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TOMM40 and APOE variants synergistically increase the risk of Alzheimer’s disease in a Chinese population

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Abstract

Background

The apolipoprotein E (APOE) ε4 allele is a strong risk factor for Alzheimer’s disease (AD) in Caucasian and African American populations. It suggests that other genetic factors may modulate AD pathogenesis in Chinese populations, among which the frequency of this allele is reduced but the AD prevalence is maintained. The translocase of outer mitochondrial membrane 40 (TOMM40), which is located adjacent to APOE, may play an APOE-dependent role in modulating AD pathogenesis.

Aims

This work aimed to investigate whether TOMM40 polymorphisms modulate AD risk independently of, or in conjunction with APOE polymorphisms in Chinese populations.

Methods

We conducted a case–control study including 834 patients with AD recruited from the Memory Clinic and 643 cognitively normal participants recruited from the community. The Taqman SNP method was used for APOE genotyping, while TOMM40 polymorphism genotyping was conducted via a polymerase chain reaction-ligase detection reaction.

Results

The TOMM40 rs10119 and rs71352238 alleles were associated with AD independently of the patient APOE status. The rs10119 AA genotype and rs71352238 CC genotype were risk genotypes of AD. Individuals carrying a TOMM40 rs10119 GG/APOE ε4+ (OR, 3.73; 95% CI 1.49-9.37; P = 0.005), TOMM40 rs10119 AG/APOE ε4+ (OR, 4.16; 95% CI 3.30-5.24; P < 0.001), or TOMM40 rs10119 AA/APOE ε4+ (OR, 14.78; 95% CI 8.56-25.54; P < 0.001) genotype exhibited a significantly higher AD risk. Those carrying a TOMM40 rs71352238 TT/APOE ε4+ (OR, 3.82; 95% CI 2.32-6.29; P < 0.001), TOMM40 rs71352238 CT/APOE ε4+ (OR, 4.40; 95% CI 3.46-5.56; P < 0.001), or TOMM40 rs71352238 CC/APOE ε4+ (OR, 14.02; 95% CI 7.81-25.17; P < 0.001) genotype also exhibited a significantly increased AD risk.

Discussion and conclusions

This study provides invaluable insights into the mechanisms underlying the prevalence of AD in Chinese populations, and supports that simultaneous TOMM40 and APOE genotyping in the clinical setting may identify individuals at high risk of developing AD.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

The authors thank all the study coordinators, research nurses, psychometrists, and lab technicians for their efforts to this study, and all the participants for their cooperation.

Funding

This work was supported by grants of National Natural Science Foundation of China (81773513), Scientific Research Projects from Shanghai Science and Technology Municipality (STCSM) (17411950106, 17411950701), Shanghai Brain-Intelligence Project from STCSM (16JC1420500), Natural Science Foundation and Major Basic Research Program of Shanghai (16JC1420100), National Chronic Disease Project (2016YFC1306402), STCSM Major Project (2018SHZDZX01), ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University.

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Author notes

  1. Zheng Zhu and Yang Yang contributed equally to this work.

Authors and Affiliations

  1. Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Zheng Zhu, Zhenxu Xiao, Qianhua Zhao, Wanqing Wu, Xiaoniu Liang, Qihao Guo & Ding Ding

  2. National Clinical Research Center for Aging Diseases, Shanghai, China

    Zheng Zhu, Zhenxu Xiao, Qianhua Zhao, Wanqing Wu, Xiaoniu Liang, Qihao Guo & Ding Ding

  3. Guanghan Personal Health Research Institute, Shanghai, China

    Yang Yang & Minhua Shao

  4. Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China

    Jianfeng Luo

  5. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden

    Yang Cao

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  1. Zheng Zhu
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Contributions

QZ and DD conceived and designed the project. QZ, ZX, WW, XL, QG recruited patients and collected samples from patients and healthy controls. ZZ, YY, QZ, MS, and DD conceived and decided the experiments, and revised the manuscript. ZZ and YY performed the experiments and wrote the manuscript. ZX assisted literature searching and manuscript formatting. YY, JL and YC provided analyzing genomic data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qianhua Zhao.

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All subjects (or their legal guardians) provided written informed consent for their participation in the study, which was approved by the Medical Ethics Committee of Huashan Hospital, Fudan University, Shanghai, China.

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Zhu, Z., Yang, Y., Xiao, Z. et al. TOMM40 and APOE variants synergistically increase the risk of Alzheimer’s disease in a Chinese population. Aging Clin Exp Res 33, 1667–1675 (2021). https://doi.org/10.1007/s40520-020-01661-6

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