Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease
1 Centre of Excellence for Alzheimer's Disease Research and Care, Faculty of Computing, Health and Science, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup Drive, Joondalup, 6027, WA, Australia
2 Sir James McCusker Alzheimer's Disease Research Unit, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Hollywood Private Hospital, Nedlands, 6009, WA, Australia
3 Mount Sinai School of Medicine, New York, New York, 10029, USA
4 Prince of Wales Medical Research Institute, UNSW, Barker Street, Randwick, NSW 2031, Australia
5 Centre for Education and Research on Aging, University of Sydney and Concord Repatriation General Hospital, Concord, NSW, 2139, Australia
6 School of Surgery and Pathology, University of Western Australia, Nedlands, Australia
7 Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, WA, 6000, Australia
8 Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
9 Department of Genetics, and Center for Narcolepsy, Department of Psychiatry, Stanford University, Stanford, CA, 94305, USA
Journal of Neuroinflammation 2008, 5:36 doi:10.1186/1742-2094-5-36Published: 20 August 2008
Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.
Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE ε4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.
APOE ε4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE ε4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.
These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.