Promoter haplotypes of interleukin-10 gene and sporadic Alzheimer's disease

doi:10.1016/j.neulet.2003.11.033

Neuroscience Letters

Volume 356, Issue 2, 12 February 2004, Pages 119-122

https://doi.org/10.1016/j.neulet.2003.11.033 Get rights and content

Abstract

Clinical and immunopathological evidence support a potential role of the pro- and anti-inflammatory cytokine network in neurodegeneration of Alzheimer's disease (AD). Moreover, association studies suggest a possible involvement of cytokine-related genes in the susceptibility to sporadic AD. Since conflicting results are associated with the pro-inflammatory pathway, we investigated a putative effect of the anti-inflammatory counterpart focusing on the interleukin-10 (IL-10) gene. The 5′ flanking region contains numerous polymorphisms; in particular, three single nucleotide polymorphisms (−1082 G/A, −819 T/C, −592 C/A) are in linkage disequilibrium resulting in three haplotypes GCC, ACC and ATA. We analyzed the IL-10 haplotype distributions in 215 Italian sporadic AD patients and 153 controls in an association case-control study. Haplotype frequencies did not reveal differences between the two samples, however the genotype GCC/ACC was more represented in AD patients (OR 1.91, 95% CI: 1.18–3.07). This putative risk factor could be independent of the presence of the ApoE ε4 allele. Our results provide new insights on a possible involvement of the IL-10 gene in susceptibility to sporadic AD even though further functional and genetic investigations are necessary to clarify its role in AD.

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Acknowledgements

This research was supported by grants from the Italian Ministry of Health and the CARIPLO Foundation.

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Cited by (50)

