Elsevier

Immunology Letters

Volume 177, September 2016, Pages 47-52
Immunology Letters

Association of interleukin-10 polymorphisms with risk factors of Alzheimer’s disease and other dementias (SADEM study)

https://doi.org/10.1016/j.imlet.2016.07.011Get rights and content

Highlights

  • This research hypothesizes possible mechanisms involved in the pathological process of dementia, as the role that IL-10 in this disease.

  • Limiting the inflammatory response could slow the development and progression of the disease.

  • These results clarify an association not only between Interleukin-10 and AD but also with other dementias in the Mexican population.

Abstract

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.

Introduction

Dementia is a chronic neurodegenerative disease characterized by visuospatial dysgnosia and memory, language, emotional, personality and complex cognition impairment [1].

The most common neuropathological hallmarks of AD are deposition of amyloid β (Aβ) in a compact structure outside the neurons, intracellular neurofibrillary tangles (NFTs) and inflammatory processes. Aβ is derived from the amyloid precursor protein (APP) by processing enzymes (α-, β- and γ-secretases). These altered proteins are deposited as extracellular plaques called senile plaques [2].

Other theories have also been described to illustrate the role of inflammation in actively contributing to the progression of the disease [3]. It is often assumed that the accumulation of Aβ in the brain results in the development of systemic inflammatory reactions by prompting immune responses. The increase in secretion has been shown to be beneficial [4], but sometimes also detrimental [6], [7], [8], [9] for the neuronal network, depending on variables such as cytokine concentration, brain region, target cell and developmental stage.

Interleukin-10 (IL-10), a potent anti-inflammatory T cell cytokine, has been proposed to protect against atherosclerosis formation [5], [6]. IL-10 is thought to be involved in the down-regulation of cytotoxic inflammatory responses by down-regulating the synthesis of pro-inflammatory cytokines, such as IL-1, IL-6 and tumor necrosis factor alpha (TNF-a) [7]. IL-10 gene is located in the human chromosome 1, at the junction of 1q31 and 1q32 [8], and its expression is regulated in part by the single nucleotide polymorphisms (SNPs) at the promoter region of IL-10 [9]. Several studies have shown the haplotypes of 3 SNPs −1082G/A (rs1800896), −829C/T(rs1800871) and −592C/A (rs1800872) are associated with the serum levels of IL-10 in Caucasians [10], [11].

Regarding the associations between IL-10 gene polymorphisms and dementia, study results are still controversial. Several lines of studies have reported that the genotypes or haplotypes of IL-10 gene, which mediate high IL-10 production, are associated with decreased risk for Alzheimer’s disease (AD) [12], [13]. 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]. A total of 406 German AD patients and 251 non-demented control subjects were investigated for the presence of three polymorphisms in the IL-10 promoter region (−1087A/G, −824C/T, −597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms was found between AD patients and controls [17]. In another study in Seattle, the IL-10 −1082 and IL-10 −592 allele and genotype frequencies were not significantly different between cases and controls [18]. Furthermore, the genotype distribution of IL-10 polymorphisms resulted as different between Caucasians and Asians [9], [19], [20], [21].

Also, the risk factors of dementia and these polymorphisms have not been studied; therefore, the purpose of this study was to investigate the associations between vascular risk factors of dementia, such as body mass index (BMI), obesity, dyslipidemia heart disease and cigarette smoke, and the promoter region polymorphisms of IL-10 gene (–1082 A/G, −819 T/C and −592 A/C) in elderly Mexican population.

Section snippets

Patients and controls

Data of the present study were retrieved from the “Study on aging and dementia in Mexico (SADEM)”. This was conducted between September 2009 to March 2010, with 3105 individuals aged 60 years old or more, that were chosen through a random sampling of eligible people ranging from 60 years old or more attached to the 24 family medicine units from the IMSS (Instituto Mexicano del Seguro Social), encompassing all Mexico City. The subjects represent a random sample of the population of adults aged

General characteristics of the study population

A total of 1184 participants (986 controls and 221 cases divided as follows: 122 with AD, 67 with VaD and 32 with AD/VaD) completed this case-control study. Table 1 shows the demographic and clinical profile of the controls and the patients with AD, VaD and AD/VaD. There was significant difference in the mean age group of AD (76.9 ± 8.3), VaD (77.2 ± 7.4) or AD/VaD (76.1 ± 8.0) in comparison to the control subjects (71.7 ± 7.8), with p < 0.001. However, there was a relatively low percentage of males in

Discussion

The present study has shed light on epidemiological and genetic aspects of 3 predominant dementias, AD, VaD and AD/VaD, clinically diagnosed in Mexican population. Evidences indicate that neuroinflammation and cytokines appear to play a critical role in the development of dementia. IL-10, an important cytokine, has an anti-inflammatory role in the brain and may be involved in the pathogenesis of dementia or AD. Therefore, any imbalance in the production of these cytokines may lead to disease

Conflicts of interest

There are no competing financial interests in this study.

Acknowledgment

This study was supported by grants from SEP-CONACYT CB-2012-01-183700 (México).

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