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

Zheng Zhu, Yang Yang, Zhenxu Xiao, Qianhua Zhao, Wanqing Wu, Xiaoniu Liang, Jianfeng Luo, Yang Cao, Minhua Shao, Qihao Guo, Ding Ding

Aging clinical and experimental research 2021 Jun

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

Citation

Zheng Zhu, Yang Yang, Zhenxu Xiao, Qianhua Zhao, Wanqing Wu, Xiaoniu Liang, Jianfeng Luo, Yang Cao, Minhua Shao, Qihao Guo, Ding Ding. TOMM40 and APOE variants synergistically increase the risk of Alzheimer's disease in a Chinese population. Aging clinical and experimental research. 2021 Jun;33(6):1667-1675