Association of an interleukin 1 alpha polymorphism with Alzheimer's disease [see Comments]

Departments of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Neurology (Impact Factor: 8.29). 09/2000; 55(4):480-3. DOI: 10.1212/WNL.55.4.480
Source: PubMed


Retrospective epidemiologic studies suggest that individuals exposed to anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs have a lower probability of developing AD as well as an older age at onset for the illness. Neuroinflammation may play an important role in the pathogenesis of AD. Interleukin 1 (IL-1), a potent proinflammatory cytokine, is colocalized immunohistochemically to neuritic plaques, a requisite neuropathologic feature for AD. A polymorphism in the 5'-flanking regulatory region at -889 of the IL-1 alpha gene (a C-to-T transition designated as IL-1A[-889] allele 2) may cause an overexpression of IL-1 alpha, a finding shown to be associated with inflammatory diseases. The IL-1A(-889) allele 2 polymorphism may be associated with AD pathogenesis.
A total of 259 patients with AD and 192 nondemented control subjects were included from two different centers (Indianapolis, IN, and Munich, Germany). Genotyping for APOE alleles and IL-1A(-889) allele 2 was performed by PCR-based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by center-, gender group-, and age group-stratified Mantel-Haenszel odds ratios, CI, and p values.
The allele frequency of IL-1A(-889) allele 2 was 46% in clinically diagnosed patients with probable AD versus 34% in control subjects from the combined centers.
The authors found an increased risk for AD with an estimated Mantel-Haenszel odds ratio of 1.68 (95% CI 1.1 to 2.6; p = 0.022) for heterozygous carriers and 7.2 (95% CI 2.0 to 24.5; p = 0.003) for individuals homozygous for IL-1A(-889) allele 2. They found no evidence for an interaction between the IL-1A and the apoE epsilon 4 polymorphisms (carriers and homozygotes), age, or gender with regard to conferred risk. The data strongly support an association between the IL-1A(-889) allele 2, especially in homozygotes, and later-onset AD.

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    • "Interactions of variations in genes relevant to inflammation, such as the PPAR and IL genes, may be reasonable candidates that may influence the course of AD. They are not only supported by pathophysiological evidence, as indicated above, but also by previous genetic association studies: (1) Associations of the PPARA L162V polymorphism with the risk of AD have been observed [14]; (2) Polymorphisms in IL1A gene have been associated with the risk [15] [16] and age-at-onset of AD [17]; however, this has not been confirmed by others [18] [19] [20] [21]; (3) Variations in IL1B have been found to be associated with AD [22] [21]; again this result is not unopposed [18]; (4) Bagli et al. [23] reported that polymorphisms of the gene encoding the inflammatory cytokine, IL-6, were related to soluble interleukin-6 receptor levels in AD; (5) Associations between polymorphisms in the IL6 gene and its promoter may influence the risk of AD [24] (6) A genetic variation of the inflammatory cytokine gene IL6, delayed the onset and reduced the risk of sporadic AD [25]; (7) A recent meta-analysis suggested that a the structure of linkage disequilibrium of the three in PPARA. Of the six SNPs shown in Table 1, only PPARA L162V was independently associated with AD: odds ratio for LL vs VL+VV = 1.3 (95% confidence interval: 1.04 – 1.5, p = 0.02), as previously reported [31]. "
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    ABSTRACT: Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk. The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided). We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.
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    • "Although not as strongly associated with AD risk as possession of ApoE4 sequences, specific polymorphisms in the genes encoding IL-1α and IL-1β are also associated with increased AD risk. Specifically, variations in the promoter region of IL1A and in the coding region of IL1B influence AD risk when homozygous in one gene or heterozygous in both [9-13]. Glial activation marked by excess production of both IL-1α and β is a constant feature in several conditions associated with increased risk for precocious development of AD: i) traumatic brain injury (TBI) [14], ii) systemic viral disease, e.g., AIDS [15]; iii) the neuronal hyperexcitability of epilepsy [16-19]; iv) chromosome 21 anomalies such as Down's syndrome [20]; and v) advancing age [21-23]. "
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    ABSTRACT: We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), β-amyloid precursor protein (βAPP), and fragments of the latter such as amyloid β-peptide (Aβ) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele. Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1β slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1β, glutamate, Aβ, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1β, Aβ, sAPP, or glutamate. Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1β induces expression of βAPP, IL-1α, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1β, IL-1β-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1β also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Aβ--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1β on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK. Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, βAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.
    Journal of Neuroinflammation 12/2011; 8(1):175. DOI:10.1186/1742-2094-8-175 · 5.41 Impact Factor
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    • "Other genes that could be considered to have a potential relevance in the risk for AD are genetic variants involved in inflammation. Notably, interleukins (IL1A, IL1B, and IL6) are one of the strongest evidence of inflammatory agents that increase the risk of AD and significant polymorphisms are implicated in AD as demonstrated in several case/control studies [44]. It is widely accepted that genetic variation is important for the pathogenesis of AD and several researchers have tried to find out polymorphisms that may be related with it but convincing outcomes have not emerged yet. "
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    Immunity & Ageing 09/2011; 8(1):7. DOI:10.1186/1742-4933-8-7 · 3.54 Impact Factor
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