Lack of Association between Tumour Necrosis Factor Receptor Superfamily Gene Polymorphisms and the Risk of Alzheimer's Disease in a Chinese Population

Abstract Objective: To investigate the association of polymorphisms in the tumour necrosis factor receptor 2 (TNFR2) and tumour necrosis factor superfamily, member 6 (TNFRSF6, FAS) genes and the risk of Alzheimer's disease (AD) in a Chinese population. Patients and Methods: One hundred and fifty Chinese AD patients and 155 cognitively intact control subjects were recruited for the study. Genotypes of TNFR2+196, FAS-670, and FAS-1377 were investigated in this study by polymerase chain reaction-restriction fragment length polymorphisms. Results: The TNFR2+196 TT genotype was more prevalent in the AD group than in the controls. However, no significant difference in genotypic and allelic frequencies between AD and control groups (p = 0.68) was observed. Conclusion: We suggested that TNFR2+196, FAS-670, and FAS-1377 genotypes were not associated with the risk of AD in our Chinese population. However, evidence suggests involvement of tumour necrosis factor-alpha pathway in the pathogenesis of AD and a more comprehensive study may be required to identify the underlying associations. Key words: Alzheimer disease; Genetic predisposition to disease; Polymorphism, genetic; Receptors, tumor necrosis factor [TEXT NOT REPRODUCIBLE IN ASCII] Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by the deposition of amyloid plaques and the formation of neurofibrillary tangles. Mutations in genes like amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) were suggested as causal for familial early-onset type of AD, which only contributes to about 5% of all AD cases. (1) For the sporadic-type AD, both genetic and environmental factors may be involved in its aetiology. (1) Several hypotheses for the pathogenesis of AD have been proposed, including the amyloid cascade, (2) axonal transport dysfunction, (3) cholesterol and apolipoprotein E (ApoE), (4) and inflammation. (5,6) Increased levels of tumour necrosis factor alpha (TNF[alpha]) were observed in AD patients (7) and Collins et al (8) reported that the TNF[alpha] haplotype (TNF-308, TNF-238, and TNFa) was associated with AD in Caucasians. However, TNF-238 polymorphism is absent in the Chinese population (9) and so we selected another 3 single nucleotide polymorphisms (SNPs) for this genetic association study. Our previous findings showed that TNF[alpha] polymorphisms (TNF-857, TNF-863, and TNF-1031) were associated with the risk of AD. (10) Therefore, genes related to the TNF[alpha] pathway might be implicated in the pathogenesis of AD. The biological effects of TNF are mediated by binding to its 2 main receptors, TNFR1 (p55 TNF receptor) and TNFR2 (p75 TNF receptor). TNFR2 is localised on chromosome 1p36.2 and has a higher affinity for TNF than TNFR1. It is widely expressed in the brain and is responsible for proinflammatory response signalling. (11) Since TNFR2 is the major receptor for TNF[alpha], polymorphisms in this receptor may affect the binding of TNF[alpha] and the downstream pathway involved in inflammation. The TNF superfamily, member 6 (TNFRSF6, FAS) encodes the Fas receptor, which is important in signal transduction that leads to apoptosis. In addition, the FAS pathway is an important mediator of amyloid-[beta]-induced neuronal death. (12) Increased levels of FAS protein have been reported in the brain, (13) serum, (14) and cerebrospinal fluid (15) of AD patients. Such evidence suggests that the TNF signalling / pathway may be important in the pathogenesis of AD and members of the pathway might be implicated in the disease. Tumour necrosis factor family of receptors orchestrates many aspects of immune cell function, including lymphoid organ development, acute inflammation, and lymphocyte co-stimulation. (16) Association of TNFR2 polymorphisms has been reported in diseases related to chronic inflammation such as rheumatoid arthritis, (17) Crohn's disease, (18) and systemic lupus erythematosus. …