Promoter haplotypes of interleukin-10 gene linked to cortex plasticity in subjects with risk of Alzheimer's disease
2018, NeuroImage: Clinical
The Alzheimer's disease (AD) aetiologic event is associated with brain inflammatory processes. In this study, we consider a haplotype of the IL-10 gene promoter region, − 1082A/− 819 T/− 592A (ATA haplotype), which is an additive and independent genetic risk factor for AD. Episodic memory change is the most striking cognitive alteration in AD. It remains unclear whether episodic memory networks can be affected by the ATA haplotype variant in amnestic mild cognitive impairment (aMCI), and if so, how this occurs. Thirty-nine aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging. An imaging genetics approach was then utilized to investigate disease-related differences in episodic memory networks between the groups based on ATA haplotype-by-aMCI interactions. Gene-brain-behaviour relationships were then further examined. This study found that the ATA haplotype risk variant was associated with abnormal functional communications in the hippocampus-frontoparietal cortices, especially in the left hippocampal network. Moreover, these ATA haplotype carriers showed a distinct phase of hyperactivity in normal aging, with rapid declines of brain function in aMCI subjects when compared to non-ATA haplotype carriers. These findings added to the accumulating evidence that promoter haplotypes of IL-10 may be important modulators of the development of aMCI.
Association of interleukin-10 polymorphisms with risk factors of Alzheimer's disease and other dementias (SADEM study)
2016, Immunology Letters
Citation Excerpt :
For example, in 95 Chinese AD patients and 117 healthy Chinese subjects, it was found that among the Chinese population, the A and C alleles at the −592 position are strongly linked to the T and C alleles at the −819 position, respectively [14]. In 215 Italian sporadic AD patients and 153 controls in an association case-control study haplotype frequencies did not reveal differences between the two samples; however, the genotype GCC/ACC was more represented in AD patients [15]. Nevertheless, other studies have shown that these polymorphisms have opposite or neutral effects for dementia [16].
Some studies have reported a genetic association between single nucleotide polymorphisms (SNPs) in the promoter region of Interleukin (IL) 10 and Alzheimer's disease (AD), with conflicting results. To further investigate the proposed association and to clarify the role of cytokines as a potential cause for AD susceptibility, we analyzed genotypes, allele distributions and haplotypes of IL-10 promoter polymorphisms −1082 (rs1800896) and −819 (rs1800871) in a Mexican population: 986 normal controls and 221 cases divided as follows: 122 with Alzheimer disease (AD), 67 with (VaD) and 32 with mixed dementia (AD/VaD). Patients with dementia showed increased frequency of “ATA, CTG, and CTA” haplotypes when compared to controls. We identified two risk haplotypes: ATA (OR = 3.56, 95%CI = 2.84–4.45, p < 0.0001), and CTA (OR = 1.90, 95%CI = 1.38–2.62, p < 0.0001), and four protection haplotypes: ATG (OR = 0.60, 95%CI = 0.45–0.82, p = 0.0012), CTG (OR = 0.38, 95%CI = 0.23–0.62, p < 0.0001), ACG (OR = 0.01, 95%CI = 0.002–1.13, p <0.0001), and CCG (OR = 0.02, 95%CI = 0.004–0.203, p < 0.0001). In summary, this is the first study in Mexican population that considers the analysis of IL-10 in patients with AD, VaD and AD/VaD. Our results showed the relevance of the role that IL-10 plays in the pathological mechanisms that result in the development of dementia. In addition, in our study, it was possible to distinguish two protective and two risk haplotypes for the development of dementia.
Genetic polymorphisms of interleukin genes and the risk of Alzheimer's disease: An update meta-analysis
2016, Meta Gene
Recently, several meta-analyses have reported an association between interleukin (IL) gene polymorphisms and the risk of Alzheimer's disease (AD). Several further papers discussing the relationship with the risk of AD have recently been published. The aim of this meta-analysis was to re-evaluate and update the associations between IL gene polymorphisms and the risk of AD.
The search sources were PubMed, Science Direct, Scopus, and Google Scholar up to July 2015, and the following search terms were used: “interleukin 1 or interleukin 6 or interleukin 10” and “variant or polymorphism or SNP” in combination with “Alzheimer's disease”. A meta-analysis using the pooled odds ratios and 95% confidence intervals was carried out to assess the associations between four polymorphisms of IL genes (− 889C > T in IL-1α, − 511C > T in IL-1β, − 174G > C in IL-6 and − 1082G > A in IL-10) and the risk of AD under the heterozygous, homozygous, dominant, and recessive models with fixed- or random-effects models.
A total of 21,864 cases and 40,321 controls from 93 individual studies were included in this meta-analysis. Our results indicated that the − 889C > T polymorphism was strongly associated with the increased risk of AD. However, three polymorphisms were not associated with the risk of AD.
Similar to previous meta-analyses, our updated meta-analysis suggested that the − 889C > T polymorphism may be a factor in AD. However, the results of our meta-analysis of the − 174G > C polymorphism differed from those of previous meta-analyses. Consequently, we suggest that the − 174G > C polymorphism may not be a risk factor for AD.
Innate Immunity Fights Alzheimer's Disease
2015, Trends in Neurosciences
Citation Excerpt :
While proinflammatory mediators have garnered the most attention in this regard, the cardinal anti-inflammatory regulators transforming growth factor-β1 (TGF-β1) [28] and interleukin-10 (IL-10) [25] are also elevated in human AD, raising a putative pathogenic role for these cytokines. Further, a functional polymorphism within the IL10 gene has been linked to increased risk for LOAD in some [29–32], but not all populations [33–35]. While an initial report suggested that the IL10 AD risk allele was associated with reduced IL-10 expression in healthy control plasma [32], these authors did not relate IL10 polymorphism to IL-10 activity in AD patients.
Alzheimer's disease (AD) is the most common age-related dementia. Pathognomonic accumulation of cerebral β-amyloid plaques likely results from imbalanced production and removal of amyloid-β (Aβ) peptides. In AD, innate immune cells lose their ability to restrict cerebral Aβ accumulation. At least in principle, mononuclear phagocytes can be enlisted to clear Aβ/β-amyloid from the brain. While the classical focus has been on dampening neuroinflammation in the context of AD, we hypothesize that rebalancing cerebral innate immunity by inhibiting actions of key anti-inflammatory cytokines returns the brain to a physiological state. Recent experiments demonstrating beneficial effects of blocking anti-inflammatory cytokine signaling in preclinical mouse models provide supportive evidence. This concept represents an important step toward innate immune-targeted therapy to combat AD.
Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology
2015, Neuron
The impact of inflammation suppressor pathways on Alzheimer’s disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1⁺Il10^−/−). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1⁺Il10^−/− mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1⁺Il10^−/− brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that “rebalancing” innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: A meta-analysis
2011, Journal of the Neurological Sciences
Citation Excerpt :
A number of studies have reported the associations between −1082G/A polymorphism in IL-10 gene and AD risk [1,2,4,11,13,15–21], but the results were inconclusive. This polymorphism was suggested as a risk factor for AD in Italian population [21] and Chinese population [19], but not in German population [13]. This is partly due to the different genetic effects in different ethnic populations [22].
The −1082G/A polymorphism in IL-10 gene has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of IL-10 −1082G/A polymorphism and AD risk by using meta-analysis.
All eligible case-control studies were searched in Pubmed and Embase. Odds ratios (OR) with the 95% confidence intervals (CI) were used to assess the association.
A total of 2158 cases and 2088 controls in 12 case-control studies were included. The results indicated that the A allele carriers (AA + AG) had a 27% increased risk of AD, when compared with the homozygote GG (OR = 1.27, 95%CI = 1.02–1.58 for AA + AG vs. GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with A allele carriers in Europeans (OR = 1.27 and 95%CI = 1.01–1.59 for AA + AG vs. GG), but not in Asians (OR = 1.37 and 95%CI = 0.32–5.88 for AA + AG vs. GG).
This meta-analysis suggested that the −1082G/A polymorphism of IL-10 gene would be a risk factor for AD. To further evaluate gene-to-gene and gene-to-environmental interactions between polymorphisms of IL-10 gene and AD risk, more studies with large groups of patients are required.

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Promoter haplotypes of interleukin-10 gene and sporadic Alzheimer's disease

Abstract

Section snippets

Acknowledgements

Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology

Brain Res.

Association study of three polymorphisms of TGF-beta 1 gene with Alzheimer's disease

J. Neurol. Neurosurg. Psychiatry

Cytokine levels and phagocytic activity in patients with Alzheimer's disease

Gerontology

Genetic polymorphisms in the cathepsin D and interleukin-6 genes and the risk of Alzheimer's disease

Neurosci. Lett.

Association between promoter polymorphic haplotypes of interleukin-10 gene and schizophrenia

Biol. Psychiatry

New polymorphisms in the IL-10 promoter region

Genes Immun.

Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region

Genes Immun.

Inflammatory markers in Alzheimer's disease and multi-infarct dementia

Mech. Ageing Dev.

Lack of association of interleukin-10 promoter region polymorphisms with Alzheimer's disease

Neurosci. Lett.

Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa

Hepatology