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Genetic Association of HLA Gene Variants with MRI Brain Structure in Alzheimer’s Disease

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Abstract

There is accumulating evidence that the human leukocyte antigen (HLA) gene variants are associated with Alzheimer’s disease (AD). However, how they affect AD occurrence is still unknown. In this study, we firstly investigated the association of gene variants in HLA gene variants and brain structures on MRI in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA on AD pathogenesis. We selected hippocampus, hippocampus CA1 subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). According to the previous association studies of HLA variants and AD, 12 SNPs in HLA were identified in the dataset following quality control measures. In total group analysis, our results showed that TNF-α SNPs at rs2534672 and rs2395488 were significantly positively associated with the volume of the left middle temporal lobe (rs2534672: P = 0.00035, Pc = 0.004; rs2395488: P = 0.0038, Pc = 0.023) at baseline. In the longitudinal study, HFE rs1800562 was remarkably correlated with the lower atrophy rate of right middle temporal lobe (P = 0.0003, Pc = 0.003) and RAGE rs2070600 was associated with the atrophy rate of right hippocampus substructure-CA1 over 2 years (P = 0.003, Pc = 0.035). Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subgroup analysis, as well as the association of rs2534672 with the baseline volume of the left middle temporal lobe in normal cognition (NC) subgroup analysis. Our study provided preliminary evidences that HLA gene variants might participate in the structural alteration of AD associated brain regions, hence modulating the susceptibility of AD.

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Acknowledgments

Data collection and sharing were funded by ADNI (National Institutes of Health U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, BioClinica, Inc., Biogen Idec Inc., Bristol-Myers Squibb Co, F. Hoffmann-LaRoche Ltd and Genetech, Inc., GE Healthcare, Innogenetics, NV, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Medpace, Inc., Merck & Co, Inc., Meso Scale Diagnostics, LLC, NeuroRx Research, Novartis Pharmaceuticals, Co, Pfizer, Inc., Piramal Imaging, Servier, Synarc Inc., and Takeda Pharmaceutical Co. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization was the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles.

This work was also supported by grants from the National Natural Science Foundation of China (81471309, 81171209, 81371406, 81501103, and 81571245), the Shandong Provincial Outstanding Medical Academic Professional Program, Qingdao Key Health Discipline Development Fund, Qingdao Outstanding Health Professional Development Fund, and Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders.

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    1. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China

      Zi-Xuan Wang, Yu Wan, Fu-Rong Sun, Meng-Shan Tan, Chen-Chen Tan, Lan Tan & Jin-Tai Yu

    2. College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, 266000, China

      Lin Tan & Lan Tan

    3. Columbia College, Columbia University, New York, NY, USA

      Jinyuan Liu

    4. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China

      Hui-Fu Wang

    5. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

      Teng Jiang

    6. Memory and Aging Center, Department of Neurology, University of California, 675 Nelson Rising Lane, Suite 190, Box 1207, San Francisco, CA, 94158, USA

      Jin-Tai Yu

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    Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

    Zi-Xuan Wang and Yu Wan contributed equally to this work.

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    Wang, ZX., Wan, Y., Tan, L. et al. Genetic Association of HLA Gene Variants with MRI Brain Structure in Alzheimer’s Disease. Mol Neurobiol 54, 3195–3204 (2017). https://doi.org/10.1007/s12035-016-9889-z

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