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Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer’s disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer’s disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I β chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.

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Acknowledgments

We are extremely grateful to the participation of the patients with AD and healthy volunteers in this study.

Funding

This study was supported by a research grant from Tehran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Rezaei Rad, Shiva Bayat & Mahdi Zamani

  2. Children Medical Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Masood Ghahvechi Akbari

  3. Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Majid Zamani

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  1. Fatemeh Rezaei Rad
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  2. Masood Ghahvechi Akbari
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  3. Majid Zamani
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  4. Shiva Bayat
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Contributions

Fatemeh Rezaei Rad: conceptualization, methodology, formal analysis, writing—original draft, visualization. Masood Ghahvechi Akbari: writing—review and editing. Majid Zamani: methodology, software, form analysis, resources, writing. Mahdi Zamani: conceptualization, methodology, resources, investigation, writing—review and editing, supervision, project administration, funding acquisition.

Corresponding author

Correspondence to Mahdi Zamani.

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This study was certified by the ethics committee and review board of the Tehran University of Medical Sciences.

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The authors declare that they have no conflict of interest.

Research Involving Human Participants and Informed Consent

Questionnaire forms were prepared for each patient and control individuals. Before being included in the study, informed consent was taken from all the patients, or their legal guardians and control subjects.

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All study participants, or their legal guardian, provided informed written consent for publication.

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Rezaei Rad, F., Ghahvechi Akbari, M., Zamani, M. et al. Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer’s Disease. Mol Neurobiol 58, 2792–2802 (2021). https://doi.org/10.1007/s12035-021-02295-z

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