Association of interleukin-1 gene polymorphisms with Alzheimer's disease

Autor: Lilian S. Murray, Deborah Dewar, Sian H MacGowan, David I. Graham, W. Sue T. Griffin, James A. R. Nicoll, Tim Moss, Seth Love, Robert E. Mrak, Gordon K. Wilcock, Janice Stewart, Margaret M. Esiri
Rok vydání: 2000
Předmět:
Zdroj: Annals of Neurology. 47:365-368
ISSN: 1531-8249
0364-5134
DOI: 10.1002/1531-8249(200003)47:3<365::aid-ana13>3.0.co;2-g
Popis: Alzheimer’s disease (AD), the most common cause of dementia, is estimated to affect 5% of those more than 65 years of age and 40% of those more than 80 years of age, or a total of approximately 20 million people worldwide. The neuropathological characteristics of AD include (β-amyloid plaques that are diagnostic when associated with dystrophic neurites,1 neurofibrillary tangles, loss of neurons and synapses, and proliferation of glial cells. There has been substantial progress, in the last few years, in unraveling the genetic influences in AD. A small proportion of AD cases are inherited as an autosomal dominant trait and are attributable to point mutations in genes that encode the β-amyloid precursor protein (βAPP),2 presenilin 1,3 or presenilin 2.4 A major genetic risk factor for the much more common sporadic AD is possession of the apolipoprotein E (ApoE) e4 allele.5 However, possession of ApoE e4 is neither necessary nor sufficient for the development of AD, leaving scope for other potential genetic or environmental influences. Interleukin-1 (IL-1) is a potent proinflammatory cytokine that is markedly overexpressed in the brains of patients with AD, predominantly in microglia,6 which suggests a role for inflammatory processes in AD pathogenesis.7 This idea has received support from epidemiological studies that show that the use of anti-inflammatory agents, in particular nonsteroidal anti-inflammatory drugs, is associated with delayed onset or slowed progression of disease.8 IL-1 has two structurally distinct forms, IL-1α and IL-1β, encoded by separate genes (IL-1A and IL-1B, respectively) located in a cluster on the long arm of chromosome 2 that also includes the IL-1 receptor antagonist gene.9 Common polymorphisms have been described in both genes and there is evidence that they have functional significance. A polymorphism of the IL-1B gene (+3953), for instance, which introduces a TaqI restriction site, results in two alleles, designated allele 1 and allele 2.10 Homozygosity for allele 2 of IL-1B is associated with a fourfold increase in production of IL-1β compared with homozygosity for allele 1.10 A polymorphism in the 5′ regulatory region of the IL-1A gene (a C-to-T transition at position −889 relative to the start site of transcription) again results in two alleles, also designated allele 1 and allele 2.11 Both of these IL-1 polymorphisms have been associated with inflammatory diseases. For instance, IL-1A allele 2 has been associated with juvenile rheumatoid arthritis.11 In view of the evidence that suggests a role for inflammatory processes, and for IL-1 in particular in AD, we hypothesized that these IL-1 polymorphisms modulate susceptibility to AD.
Databáze: OpenAIRE
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