU - Chu, Leung Wing
AU - Song, You Qiang
N1 - Funding Information:
We would like to thank Dr. Chen Li Liu and Ms. Yuk Kuen Woo for their help in solving technical problems and valuable suggestions for the procedures of the experiment. We would also like to thank Mr. Paul Fraley for his time, efforts, and suggestions in editing. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that none of the authors has any financial or any other kind of personal conflicts with this study. This study was funded by Grant 81271226 from the National Natural Science Foundation of China to Dr. You-Qiang Song. Author Contributions: Chu, Song: study concept and design, drafting the manuscript. Chen: performing the experiment, statistical analysis, interpretation of data, writing the manuscript. Ho, Ha: performing the experiment, data collection. Fan, Kao: statistical analysis. Sponsor's Role: The funding source was not involved in the study design; data collection, analysis, or interpretation; or in the decision to submit the manuscript for publication.
Publisher Copyright:
© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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 α gene (ESR1), estrogen receptor β 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 ε4 status, their genetic effects continued to be significant in the APOE ε4-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.
AB - 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 α gene (ESR1), estrogen receptor β 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 ε4 status, their genetic effects continued to be significant in the APOE ε4-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.
KW - Alzheimer's disease
KW - estrogen metabolic pathway
KW - polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85012867349&partnerID=8YFLogxK
U2 - 10.1111/jgs.14537
DO - 10.1111/jgs.14537
M3 - Journal article
C2 - 28102888
AN - SCOPUS:85012867349
SN - 0002-8614
VL - 65
SP - 332
EP - 339
JO - Journal of the American Geriatrics Society
JF - Journal of the American Geriatrics Society
IS - 2
ER -