Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease

Abstract

Background and aim: Inflammation has been extensively implicated in the pathogenesis of Alzheimer's disease (AD). Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine interleukin (IL)-18 has not been associated with AD. The aim of this study was to investigate the impact of two polymorphisms of the human IL-18 gene promoter at positions 2607 (C/A) and 2137 (G/C) on both susceptibility to and progression of AD. Results: The results revealed that the genotype distribution of the 2607 (C/A) polymorphism was different between patients with AD and control subjects (x 2 = 7.99, df = 2, p = 0.0184). In particular, carriers of the CC genotype were at increased risk of developing AD (OR 2.33; 95% CI 1.29 to 4.22; p = 0.0052). The observed genotypes were in Hardy-Weinberg equilibrium, as for the 2607 polymorphism, whereas the 2137 polymorphism appeared in Hardy-Weinberg disequilibrium only in the patient group (p = 0.0061). Finally, in a 2 year follow-up study, the 2137 CC genotype was strongly and specifically associated with a faster cognitive decline (F = 4.024; df = 4,192; p = 0.0037 for time by IL-18 2137 G/C group interaction) with no interaction effect with the apolipoprotein E e4/non-e4 allele presence. Conclusion: As IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…The C allele of IL-18 -137 G/C has a negative correlation with AD risk in Han Chinese [34], but the CC genotype is strongly associated with accelerated cognitive decline in Caucasians [33]. Meanwhile, the C allele of IL-18 -607 and the CC genotype are associated with increased AD risk in Han Chinese and Italian Caucasian populations, respectively [33,34]. Functional analyses have revealed that the IL-18 -607 CC genotype results in significantly elevated IL-18 production by blood mononuclear cells in AD patients [35], implying that this polymorphism exacerbates AD processes via the promotion of IL-18 secretion.…”

“…Two SNPs in the promoter region of its gene have been reported to influence AD, -137 G/C and -607 C/A. The C allele of IL-18 -137 G/C has a negative correlation with AD risk in Han Chinese [34], but the CC genotype is strongly associated with accelerated cognitive decline in Caucasians [33]. Meanwhile, the C allele of IL-18 -607 and the CC genotype are associated with increased AD risk in Han Chinese and Italian Caucasian populations, respectively [33,34].…”

Impact of the IL-18 gene polymorphism in response to antiviral therapy in chronic HCV genotype 4 patients

“…Similarly, the -607C>A promoter variant disrupts the binding site for a cAMP-responsive protein. IL-18 variants have been associated with various chronic infl ammatory conditions and viral diseases, such as hepatitis B 16 and Alzheimer's disease 17,18 .…”

Microglial NLRP3 Activity in Alzheimer's Disease

“…Furthermore, studies demonstrate that mutations in the IL-18 gene are also associated with the development of AD. For example, individuals carrying the CC genotype are at increased risk of developing AD [35]. Additionally, -607 C allele and -137 G allele were implicated in the risk of late-onset AD [36].…”